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

Idiopathic Pulmonary Fibrosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02802345
• Other study ID #: 1199.36
• Secondary ID: 2015-002619-14
• Status: Completed
• Phase: Phase 3
• Start date: June 30, 2016
• Est. completion date: April 13, 2018

Study information

• Verified date: December 2018
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 274
• Est. completion date: April 13, 2018
• Est. primary completion date: December 19, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Fibrosis
• Idiopathic Interstitial Pneumonias
• Idiopathic Pulmonary Fibrosis
• Pulmonary Fibrosis

Intervention

Drug:
• Nintedanib

• Placebo

• Sildenafil

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Royal Prince Alfred Hospital	Camperdown, Sydney	New South Wales
Australia	The Alfred Hospital	Melbourne	Victoria
Belgium	Ziekenhuis Netwerk Antwerpen (ZNA) - Campus Middelheim	Antwerpen
Belgium	ULB Hopital Erasme	Bruxelles
Belgium	UZ Leuven	Leuven
Canada	University of Alberta Hospital (University of Alberta)	Edmonton	Alberta
Canada	QEII Health Sciences Centre (Dalhousie University)	Halifax	Nova Scotia
Canada	St. Joseph's Healthcare Hamilton	Hamilton	Ontario
Canada	Toronto General Hospital	Toronto	Ontario
Canada	St. Paul's Hospital	Vancouver	British Columbia
France	HOP Louis Pradel	Bron cedex
France	HOP Calmette	Lille
France	HOP Nord	Marseille
France	HOP Arnaud de Villeneuve	Montpellier
France	HOP Pasteur	Nice
France	HOP Bichat	Paris
France	HOP Européen G. Pompidou	Paris
France	HOP Pontchaillou	Rennes
Germany	Fachkrankenhaus Coswig GmbH	Coswig
Germany	Ruhrlandklinik, Westdeutsches Lungenzentrum am Universitätsklinikum Essen gGmbH	Essen
Germany	Universitätsklinikum Freiburg	Freiburg im Breisgau
Germany	Universitätsklinikum Gießen und Marburg GmbH	Gießen
Germany	Universitätsmedizin Greifswald	Greifswald
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Lungenfachklinik Immenhausen	Immenhausen
Germany	Wissenschaftliches Institut Bethanien	Solingen
India	Care Institute Of Medical Sciences	Ahmedabad
India	Sanjivani Superspeciality Hospital Pvt. Ltd.	Ahmedabad
India	Sri Bala Medical Centre & Hospitals	Coimbatore
India	Fortis Hospital	Kolkata
India	Jehangir Clinical Development Centre Pvt. Ltd.	Pune
Italy	Osp. Clin. SS. Anunziata	Chieti Scalo
Italy	Ospedale Colonnello D Avanzo	Foggia
Italy	Ospedale "G.B. Morgagni - L. Pierantoni" ausl forli	FORLì
Italy	Osp. S. Giuseppe Fatebenefratelli	Milano
Italy	Università di Modena e Reggio Emilia	Modena
Italy	Azienda Ospedaliera Universitaria di Padova	Padova
Italy	Az. Ospedaliera Universitaria Polic.Tor Vergata	Roma
Italy	Policlinico Gemelli	Roma
Italy	A.O.U. Senese Policlinico Santa Maria alle Scotte	Siena
Italy	Ospedale Riuniti di Ancona	Torrette Di Ancona (Ancona)
Japan	Tosei General Hospital	Aichi, Seto
Japan	Kurume University Hospital	Fukuoka, Kurume
Japan	Ogaki Municipal Hospital	Gifu, Ogaki
Japan	National Hospital Organization Himeji Medical Center	Hyogo, Himeji
Japan	Ibarakihigashi National Hospial	Ibaraki, Naka-gun
Japan	Kanagawa Cardiovascular and Respiratory Center	Kanagawa, Yokohama
Japan	National Hospital Organization Kinki-Chuo Chest Medical Center	Osaka, Sakai
Japan	Nippon Medical School Hospital	Tokyo, Bunkyo-ku
Japan	Toho University Omori Medical Center	Tokyo, Ota-ku
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Mexico	Nuevo Hospital Civil de Guadalajara DR. JUAN I. MENCHACA	Guadalajara
Mexico	Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas	Mexico
Mexico	Centro Respiratorio de Mexico	México
Mexico	Centro de Prevención y Rehabilitación de Enfermedades Pulmon	Monterrey
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital Universitari de Girona Doctor Josep Trueta	Girona
Spain	Hospital Clínico San Carlos	Madrid
