Idiopathic Interstitial Pneumonias / Hypertension,Pulmonary
Conditions
Brief summary
To evaluate the efficacy and safety of 26-weeks of treatment with riociguat vs. placebo in patients with symptomatic PH (pulmonary hypertension) associated with IIP (idiopathic interstitial pneumonias).
Detailed description
Number of participants with Adverse Events (AEs) will be reported in Adverse Events section.
Interventions
DRUGRiociguat (Adempas, BAY63-2521)
Active drug 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID/day as per individual dose titration. The starting dose will be 0.5 mg TID, and the dose will be adjusted every two weeks for ten weeks in 0.5 mg increments up to a maximum dose of 2.5 mg TID based on patient's systolic blood pressure and well-being.
DRUGPlacebo
Inactive dosed at 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg and 2.5 mg TID/day as per individual dose titration for 26 weeks
Sponsors
Bayer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Inclusion Criteria: * Men or women aged from ≥18 to ≤80 years * Diagnosed with one of the following (confirmed using a multidisciplinary approach, as per ATS(American Thoracic Society) / ERS(European Respiratory Society) / JRS (Japanese Respiratory Society) / ALAT(Latin American Thoracic Association) guidelines: * Major IIPs (idiopathic interstitial pneumonias) diagnosis or suspected as one of the following: * Idiopathic pulmonary fibrosis * Idiopathic nonspecific interstitial pneumonia * Respiratory bronchiolitis-interstitial lung disease * Desquamative interstitial pneumonia * Cryptogenic organizing pneumonia * Acute interstitial pneumonia * Rare IIPs diagnosis by one of the following: * Idiopathic lymphoid interstitial pneumonia * Idiopathic pleuroparenchymal fibroelastosis * Unclassifiable idiopathic interstitial pneumonias * Forced Vital Capacity (FVC) ≥ 45 % * 6MWD (6 minutes walking distance) ≥ 150 m to ≤ 450 m {under stable O2(oxygen) supplementation via nasal cannula} * Diagnosis of PH (pulmonary hypertension) confirmed by right heart catheter (RHC) with (mean artery pulmonary artery pressure )mPAP ≥ 25 mmHg and (pulmonary artery wedge pressure)PAWP ≤15 mmHg at rest * Systolic blood pressure (SBP) ≥ 95 mmHg and no signs or symptoms of hypotension * WHO functional class II-IV * Women of childbearing potential can only be included in the study if a pregnancy test is negative. Women of childbearing potential must agree to use adequate contraception when sexually active. 'Adequate contraception' is defined as any combination of at least 2 effective methods of birth control, of which at least one is a physical barrier (e.g. condoms with hormonal contraception or implants or combined oral contraceptives, certain intrauterine devices). Adequate contraception is required from the signing of the informed consent form up until 4 weeks after the last study drug administration *
Exclusion criteria
* Known significant left heart disease: * Pulmonary venous hypertension indicated by baseline pulmonary capillary wedge pressure \> 15 mmHg * Symptomatic coronary artery disease * Systolic left-ventricular dysfunction with an left ventricular ejection fraction (LVEF) \<45% * Active state of hemoptysis or pulmonary hemorrhage, including those events managed by bronchial artery embolization * Any history of bronchial artery embolization or massive hemoptysis within 3 months prior to screening. Massive hemoptysis being defined as acute bleeding \>240 mL in a 24-hour period or recurrent bleeding \>100 mL/d over several days * Difference \> 15% between the eligibility and the baseline 6MWD test * Forced expiratory volume in one second (FEV1) / Forced Vital Capacity (FVC) \<0.65 after bronchodilator administration * Initiation in cytotoxic, immunosuppressive, cytokine modulating therapy initiated within 3 months prior to screening. Such agents might include. azathioprine, cyclophosphamide, corticosteroids, etanercept, tumor necrosis factor alpha (TNFα) inhibitors and others * Any specific treatment for (pulmonary arterial hypertension) PAH/PH (pulmonary hypertension )within 3 months prior to screening * Concomitant use of the following medication: nitrates or (nitric oxide) NO donors (such as amyl nitrite) in any form, phosphodiesterase 5 inhibitors (such as sildenafil, tadalafil, vardenafil) and non-specific phosphodiesterase (PDE) inhibitors (theophylline, dipyridamole), * Pregnant women (i.e. positive pregnancy test or other signs of pregnancy), or breast feeding women, or women of childbearing potential not using adequate contraception (as defined in the aforementioned inclusion criterion) and not willing to agree to 4 weekly pregnancy testing from Visit 1(first administration of study drug) onwards until 4 weeks after last study drug intake
