Efficacy and safety of nintedanib in patients with PF-ILD

Phase 1

• Conditions: The aim of the current study is to investigate the efficacy and safety of 150 mg bid nintedanib over 52 weeks in patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD) defined as patients who present with features of diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography (HRCT) and whose lung function and respiratory symptoms or chest imaging have worsened despite treatment with unapproved medications used in clinical practice to treat ILD.; Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

• Registration Number: EUCTR2015-003360-37-GB
• Lead Sponsor: Boehringer Ingelheim Limited

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2017-02-17
• Last Update Posted: 16 December 2019

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Not specified
• Target Recruitment: 600

Inclusion Criteria

1. Written Informed Consent consistent with ICH-GCP and local laws signed prior to entry into the study (and prior to any study procedure including shipment of HRCT to reviewer).
2. Male or female patients aged >= 18 years at Visit 1.
3. Patients with physician diagnosed ILD who fulfil at least one of the following criteria for PF-ILD within 24 months of screening visit (Visit 1) despite treatment with unapproved medications used in clinical practice to treat ILD, as assessed by the investigator (refer to Exclusion Criteria):
a. Clinically significant decline in FVC % pred based on a relative decline of >=10%
b. Marginal decline in FVC % pred based on a relative decline of >=5-<10% combined with worsening of respiratory symptoms
c. Marginal decline in FVC % pred based on a relative decline of >=5-<10% combined with increasing extent of fibrotic changes on chest imaging
d. Worsening of respiratory symptoms as well as increasing extent of fibrotic changes on chest imaging
[Note: Changes attributable to comorbidities e.g. infection, heart failure must be excluded. Unapproved medications used in the clinical practice to treat ILD include but are not limited to corticosteroid, azathioprine, mycophenolate mofetil (MMF), n-acetylcysteine (NAC), rituximab, cyclophosphamide, cyclosporine, tacrolimus].
4. Fibrosing lung disease on HRCT, defined as reticular abnormality with traction bronchiectasis with or without honeycombing, with disease extent of >10%, performed within 12 months of Visit 1 as confirmed by central readers.
5. For patients with underlying CTD: stable CTD as defined by no initiation of new therapy or withdrawal of therapy for CTD within 6 weeks prior to Visit 1.
6. DLCO corrected for Haemoglobin (Hb) [visit 1] >= 30% and <80% predicted of normal at Visit 2.
7. FVC >= 45% predicted at Visit 2.
Are the trial subjects under 18? no
Number of subjects for this age range: 0
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 450
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 150

Exclusion Criteria

1. AST, ALT > 1.5 x ULN at Visit 1
2. Bilirubin > 1.5 x ULN at Visit 1
3. Creatinine clearance <30 mL/min calculated by Cockcroft-Gault formula at Visit 1.
4. Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment).
5. Previous treatment with nintedanib or pirfenidone.
6. Other investigational therapy received within 1 month or 6 half-lives (whichever was greater) prior to screening visit (Visit 1).
7. Use of any of the following medications for the treatment of ILD: azathioprine (AZA), cyclosporine, MMF, tacrolimus, oral corticosteroids (OCS) >20mg/day and the combination of OCS+AZA+NAC within 4 weeks of Visit 2, cyclophosphamide within 8 weeks of Visit 2, rituximab within 6 months of Visit 2.
8. Diagnosis of IPF based on ATS/ERS/JRS/ALAT 2011 Guidelines.
9. Significant Pulmonary Arterial Hypertension (PAH) defined by any of the following:
a. Previous clinical or echocardiographic evidence of significant right heart failure
b. History of right heart catheterization showing a cardiac index <= 2 l/min/m²
c. PAH requiring parenteral therapy with epoprostenol/treprostinil
10. Primary obstructive airway physiology (pre-bronchodilator FEV1/FVC < 0.7 at Visit 1).
11. In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
12. Major extrapulmonary physiological restriction (e.g. chest wall abnormality, large pleural effusion)
13. Cardiovascular diseases, any of the following:
a. Severe hypertension, uncontrolled under treatment (>=160/100 mmHg), within 6 month of Visit 1
b. Myocardial infarction within 6 months of Visit 1
c. Unstable cardiac angina within 6 months of Visit 1
14. Bleeding risk, any of the following:
a. Known genetic predisposition to bleeding.
b. Patients who require
i. Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors, heparin, hirudin)
ii. High dose antiplatelet therapy.
c. History of haemorrhagic central nervous system (CNS) event within 12 months of Visit 1.
d. Any of the following within 3 months of Visit 1:
i. Haemoptysis or haematuria
ii. Active gastro-intestinal (GI) bleeding or GI - ulcers
iii. Major injury or surgery (Investigators judgment).
e. Coagulation parameters: International normalized ratio (INR) >2, prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT) by >1.5 x ULN at Visit 1.
15. History of thrombotic event (including stroke and transient ischemic attack) within 12 months of Visit 1.
16. Known hypersensitivity to the trial medication or its components (i.e. soya lecithin)
17. Patients with peanut allergy.
18. Other disease that may interfere with testing procedures or in the judgment of the Investigator may interfere with trial participation or may put the patient at risk when participating in this trial.
19. Life expectancy for disease other than ILD < 2.5 years (I

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To demonstrate a reduction of lung function decline, as measured by the annual rate of decline in FVC for nintedanib compared to placebo.;Secondary Objective: The main secondary objectives of the trial are to investigate the effect of treatment on quality of life using the King's Brief Interstitial Lung Disease Questionnaire (K-BILD), and to assess the effect of nintedanib on time to first acute ILD exacerbation and overall survival over 52 weeks.;<br> Primary end point(s): 1: Annual rate of decline in Forced Vital Capacity<br> ;<br> Timepoint(s) of evaluation of this end point: 1: 52 weeks<br>