Articles
Riociguat for idiopathic interstitial pneumonia-associated pulmonary hypertension (RISE-IIP): a randomised, placebo-controlled phase 2b study

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Summary

Background

Idiopathic interstitial pneumonias are often complicated by pulmonary hypertension, increasing morbidity and mortality. There are no approved treatments for pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP). We aimed to evaluate the efficacy and safety of riociguat in patients with PH-IIP.

Methods

RISE-IIP was a double-blind, randomised, placebo-controlled study done at 65 pulmonary hypertension and interstitial lung disease centres in 19 countries to evaluate the efficacy and safety of riociguat in patients with PH-IIP. Eligible patients were adults (aged 18–80 years) diagnosed with idiopathic interstitial pneumonia (as per American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines), forced vital capacity (FVC) of at least 45%, 6MWD of 150–450 m, WHO functional classes II–IV, precapillary pulmonary hypertension confirmed by right heart catheterisation, systolic blood pressure of at least 95 mm Hg, and no signs or symptoms of hypotension. Patients were randomly allocated (1:1) using an interactive voice and web response system to riociguat (0·5–2·5 mg three times daily) or placebo for 26 weeks (main study), after which they could enter an open-label extension in which all patients received riociguat. The primary endpoint was change in 6-min walking distance (6MWD) in the intention-to-treat population. Prespecified safety variables included adverse events and serious adverse events, laboratory parameters, and adverse events of special interest (haemoptysis and symptomatic hypotension), assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02138825.

Findings

Between June 4, 2014, and May 5, 2016, we enrolled 229 participants. After the exclusion of 82 participants, 147 were randomly allocated to treatment (73 to riociguat, 74 to placebo). The study was terminated early (median treatment duration 157 days [range 6–203]) at the request of the data monitoring committee owing to increased serious adverse events (main study: 27 [37%] of 73 participants in the riociguat group vs 17 [23%] of 74 in the placebo group) and mortality in patients receiving riociguat, and the absence of efficacy signals in the riociguat group. 11 patients died in the main study (eight in the riociguat group, three in the placebo group), and nine died in the extension phase (one in the riociguat group, eight in the former placebo group; all received riociguat). In the main study, the most common adverse events were peripheral oedema (16 [22%] of 73 in the riociguat group vs seven [9%] of 74 in the placebo group) and diarrhoea (11 [15%] vs seven [9%]). The most common serious adverse events were worsening of interstitial lung disease (main study: six [8%] of 73 in the riociguat group vs five [7%] of 74 in the placebo group) and pneumonia (four [5%] vs one [1%]). Riociguat did not improve 6MWD versus placebo at 26 weeks (least-squares mean difference 21 m; 95% CI −9 to 52).

Interpretation

In patients with PH-IIP, riociguat was associated with increased serious adverse events and mortality, and an unfavourable risk–benefit profile. Riociguat should not be used in patients with PH-IIP.

Funding

Bayer AG and Merck & Co.

Introduction

Idiopathic interstitial pneumonias are heterogeneous fibrotic lung disorders frequently complicated by pulmonary hypertension.1, 2 In the revised American Thoracic Society (ATS)/European Respiratory Society (ERS) classification of idiopathic interstitial pneumonia, major subtypes include idiopathic pulmonary fibrosis, idiopathic nonspecific interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia, cryptogenic organising pneumonia, and acute interstitial pneumonia.3 Of these, idiopathic pulmonary fibrosis is the most common and well studied.3, 4 At the time of idiopathic pulmonary fibrosis diagnosis, pulmonary hypertension is present in 8–15% of patients;5 however, this value increases to about 50% during follow-up or at the time of lung transplantation,6, 7, 8, 9 and its presence is associated with substantially increased morbidity and mortality.5, 6, 10, 11, 12, 13, 14, 15, 16, 17, 18

