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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT02802345
• Date of registration: 14/06/2016
• Prospective Registration: Yes
• Primary sponsor: Boehringer Ingelheim
• Public title: Efficacy and Safety of Nintedanib Co-administered With Sildenafil in Idiopathic Pulmonary Fibrosis Patients With Advanced Lung Function Impairment
• Scientific 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
• Date of first enrolment: June 30, 2016
• Target sample size: 274
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02802345
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Double (Participant, Investigator).
• Phase: Phase 3

Countries of recruitment

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

Contacts

• Name: Boehringer Ingelheim
• Affiliation: Boehringer Ingelheim

Key inclusion & exclusion 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.



Age minimum: 40 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Idiopathic Pulmonary Fibrosis

Intervention(s)

Drug: Sildenafil

Drug: Placebo

Drug: Nintedanib

Primary Outcome(s)

Change From Baseline in St George's Respiratory Questionnaire (SGRQ) Total Score at Week 12 [Time Frame: Baseline and week 12]

Secondary Outcome(s)

Change From Baseline in Dyspnoea Using the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) at Week 12 [Time Frame: Baseline and week 12]

Change From Baseline in Dyspnoea Using UCSD SOBQ at Week 24 [Time Frame: Baseline and week 24]

Change From Baseline in SGRQ Total Score at Week 24 [Time Frame: Baseline and week 24]

Percentage of Patients With On-treatment Serious Adverse Events (SAE) From Baseline to Week 24 [Time Frame: Baseline and week 24]

Secondary ID(s)

1199.36

2015-002619-14

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 11/01/2019
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02802345