Spain	Hospital Quirónsalud Madrid	Pozuelo de Alarcón
Spain	Hospital General Universitario de Valencia	Valencia
United Kingdom	Southmead Hospital	Bristol
United Kingdom	Papworth Hospital	Cambridge
United Kingdom	Ninewells Hospital & Medical School	Dundee, Scotland
United Kingdom	Queen Elizabeth University Hospital	Glasgow
United Kingdom	Northern General Hospital	Sheffield
United Kingdom	South Tyneside District Hospital	Tyne And Wear
United States	Michigan Clinical Research Unit	Ann Arbor	Michigan
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Lowcountry Lung and Crit Care	Charleston	South Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	The Lung Research Center, LLC	Chesterfield	Missouri
United States	University of Chicago	Chicago	Illinois
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Clinical Research Solutions	Dayton	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Florida College of Medicine	Jacksonville	Florida
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Minnesota Lung Center	Minneapolis	Minnesota
United States	NewYork-Presbyterian/Weill Cornell Medical Center	New York	New York
United States	The Oregon Clinic	Portland	Oregon
United States	Pulmonary Associates of Richmond, Inc.	Richmond	Virginia
United States	Pulmonary Assoc of Stamford	Stamford	Connecticut
United States	Mercy Respiratory Specialist	Toledo	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Germany,  India,  Italy,  Japan,  Korea, Republic of,  Mexico,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Total Score at Week 12	The SGRQ is a 50-item questionnaire developed to measure health status (quality of life). Scores are calculated for three domains: Symptoms, Activity and Impacts (Psycho-social) as well as a total score. A minimum change in score of 4 units was established as clinically relevant after patient and clinician testing. Scores range from 0 to 100, with higher scores indicating more limitations. The mean and standard error presented are actually adjusted mean for change from baseline and its standard error.	Baseline and week 12
Secondary	Change From Baseline in Dyspnoea Using the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) at Week 12	The UCSD SOBQ is a 24-item questionnaire developed to measure breathlessness on a scale between zero and five where 0 is not at all breathless and 5 is maximally breathless or too breathless to do the activity. The mean and standard error presented for descriptive statistics are actually adjusted mean for change from baseline and its standard error.	Baseline and week 12
Secondary	Change From Baseline in SGRQ Total Score at Week 24	The SGRQ is a 50-item questionnaire developed to measure health status (quality of life). Scores are calculated for three domains: Symptoms, Activity and Impacts (Psycho-social) as well as a total score. A minimum change in score of 4 units was established as clinically relevant after patient and clinician testing. The mean and standard error presented for descriptive statistics are actually adjusted mean for change from baseline and its standard error.	Baseline and week 24
Secondary	Change From Baseline in Dyspnoea Using UCSD SOBQ at Week 24	The UCSD SOBQ is a 24-item questionnaire developed to to measure breathlessness on a scale between zero and five where 0 is not at all breathless and 5 is maximally breathless or too breathless to do the activity. The mean and standard error presented for descriptive statistics are actually adjusted mean for change from baseline and its standard error.	Baseline and week 24
Secondary	Percentage of Patients With On-treatment Serious Adverse Events (SAE) From Baseline to Week 24	Percentage of patients with on-treatment serious adverse events (SAE) from baseline to Week 24 is presented.	Baseline and week 24

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