Please select the eligibility criteria that correspond to the clinical trial below.
Title: Rehabilitation of IPF Patients: Effects of Exercise and Oxidant Stress
Brief Summary: The incidence and prevalence of IPF increase exponentially with age, and IPF occurs more often in older males. Cigarette smoking and environmental dust exposures are known risk factors for developing IPF. For example, the recently deployed military population, as it ages, is at especially increased risk of IPF. No effective therapies exist, although lung transplantation is used to extend survival of selected patients.

Defining specific therapy to improve exercise tolerance and dyspnea in IPF patients is thus an urgent priority of veteran-oriented research programs.


Options:
A: Inclusion Criteria:

* Clinical presentation consistent with IPF with onset between three months and 48 months prior to screening.
* Diagnosis made by high-resolution computed tomographic scan showing highly probable IPF.
* Absence of severe pulmonary hypertension (i.e., PAsys must be less than 55 mm Hg, based on echocardiography) and absence of decompensated right heart failure (NYHA class I or II acceptable).
* Age 40 through 80, inclusive.
* Abnormal pulmonary function tests (FVC 40-90% predicted or DLCO 30-90% predicted or impaired gas exchange with rest or exercise).
* Six-minute walk distance 150 m and 500 m.
* Worsening as demonstrated by any one of the following within the past year: \> 10% decrease in percent predicted forced vital capacity or worsening dyspnea at rest or upon exertion, based on history.
* Ability to understand and sign a written informed consent form and comply with the requirements of the study.
* Absence of clinical features suggesting infection, neoplasm, sarcoidosis or collagen-vascular disease.

Exclusion Criteria:

* Echocardiographic evidence of severe pulmonary hypertension (PAsys\>55 mm Hg, based on echocardiography or TR velocity 3.2 m/sec).
* Severe heart failure (NYHA class III or IV or LVEF \< 45%).
* Six-minute walk distance \< 150 m or \> 500 m.
* FEV1/FVC ratio \< 0.7 at screening (post-bronchodilator).
* Residual volume \> 100% predicted.
* Any condition other than IPF likely to result in the death of the participant within the next two years.
* History of unstable or deteriorating cardiac or neurologic disease.
* Pregnancy or lactation. Patients who are: (a) pregnant or (b) breast feeding are excluded from the study.
* Current treatment with corticosteroids (either oral or inhaled), Cytoxan, azathioprine, colchicine, pirfenidone, anti-tumor necrosis factor therapy or endothelin receptor blockers. Prior treatment is permitted, but at least four weeks of treatment washout prior to inclusion in this study are required.
* Investigational therapy for any indication within 28 days prior to enrollment.
* Degenerative arthritis, cerebrovascular accident or other limitation to mobility preventing completion of the 6-minute walk test.
* Oxygen saturation on room air \<80% at rest.
B: Inclusion criteria:

* Written Informed Consent consistent with International Conference on Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) and local laws signed prior to entry into the study (and prior to any study procedure including shipment of High Resolution Computer Tomography (HRCT) to reviewer).
* Male or female patients aged \>= 18 years at Visit 1.
* Patients with physician diagnosed Interstitial Lung Disease (ILD) who fulfil at least one of the following criteria for Progressive Fibrosing Interstitial Lung Disease (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):

  * Clinically significant decline in Forced Vital Capacity (FVC) % pred based on a relative decline of \>=10%
  * Marginal decline in FVC % pred based on a relative decline of .\>=5-\<10% combined with worsening of respiratory symptoms
  * Marginal decline in FVC % pred based on a relative decline of \>=5-\<10% combined with increasing extent of fibrotic changes on chest imaging
  * Worsening of respiratory symptoms as well as increasing extent of fibrotic changes on chest imaging \[Note: Changes attributable to comorbidities e.g. infection, heart failure must be excluded. Unapproved medications used in the clinical practice to treat ILD include but are not limited to corticosteroid, azathioprine, mycophenolate mofetil (MMF), n-acetylcysteine (NAC), rituximab, cyclophosphamide, cyclosporine, tacrolimus\].
* 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.
* For patients with underlying Connective Tissue Disease (CTD): stable CTD as defined by no initiation of new therapy or withdrawal of therapy for CTD within 6 weeks prior to Visit 1.
* Carbon Monoxide Diffusion Capacity (DLCO) corrected for Haemoglobin (Hb) \[visit 1\] ≥ 30% and \<80% predicted of normal at Visit 2
* FVC \>= 45% predicted at Visit 2

Exclusion criteria:

* Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) \> 1.5 x Upper Limit of Normal (ULN) at Visit 1
* Bilirubin \> 1.5 x ULN at Visit 1
* Creatinine clearance \<30 mL/min calculated by Cockcroft-Gault formula at Visit 1 \[Note: Laboratory parameters from Visit 1 have to satisfy the laboratory threshold values as shown above. Visit 2 laboratory results will be available only after randomization. In case at Visit 2 the results do no longer satisfy the entry criteria, the Investigator has to decide whether it is justified that the patient remains on study drug. The justification for decision needs to be documented. Laboratory parameters that are found to be abnormal at Visit 1 are allowed to be re-tested (once) if it is thought to be a measurement error (i.e. there was no abnormal result of this test in the recent history of the patient and there is no related clinical sign) or the result of a temporary and reversible medical condition, once that condition is resolved\].
* Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment).
* Previous treatment with nintedanib or pirfenidone.
* Other investigational therapy received within 1 month or 6 half-lives (whichever was greater) prior to screening visit (Visit 1).
* Use of any of the following medications for the treatment of Interstitial Lung Disease (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.