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in 6 Minute Walking Distance (6MWD) From Baseline to Week 26 | Baseline to 26 weeks | The 6MWD test is designed to evaluate a patient's exercise capacity while performing an everyday activity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Worsening | From baseline to week 26 | The combined endpoint time to clinical worsening, made up of the following components, defined by the first occurrence: all-cause mortality; need for hospitalization due to worsening cardiopulmonary (CP) status, attributable to progression of disease (including but not limited to increased shortness of breath or increased leg swelling); \>15% decrease in the 6MWD test; worsening of WHO functional class. |
Countries
Argentina, Australia, Belgium, Canada, Colombia, Denmark, France, Germany, Greece, Israel, Italy, Japan, New Zealand, Portugal, Russia, Saudi Arabia, Spain, Switzerland, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Overall, 229 participants were enrolled into the study centers in 19 countries worldwide, from 04-Jun-2014 (first patient first visit) to 14-Sep-2016 (last patient last visit).
Pre-assignment details
A total of 147 participants were randomized and entered the main study phase, of whom 73 were assigned to riociguat and 74 to placebo.
Participants by arm
| Arm | Count |
|---|---|
| Riociguat (Adempas, BAY63-2521) In the main study treatment phase participants received Riociguat titrated to optimal dose within range of 0.5 mg TID (3 times a day) to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension (LTE) phase, which included a blinded sham titration phase of 10 weeks followed by an open-label extension phase. During the open-label extension phase participants were to be treated with Riociguat until commercial access in the indication of pulmonary hypertension (PH) associated with idiopathic interstitial pneumonias (IIP) or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor's global team. | 73 |
| Placebo In the main study treatment phase participants received sham titration within range of 0.5 mg TID to 2.5 mg TID for 10 weeks followed by maintenance period of 16 weeks. This phase was followed by a long-term extension (LTE) phase, which included a blinded titration phase to optimal dose of Riociguat of 10 weeks followed by an open-label extension phase. During the open-label extension phase participants were to be treated with Riociguat until commercial access in the indication of PH associated with IIP or until an agreed time point is defined with the individual country, local regulatory authority and the Sponsor's global team. | 74 |
| Total | 147 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Long-term Extension | Study termination by sponsor | 32 | 38 |
| Main Study Treatment | Adverse Event | 11 | 3 |
| Main Study Treatment | Death | 1 | 2 |
| Main Study Treatment | Medical decision | 1 | 0 |
| Main Study Treatment | Protocol Violation | 2 | 2 |
| Main Study Treatment | Sponsor decision | 12 | 18 |
| Main Study Treatment | Study terminated by sponsor | 10 | 9 |
| Main Study Treatment | Withdrawal by Subject | 3 | 1 |
| Safety Follow-up | Adverse Event | 4 | 3 |
| Safety Follow-up | clinic worsening | 1 | 0 |
| Safety Follow-up | Death | 11 | 5 |
| Safety Follow-up | logistical difficulties | 0 | 1 |
| Safety Follow-up | progressive disease | 0 | 2 |
| Safety Follow-up | too unwell to attend the visit | 0 | 1 |
| Safety Follow-up | treatment unblinded | 0 | 1 |
| Safety Follow-up | withdrawal by PI | 1 | 0 |
