Efficacy and Safety of Nintedanib When Co-administered With Sildenafil in Idiopathic Pulmonary Fibrosis Patients With Advanced Lung Function Impairment

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02802345
Recruitment Status : Completed
First Posted : June 16, 2016
Last Update Posted : November 27, 2018
Information provided by (Responsible Party):
Boehringer Ingelheim

Brief Summary:
To assess efficacy and safety of concomitant treatment with nintedanib and sildenafil in Idiopathic Pulmonary Fibrosis (IPF) patients with advanced lung function impairment.

Condition or disease Intervention/treatment Phase
Idiopathic Pulmonary Fibrosis Drug: Nintedanib Drug: Placebo Drug: Sildenafil Phase 3

Expanded Access : Boehringer Ingelheim has indicated that access to an investigational treatment associated with this study is available outside the clinical trial.  

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 274 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: INSTAGE: A 24-week, Double-blind, Randomized, Parallel-group Study Evaluating the Efficacy and Safety of Oral Nintedanib Co-administered With Oral Sildenafil, Compared to Treatment With Nintedanib Alone, in Patients With Idiopathic Pulmonary Fibrosis (IPF) and Advanced Lung Function Impairment
Actual Study Start Date : June 30, 2016
Actual Primary Completion Date : December 19, 2017
Actual Study Completion Date : April 13, 2018

Arm Intervention/treatment
Experimental: Nintedanib + placebo matching sildenafil Drug: Nintedanib
Drug: Placebo
Active Comparator: Nintedanib + Sildenafil Drug: Nintedanib
Drug: Sildenafil

Primary Outcome Measures :
  1. change from baseline in St George's Respiratory Questionnaire (SGRQ) total score at week 12 [ Time Frame: week 12 ]

Secondary Outcome Measures :
  1. change from baseline in SGRQ total score at week 24 [ Time Frame: week 24 ]
  2. change from baseline in UCSD SOBQ at week 24 [ Time Frame: week 24 ]
  3. Percentage of patients with on-treatment Serious Adverse Events (SAE) from baseline to week 24 [ Time Frame: week 24 ]
  4. change from baseline in dyspnea using the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) at week 12 [ Time Frame: week 12 ]

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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion criteria:

  • Written informed consent consistent with International Conference on Harmonization-Good Clinical Practice and local laws, signed prior to any study procedures being performed (including any required washout);
  • Male or female patients aged >= 40 years at visit 1;
  • A clinical diagnosis of IPF within the last 6 years before visit 1, based upon the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American thoracic Association 2011 guideline [P11-07084];
  • Combination of high-resolution computed tomography (HRCT) pattern, and if available, surgical lung biopsy pattern consistent with a diagnosis of IPF as assessed by the investigator based on a HRCT scan performed within 18 months of visit 1;
  • Carbon Monoxide Diffusion Capacity (corrected for Hb) less or equal to 35% predicted of normal at visit 1.

Exclusion criteria:

  • Previous enrolment in this trial;
  • Alanine Transaminase, Aspartate Transaminase > 1.5 fold upper limit of normal (ULN) at visit 1;
  • Total bilirubin > 1.5 fold ULN at visit 1;
  • Relevant airways obstruction (i.e. pre-bronchodilator Forced Expiratory Volume in 1 second/Forced Vital Capacity <0.7 at visit 1)
  • History of myocardial infarction within 6 months of visit 1 or unstable angina within 1 month of visit 1
  • Bleeding Risk:

    • Known genetic predisposition to bleeding;
    • Patients who require fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors, heparin, hirudin, etc.) or high dose antiplatelet therapy;
    • History of haemorrhagic central nervous system (CNS) event within 12 months prior to visit 1;
    • History of haemoptysis or haematuria, active gastro-intestinal bleeding or ulcers and/or major injury or surgery within 3 months prior to visit 1;
    • International normalised ratio (INR) > 2 at visit 1;
    • Prothrombin time (PT) and activated partial thromboplastin time (aPTT) > 150% of institutional ULN at visit 1;
  • Planned major surgery during the trial participation, including lung transplantation, major abdominal or major intestinal surgery;
  • History of thrombotic event (including stroke and transient ischemic attack) within 12 months of visit 1;
  • Creatinine clearance < 30 mL/min calculated by Cockcroft-Gault formula at visit 1;
  • Presence of aortic stenosis (AS) per investigator judgement at visit 1;
  • Severe chronic heart failure: defined by left ventricular ejection fraction (EF) < 25% per investigator judgement at visit 1;
  • Presence of idiopathic hypertrophic subaortic stenosis (IHSS) per investigator judgement at visit 1;
  • Second-degree or third-degree atrioventricular (AV) block on electrocardiogram (ECG) per investigator judgement at visit 1;
  • Hypotension (systolic blood pressure [SBP] < 100 mm Hg or diastolic blood pressure [DBP] < 50 mm Hg) (symptomatic orthostatic hypotension) at visit 1;
  • Uncontrolled systemic hypertension (SBP > 180 mmHg; or DBP > 100 mmHg) at visit 1;
  • Known penile deformities or conditions (e.g., sickle cell anemia, multiple myeloma, leukemia) that may predispose to priapism;
  • Retinitis pigmentosa;
  • History of vision loss;
  • History of nonarteritic ischemic optic neuropathy;
  • Veno-occlusive disease;
  • History of acute IPF exacerbation or respiratory infection within 8 weeks of visit 2.
  • Treatment with nitrates, n-acetylcysteine, pirfenidone, azathioprine, cyclophosphamide, cyclosporine, prednisone >15 mg daily or >30 mg every 2 days OR equivalent dose of other oral corticosteroids as well as any investigational drug within 4 weeks of visit 2;
  • Treatment with prostaglandins (e.g., epoprostenol, treprostinil), endothelin-1 antagonists (e.g., bosentan, sitaxsentan, ambrisentan), phosphodiesterase inhibitors (e.g., sildenafil, tadalafil, vardenafil) or a stimulator of guanylatcyclase (e.g.,riociguat) within 4 weeks of visit 2;
  • Treatment with potent cytochrome CYP3A4 inhibitors such as ketoconazole, itraconazole and ritonavir within 4 weeks of visit 2;
  • Supplementation with L-arginine and concurrent use of grapefruit juice or St John's wort within 4 weeks of visit 2;
  • Treatment with the reduced dose of nintedanib (100 mg bid) within 4 weeks of visit 2; 27. Permanent discontinuation of nintedanib in the past due to adverse events considered drug-related;
  • Known hypersensitivity or intolerance to nintedanib, sildenafil, galactose, peanut or soya or any other components of the study medication;
  • A disease or condition which in the opinion of the investigator may interfere with testing procedures or put the patient at risk when participating in this trial;
  • Alcohol or drug abuse which in the opinion of the treating physician would interfere with treatment;
  • Further exclusion criteria apply.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02802345

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Sponsors and Collaborators
Boehringer Ingelheim
Study Chair: Boehringer Ingelheim Boehringer Ingelheim

Additional Information:
Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Boehringer Ingelheim Identifier: NCT02802345     History of Changes
Other Study ID Numbers: 1199.36
2015-002619-14 ( EudraCT Number )
First Posted: June 16, 2016    Key Record Dates
Last Update Posted: November 27, 2018
Last Verified: November 2018

Additional relevant MeSH terms:
Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis
Idiopathic Interstitial Pneumonias
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Lung Diseases, Interstitial
Sildenafil Citrate
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents
Antineoplastic Agents