Clinical trial NCT02802345: Efficacy and Safety of Nintedanib Co-administered With Sildenafil in Idiopathic Pulmonary Fibrosis Patients With Advanced Lung Function Impairment
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Idiopathic Pulmonary Fibrosis
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2016-06-16
Enrollment: 274
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Total Score at Week 12
timeFrame: Baseline and week 12
Secondary outcomes:
measure: Change From Baseline in Dyspnoea Using the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) at Week 12
timeFrame: Baseline and week 12
measure: Change From Baseline in SGRQ Total Score at Week 24
timeFrame: Baseline and week 24
measure: Change From Baseline in Dyspnoea Using UCSD SOBQ at Week 24
timeFrame: Baseline and week 24
measure: Percentage of Patients With On-treatment Serious Adverse Events (SAE) From Baseline to Week 24
timeFrame: Baseline and week 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Stamford
country: United States
facility: Pulmonary Assoc of Stamford
state: Connecticut
city: Jacksonville
country: United States
facility: University of Florida College of Medicine
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Ann Arbor
country: United States
facility: Michigan Clinical Research Unit
state: Michigan
city: Minneapolis
country: United States
facility: Minnesota Lung Center
state: Minnesota
city: Chesterfield
country: United States
facility: The Lung Research Center, LLC
state: Missouri
city: New York
country: United States
facility: NewYork-Presbyterian/Weill Cornell Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Dayton
country: United States
facility: Clinical Research Solutions
state: Ohio
city: Toledo
country: United States
facility: Mercy Respiratory Specialist
state: Ohio
city: Portland
country: United States
facility: The Oregon Clinic
state: Oregon
city: Charleston
country: United States
facility: Lowcountry Lung and Crit Care
state: South Carolina
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Richmond
country: United States
facility: Pulmonary Associates of Richmond, Inc.
state: Virginia
city: Camperdown, Sydney
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: The Alfred Hospital
state: Victoria
city: Antwerpen
country: Belgium
facility: Ziekenhuis Netwerk Antwerpen (ZNA) - Campus Middelheim
city: Bruxelles
country: Belgium
facility: ULB Hopital Erasme
city: Leuven
country: Belgium
facility: UZ Leuven
city: Edmonton
country: Canada
facility: University of Alberta Hospital (University of Alberta)
state: Alberta
city: Vancouver
country: Canada
facility: St. Paul's Hospital
state: British Columbia
city: Halifax
country: Canada
facility: QEII Health Sciences Centre (Dalhousie University)
state: Nova Scotia
city: Hamilton
country: Canada
facility: St. Joseph's Healthcare Hamilton
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital
state: Ontario
city: Bron cedex
country: France
facility: HOP Louis Pradel
city: Lille
country: France
facility: HOP Calmette
city: Marseille
country: France
facility: HOP Nord
city: Montpellier
country: France
facility: HOP Arnaud de Villeneuve
city: Nice
country: France
facility: HOP Pasteur
city: Paris
country: France
facility: HOP Européen G. Pompidou
city: Paris
country: France
facility: HOP Bichat
city: Rennes
country: France
facility: HOP Pontchaillou
city: Coswig
country: Germany
facility: Fachkrankenhaus Coswig GmbH
city: Essen
country: Germany
facility: Ruhrlandklinik, Westdeutsches Lungenzentrum am Universitätsklinikum Essen gGmbH
city: Freiburg im Breisgau
country: Germany
facility: Universitätsklinikum Freiburg
city: Gießen
country: Germany
facility: Universitätsklinikum Gießen und Marburg GmbH
city: Greifswald
country: Germany
facility: Universitätsmedizin Greifswald
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Immenhausen
country: Germany
facility: Lungenfachklinik Immenhausen
city: Solingen
country: Germany
facility: Wissenschaftliches Institut Bethanien
city: Ahmedabad
country: India
facility: Sanjivani Superspeciality Hospital Pvt. Ltd.
city: Ahmedabad
country: India
facility: Care Institute Of Medical Sciences
city: Coimbatore
country: India
facility: Sri Bala Medical Centre & Hospitals
city: Kolkata
country: India
facility: Fortis Hospital
city: Pune
country: India
facility: Jehangir Clinical Development Centre Pvt. Ltd.