| Safety Follow-up | Withdrawal by Subject | 5 | 3 |
| Safety Follow-up | withdrawn due to lung transplant | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Placebo | Riociguat (Adempas, BAY63-2521) |
|---|---|---|---|
| 6 minute walking distance (6MWD) category < 320 m | 75 Participants | 32 Participants | 43 Participants |
| 6 minute walking distance (6MWD) category >= 320 m and <380m | 40 Participants | 28 Participants | 12 Participants |
| 6 minute walking distance (6MWD) category >= 380 m | 32 Participants | 14 Participants | 18 Participants |
| Age, Customized >=65 - <75 years | 80 Participants | 45 Participants | 35 Participants |
| Age, Customized <65 years | 37 Participants | 17 Participants | 20 Participants |
| Age, Customized >=75 years | 30 Participants | 12 Participants | 18 Participants |
| Classification of Idiopathic Interstitial Pneumonia Acute interstitial pneumonia | 1 Participants | 1 Participants | 0 Participants |
| Classification of Idiopathic Interstitial Pneumonia Cryptogenic organizing pneumonia | 1 Participants | 1 Participants | 0 Participants |
| Classification of Idiopathic Interstitial Pneumonia Idiopathic lymphoid interstitial pneumonia | 2 Participants | 2 Participants | 0 Participants |
| Classification of Idiopathic Interstitial Pneumonia Idiopathic nonspecific interstitial pneumonia | 23 Participants | 14 Participants | 9 Participants |
| Classification of Idiopathic Interstitial Pneumonia Idiopathic pulmonary fibrosis | 103 Participants | 49 Participants | 54 Participants |
| Classification of Idiopathic Interstitial Pneumonia Resp. bronchiolitis-interstitial lung disease | 1 Participants | 0 Participants | 1 Participants |
| Classification of Idiopathic Interstitial Pneumonia Unclassifiable idiopathic interstitial pneumonias | 16 Participants | 7 Participants | 9 Participants |
| Pulmonary hypertension (PH) subtype (Nice Clinical Classification) Other | 0 Participants | 0 Participants | 0 Participants |
| Pulmonary hypertension (PH) subtype (Nice Clinical Classification) PH owing to respiratory disease and /or hypoxia | 147 Participants | 74 Participants | 73 Participants |
| Sex: Female, Male Female | 52 Participants | 29 Participants | 23 Participants |
| Sex: Female, Male Male | 95 Participants | 45 Participants | 50 Participants |
| World Health Organization (WHO) functional class Class II | 38 Participants | 22 Participants | 16 Participants |
| World Health Organization (WHO) functional class Class III | 95 Participants | 45 Participants | 50 Participants |
| World Health Organization (WHO) functional class Class IV | 14 Participants | 7 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 54 / 73 | 52 / 74 | 26 / 32 | 32 / 38 |
| serious Total, serious adverse events | 27 / 73 | 17 / 74 | 12 / 32 | 21 / 38 |
Outcome results
Primary
Mean Change in 6 Minute Walking Distance (6MWD) From Baseline to Week 26
The 6MWD test is designed to evaluate a patient's exercise capacity while performing an everyday activity.
Time frame: Baseline to 26 weeks
Population: Intent to treat (ITT) analysis set: participants randomized and received at least one dose of study medication.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521) | Mean Change in 6 Minute Walking Distance (6MWD) From Baseline to Week 26 | 3.63 Meter | Standard Deviation 60.8 |
| Placebo | Mean Change in 6 Minute Walking Distance (6MWD) From Baseline to Week 26 | -15.94 Meter | Standard Deviation 63.7 |
Comparison: The evaluation of primary efficacy endpoint will be based on change from baseline in 6MWD using analysis of covariance (ANCOVA) with baseline 6MWD, treatment arm and region as factors.p-value: 0.207495% CI: [-8.75, 51.71]ANCOVA
Secondary
Number of Participants With Clinical Worsening
The combined endpoint time to clinical worsening, made up of the following components, defined by the first occurrence: all-cause mortality; need for hospitalization due to worsening cardiopulmonary (CP) status, attributable to progression of disease (including but not limited to increased shortness of breath or increased leg swelling); \>15% decrease in the 6MWD test; worsening of WHO functional class.