Note: Patients whose Rheumatoid Arthritis (RA)/Connective Tissue Disease (CTD) is managed by these medications should not be considered for participation in the current study unless change in RA/CTD medication is medically indicated (see Inclusion Criteria)

* Diagnosis of Idiopathic Pulmonary Fibrosis (IPF) based on American Thoracic Society (ATS)/ European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (ALAT) 2011 Guidelines.
* Significant Pulmonary Arterial Hypertension (PAH) defined by any of the following:

  * Previous clinical or echocardiographic evidence of significant right heart failure
  * History of right heart catheterization showing a cardiac index \<= 2 l/min/m²
  * PAH requiring parenteral therapy with epoprostenol/treprostinil
  * Primary obstructive airway physiology (pre-bronchodilator FEV1/FVC \< 0.7 at Visit 1).
  * In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
* Major extrapulmonary physiological restriction (e.g. chest wall abnormality, large pleural effusion)
* Cardiovascular diseases, any of the following:

  * Severe hypertension, uncontrolled under treatment (≥160/100 mmHg), within 6 month of Visit 1
  * Myocardial infarction within 6 months of Visit 1
  * Unstable cardiac angina within 6 months of Visit 1
* Bleeding risk, any of the following:

  * Known genetic predisposition to bleeding.
  * Patients who require

    * Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors, heparin, hirudin)
    * High dose antiplatelet therapy. \[Note: Prophylactic low dose heparin or heparin flush as needed for maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 I.U. s.c. per day), as well as prophylactic use of antiplatelet therapy (e.g. acetyl salicylic acid up to 325 mg/day, or clopidogrel at 75 mg/day, or equivalent doses of other antiplatelet therapy) are not prohibited\].
  * History of haemorrhagic central nervous system (CNS) event within 12 months of Visit 1.
  * Any of the following within 3 months of Visit 1:

    * Haemoptysis or haematuria
    * Active gastro-intestinal (GI) bleeding or GI - ulcers
    * Major injury or surgery (Investigators judgment).
  * 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.
* History of thrombotic event (including stroke and transient ischemic attack) within 12 months of Visit 1.
* Known hypersensitivity to the trial medication or its components (i.e. soya lecithin)
* Patients with peanut allergy.
* 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.
* Life expectancy for disease other than ILD \< 2.5 years (Investigator assessment).
* Planned major surgical procedures.
* Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
* Women of childbearing potential\* not willing or able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly as well as one barrier method for 28 days prior to and 3 months after nintedanib administration. A list of contraception methods meeting these criteria is provided in the patient information.
* In the opinion of the Investigator, active alcohol or drug abuse.
* Patients not able to understand or follow trial procedures including completion of self-administered questionnaires without help. \*A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
C: Inclusion Criteria:

* confirmed diagnosis of IPF based on the criteria of the American Thoracic Society/European Respiratory Society 2011 guidelines;
* ≥ 40 years-of-age;
* ambulatory without the use of an assistive device;
* stable clinical condition (i.e., no pulmonary exacerbation for at least 6 weeks);
* no changes in medication for at least 4 weeks before enrollment;
* currently sedentary (i.e., exercise or participate in sports less than 3 times per week for 20 min in the past 6 months) and do not play any exergames;
* report dyspnea on exertion leading to a limitation in performing daily activities (i.e., Medical Research Council (MRC) dyspnea grade \>1);
* able to read and follow exercise directions in English on the television screen;
* have permission from their treating physician to participate in moderate-intensity exercise;
* able to provide informed consent by understanding the nature of study participation.

Exclusion Criteria:

* contraindication for moderate-intensity exercise (e.g., unstable cardiac disease),
* severe musculoskeletal, vestibular, or neurological disorders limiting exercise performance, or inability to perform the 6-min walk test or 15-step test,
* requires \> 6 lpm supplemental oxygen therapy via nasal cannula during exercise to maintain SpO2 \>88%;
* MRC dyspnea grade 4 or 5; IPF patients with MRC dyspnea grade 4 or 5 have been reported to show little or no improvement, or deteriorated following pulmonary rehab;
* stage 2 hypertension,
* anemia (hemoglobin \< 8 g/dL);
* collagen vascular disease;
* obstructive lung disease,
* non-parenchymal restrictive lung disease,
* occupational lung disease (pneumoconiosis, hypersensitivity pneumonitis),
* sarcoidosis,
* other idiopathic interstitial pneumonia;
* currently participating or have participated (in the past 30 days) in another clinical trial which can affect the outcomes of the proposed study; or
* planning to move out of Alabama within the next 6 months.
D: Select Inclusion Criteria:

1. Diagnosis of idiopathic pulmonary fibrosis (IPF), consistent with the ATS 2011 Guidelines, of 6-48 months' duration
2. Age 40 to 80 at randomization
3. Percent Forced Vital Capacity (%FVC) ≥50% and ≤90% at screening
4. Percent Carbon Monoxide Diffusing Capacity (%DLCO) ≥30% and ≤90% at screening

Select Exclusion Criteria:

1. Forced expiratory volume in one second (FEV1)/FVC ratio \<0.8 after administration of bronchodilator at Screening
2. Expected to receive a lung transplant within 1 year from randomization or, for patients at sites in the United States, on a lung transplant waiting list at randomization
3. Known explanation for interstitial lung disease
4. History of asthma or chronic obstructive pulmonary disease
5. Active infection
6. Ongoing IPF treatments including investigational therapy, immunosuppressants, and cytokine modulating agents
7. History of unstable or deteriorating cardiac or pulmonary disease (other than IPF) within the previous 6 months

Answer: A