city: Chieti Scalo
country: Italy
facility: Osp. Clin. SS. Anunziata
city: Foggia
country: Italy
facility: Ospedale Colonnello D Avanzo
city: FORLì
country: Italy
facility: Ospedale "G.B. Morgagni - L. Pierantoni" ausl forli
city: Milano
country: Italy
facility: Osp. S. Giuseppe Fatebenefratelli
city: Modena
country: Italy
facility: Università di Modena e Reggio Emilia
city: Padova
country: Italy
facility: Azienda Ospedaliera Universitaria di Padova
city: Roma
country: Italy
facility: Az. Ospedaliera Universitaria Polic.Tor Vergata
city: Roma
country: Italy
facility: Policlinico Gemelli
city: Siena
country: Italy
facility: A.O.U. Senese Policlinico Santa Maria alle Scotte
city: Torrette Di Ancona (Ancona)
country: Italy
facility: Ospedale Riuniti di Ancona
city: Aichi, Seto
country: Japan
facility: Tosei General Hospital
city: Fukuoka, Kurume
country: Japan
facility: Kurume University Hospital
city: Gifu, Ogaki
country: Japan
facility: Ogaki Municipal Hospital
city: Hyogo, Himeji
country: Japan
facility: National Hospital Organization Himeji Medical Center
city: Ibaraki, Naka-gun
country: Japan
facility: Ibarakihigashi National Hospial
city: Kanagawa, Yokohama
country: Japan
facility: Kanagawa Cardiovascular and Respiratory Center
city: Osaka, Sakai
country: Japan
facility: National Hospital Organization Kinki-Chuo Chest Medical Center
city: Tokyo, Bunkyo-ku
country: Japan
facility: Nippon Medical School Hospital
city: Tokyo, Ota-ku
country: Japan
facility: Toho University Omori Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Guadalajara
country: Mexico
facility: Nuevo Hospital Civil de Guadalajara DR. JUAN I. MENCHACA
city: Mexico
country: Mexico
facility: Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas
city: Monterrey
country: Mexico
facility: Centro de Prevención y Rehabilitación de Enfermedades Pulmon
city: México
country: Mexico
facility: Centro Respiratorio de Mexico
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Girona
country: Spain
facility: Hospital Universitari de Girona Doctor Josep Trueta
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Pozuelo de Alarcón
country: Spain
facility: Hospital Quirónsalud Madrid
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
city: Bristol
country: United Kingdom
facility: Southmead Hospital
city: Cambridge
country: United Kingdom
facility: Papworth Hospital
city: Dundee, Scotland
country: United Kingdom
facility: Ninewells Hospital & Medical School
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: Sheffield
country: United Kingdom
facility: Northern General Hospital
city: Tyne And Wear
country: United Kingdom
facility: South Tyneside District Hospital
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Richeldi L, Kolb M, Jouneau S, Wuyts WA, Schinzel B, Stowasser S, Quaresma M, Raghu G. Efficacy and safety of nintedanib in patients with advanced idiopathic pulmonary fibrosis. BMC Pulm Med. 2020 Jan 8;20(1):3. doi: 10.1186/s12890-019-1030-4.
citation: Behr J, Kolb M, Song JW, Luppi F, Schinzel B, Stowasser S, Quaresma M, Martinez FJ. Nintedanib and Sildenafil in Patients with Idiopathic Pulmonary Fibrosis and Right Heart Dysfunction. A Prespecified Subgroup Analysis of a Double-Blind Randomized Clinical Trial (INSTAGE). Am J Respir Crit Care Med. 2019 Dec 15;200(12):1505-1512. doi: 10.1164/rccm.201903-0488OC.
citation: Kolb M, Raghu G, Wells AU, Behr J, Richeldi L, Schinzel B, Quaresma M, Stowasser S, Martinez FJ; INSTAGE Investigators. Nintedanib plus Sildenafil in Patients with Idiopathic Pulmonary Fibrosis. N Engl J Med. 2018 Nov 1;379(18):1722-1731. doi: 10.1056/NEJMoa1811737. Epub 2018 Sep 15.