Research in context

Evidence before this study

We searched PubMed for papers published between Jan 2, and Feb 28, 2014, using the search terms “pulmonary hypertension” AND “idiopathic interstitial pneumonias” AND “interstitial lung disease” AND “idiopathic pulmonary fibrosis”. Pulmonary hypertension complicating idiopathic interstitial pneumonias (PH-IIPs), specifically idiopathic pulmonary fibrosis, is associated with worse functional status and increased mortality. Several studies have addressed the potential benefit of pulmonary vasodilatory medications in patients with PH-IIP, but most of these have been retrospective or small case series. One prospective study of bosentan in PH-IIP was negative; however, a small phase 2 randomised controlled study of riociguat suggested a beneficial response. The endothelin receptor antagonist ambrisentan has been contraindicated in PH-IIP and there is no evidence of benefit for other endothelin receptor antagonists in PH-IIP. Additionally, there are scarce data regarding the use of prostanoids as a therapeutic option, whereas data on the use of sildenafil are conflicting. Therefore, it remains unknown if treating PH-IIP is beneficial, but this is an area that warrants further study given the very poor prognosis associated with PH-IIP.

Added value of this study

This randomised, placebo-controlled, phase 2b study investigated riociguat for the treatment PH-IIP in a cohort of 147 patients. To our knowledge, it is the largest prospective randomised controlled study to date evaluating the treatment of pulmonary hypertension complicating any form of idiopathic pulmonary pneumonitis (mostly idiopathic pulmonary fibrosis). Patients experienced a greater number of serious adverse events in the riociguat group than in the placebo group, and there were more deaths in the riociguat group than in the placebo group, with no evidence of clinical benefit. As a result of this unfavourable risk–benefit profile, the study was terminated early. This study documents harm and is an important message for those who are inclined to treat pulmonary hypertension complicating idiopathic pulmonary fibrosis and other forms of lung disease with off-label pulmonary arterial hypertension therapies.

Implications of all the available evidence

Our data suggest that riociguat should not be used in patients with PH-IIP due to the absence of benefit and potential presence of harm. Studies in this patient population are, however, feasible, and there remains an urgent unmet medical need to address this challenging condition.

Although there are approved treatments for idiopathic pulmonary fibrosis (eg, pirfenidone and nintedanib), there are none for pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP). Drugs approved for the treatment of pulmonary arterial hypertension have been evaluated in idiopathic pulmonary fibrosis,19, 20, 21, 22, 23, 24, 25 but these studies have been invariably accompanied by limitations. These studies have either focused on fibrotic processes alone, included only small numbers of patients or did not adequately evaluate the presence of pulmonary hypertension. Overall, the clinical benefit of drugs approved for pulmonary arterial hypertension has not been shown in patients with pulmonary hypertension and idiopathic pulmonary fibrosis,19, 20, 21, 22, 23, 24, 25 and guidelines recommend against their use for this indication outside of clinical trials.26, 27 Thus, the management of pulmonary hypertension in idiopathic interstitial pneumonias represents an urgent unmet medical need, including the identification of which (if any) specific phenotype is appropriate for treatment with medication approved for pulmonary arterial hypertension.

Riociguat is a soluble guanylate cyclase stimulator approved for treatment of pulmonary hypertension in WHO group 1 (pulmonary arterial hypertension) and group 4 (inoperable, persistent, or recurrent chronic thromboembolic pulmonary hypertension [CTEPH]). In a 12-week, open-label, phase 2, pilot study28 in 22 patients with pulmonary hypertension and interstitial lung disease, riociguat improved 6-min walking distance (6MWD), cardiac output, and pulmonary vascular resistance, but not mean pulmonary arterial pressure. Adverse events were consistent with those observed in previous studies.29, 30, 31 Four patients discontinued riociguat during the 12-week trial period owing to adverse events, and another six did so during the 12-month extension period.

Soluble guanylate cyclase stimulators inhibit experimental fibrosis by blocking transforming growth factor β signalling, which plays an important role in the development of fibrosis.32 Furthermore, anti-fibrotic effects of riociguat have consistently been shown in several animal models.33, 34, 35, 36 Based on these findings, together with the positive risk–benefit profile of riociguat in patients with pulmonary arterial hypertension or CTEPH, and the data from the open-label pilot study in patients with pulmonary hypertension associated with interstitial lung disease, we hypothesised that patients with PH-IIP might benefit from riociguat treatment. Here, we report the findings from the riociguat in patients with symptomatic pulmonary hypertension associated with idiopathic interstitial pneumonias (RISE-IIP) study and its long-term extension.