Time frame: From baseline to week 26
Population: Intent to treat (ITT) analysis set: participants randomized and received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521) | Number of Participants With Clinical Worsening | >15% decrease in 6MWD | 9 Participants |
| Riociguat (Adempas, BAY63-2521) | Number of Participants With Clinical Worsening | Hospitalization due to worsening CP status | 15 Participants |
| Riociguat (Adempas, BAY63-2521) | Number of Participants With Clinical Worsening | All-cause mortality | 1 Participants |
| Riociguat (Adempas, BAY63-2521) | Number of Participants With Clinical Worsening | Worsening of WHO functional class | 9 Participants |
| Riociguat (Adempas, BAY63-2521) | Number of Participants With Clinical Worsening | No clinical event | 39 Participants |
| Placebo | Number of Participants With Clinical Worsening | Worsening of WHO functional class | 12 Participants |
| Placebo | Number of Participants With Clinical Worsening | No clinical event | 38 Participants |
| Placebo | Number of Participants With Clinical Worsening | >15% decrease in 6MWD | 17 Participants |
| Placebo | Number of Participants With Clinical Worsening | All-cause mortality | 0 Participants |
| Placebo | Number of Participants With Clinical Worsening | Hospitalization due to worsening CP status | 7 Participants |
Comparison: The difference in incidences in clinical worsening and mortality will be analyzed using Mantel-Haenszel weights, stratified by region.p-value: 0.3437Mantel Haenszel
Post Hoc
Number of Deaths Per Study Phase for Placebo Group
In the main study treatment phase participants received Placebo until 26 weeks. This phase was followed by a long-term extension (LTE) phase, during which participants were treated with Riociguat. At the time of study termination, all treated participants were taken off study drug and started the safety follow-up phase, regardless of whether they were in the main phase or in the LTE.
Time frame: From start of treatment to end of study
Population: Intent to treat (ITT) analysis set: participants randomized and received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521) | Number of Deaths Per Study Phase for Placebo Group | Main study treatment | 3 Participants |
| Riociguat (Adempas, BAY63-2521) | Number of Deaths Per Study Phase for Placebo Group | Long-term extension: received Riociguat | 8 Participants |
| Riociguat (Adempas, BAY63-2521) | Number of Deaths Per Study Phase for Placebo Group | Safety follow-up: only treated with Placebo | 3 Participants |
| Riociguat (Adempas, BAY63-2521) | Number of Deaths Per Study Phase for Placebo Group | Safety follow-up: received Riociguat in LTE | 1 Participants |
Post Hoc
Number of Deaths Per Study Phase for Riociguat Group
In the main study treatment phase participants received Riociguat until 26 weeks. This phase was followed by a long-term extension (LTE) phase, during which participants continued with Riociguat treatment. At the time of study termination, all treated participants were taken off study drug and started the safety follow-up phase, regardless of whether they were in the main phase or in the LTE.
Time frame: From start of treatment to end of study
Population: Intent to treat (ITT) analysis set: participants randomized and received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Riociguat (Adempas, BAY63-2521) | Number of Deaths Per Study Phase for Riociguat Group | Main study treatment | 8 Participants |
| Riociguat (Adempas, BAY63-2521) | Number of Deaths Per Study Phase for Riociguat Group | Long-term extension | 1 Participants |
| Riociguat (Adempas, BAY63-2521) | Number of Deaths Per Study Phase for Riociguat Group | Safety follow-up | 3 Participants |
Post Hoc
Number of Serious Adverse Events During Safety Follow-up Phase
At the time of study termination, all participants entered safety follow-up phase regardless of whether they were in the main phase or in the LTE. Participants who had the End of Treatment visit prior to the implementation of the 120-day safety follow-up were followed-up for at least 30 days.
Time frame: From start of safety follow-up phase until end of study
Population: Safety analysis set: participants randomized and received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Riociguat (Adempas, BAY63-2521) | Number of Serious Adverse Events During Safety Follow-up Phase | 18 Participants |
| Placebo | Number of Serious Adverse Events During Safety Follow-up Phase | 14 Participants |