Section snippets

Study design and participants

The rationale for the RISE-IIP study design has been published.37 RISE-IIP was a multicentre, randomised, double-blind, placebo-controlled phase 2b study done at 65 interstitial lung disease and pulmonary hypertension centres in 19 countries.

We included adults (aged 18–80 years) diagnosed with idiopathic interstitial pneumonia according to ATS/ERS/Japanese Respiratory Society/Latin American Thoracic Association guidelines.38 Key inclusion criteria were forced vital capacity (FVC) of at least

Results

Between June 4, 2014, and May 5, 2016, we enrolled 229 participants at 65 interstitial lung disease and pulmonary hypertension centres in 19 countries. After 82 participants were excluded, 73 were assigned to riociguat (up to 2·5 mg) and 74 to placebo. RISE-IIP was terminated early at the request of the data monitoring committee, on the basis of an unfavourable risk–benefit profile owing to the high number of serious adverse events and deaths and the absence of efficacy signals in the riociguat

Discussion

In the RISE-IIP study, riociguat treatment did not improve 6MWD or time to clinical worsening after 26 weeks in patients with PH-IIP. The study was terminated early upon the recommendation of the data monitoring committee because of a higher incidence of deaths, serious adverse events, and adverse event-related drug discontinuations in the main treatment phase in those treated with riociguat than with placebo. During the long-term extension, more patients switching from placebo to riociguat

Data sharing

Availability of the data underlying this publication will be determined according to Bayer's commitment to the European Federation of Pharmaceutical Industries and Associations and Pharmaceutical Research and Manufacturers of America principles for responsible clinical trial data sharing, pertaining to scope, time point and process of data access. Bayer commits to sharing upon request from qualified scientific and medical researchers patient-level clinical trial data, study-level clinical trial

References (50)

  • SD Nathan et al.

    Idiopathic interstitial pneumonia-associated pulmonary hypertension: A target for therapy?

    Respir Med

    (2017)
  • M Colombat et al.

    Pulmonary vascular lesions in end-stage idiopathic pulmonary fibrosis: Histopathologic study on lung explant specimens and correlations with pulmonary hemodynamics

    Hum Pathol

    (2007)
  • MT Durheim et al.

    Association of hospital admission and forced vital capacity endpoints with survival in patients with idiopathic pulmonary fibrosis: analysis of a pooled cohort from three clinical trials

    Lancet Respir Med

    (2015)
  • AW Brown et al.

    Outcomes after hospitalization in idiopathic pulmonary fibrosis: a cohort study

    Chest

    (2015)
  • R Vij et al.

    Diagnosis and treatment of connective tissue disease-associated interstitial lung disease

    Chest

    (2013)
  • KM Antoniou et al.

    Interstitial lung disease

    Eur Respir Rev

    (2014)
  • L Farkas et al.

    Pulmonary hypertension and idiopathic pulmonary fibrosis: a tale of angiogenesis, apoptosis, and growth factors

    Am J Respir Cell Mol Biol

    (2011)
  • WD Travis et al.

    An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias

    Am J Respir Crit Care Med

    (2013)
  • R Prasad et al.

    Diagnosis of idiopathic pulmonary fibrosis: Current issues

    Intractable Rare Dis Res

    (2015)
  • M Kimura et al.

    Pulmonary hypertension as a prognostic indicator at the initial evaluation in idiopathic pulmonary fibrosis

    Respiration

    (2013)
  • AF Shorr et al.

    Pulmonary hypertension in patients with pulmonary fibrosis awaiting lung transplant

    Eur Respir J

    (2007)
  • TJ Corte et al.

    Pulmonary vascular resistance predicts early mortality in patients with diffuse fibrotic lung disease and suspected pulmonary hypertension

    Thorax

    (2009)
  • MM Hoeper et al.

    Pulmonary hypertension in patients with chronic fibrosing idiopathic interstitial pneumonias

    PLoS One

    (2015)
  • G Pitsiou et al.

    Pulmonary hypertension in idiopathic pulmonary fibrosis: a review

    Respiration

    (2011)
  • G Raghu et al.

    Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial

    Ann Intern Med

    (2013)
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    At the time of publication, Z Yao is employed by BeiGene, Beijing, China

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