A Study to Evaluate Long-term Safety of Nintedanib in Children and Adolescents With Interstitial Lung Disease (InPedILD®-ON)

Inclusion criteria

For new patients:

• Children and adolescents 6 to 17 years old at Visit 2. In France, only adolescents 12 to 17 years old at Visit 2.
• Signed and dated written informed consent and assent, where applicable, in accordance with ICH-GCP and local legislation prior to admission to the trial.
• Male or female patients. Female of childbearing potential (WOCBP1) must confirm that sexual abstinence is standard practice and will be continued until 3 months after last drug intake, or be ready and able to use a highly effective method of birth control per ICH M3 (R2) that results in a low failure rate of less than 1% per year when used consistently and correctly, in combination with one barrier method, from 28 days prior to initiation of study treatment, during treatment and until 3 months after last drug intake. Sexual abstinence is defined as abstinence from any sexual act that may result in pregnancy.
• Patients with evidence of fibrosing Interstitial Lung Disease (ILD) on High-Resolution Computed Tomography (HRCT) within 12 months of Visit 1 as assessed by the investigator and confirmed by central review.
• Patients with Forced Vital Capacity (FVC) % predicted ≥25% at Visit 2.
• Patients with clinically significant disease at Visit 2, as assessed by the investigator based on any of the following:

• Fan score ≥3, or
• Documented evidence of clinical progression over time based on either

• a 5-10% relative decline in FVC % predicted accompanied by worsening symptoms, or
• a ≥10% relative decline in FVC % predicted, or
• increased fibrosis on HRCT, or
• other measures of clinical worsening attributed to progressive lung disease (e.g. increased oxygen requirement, decreased diffusion capacity).

For roll-over patients from the InPedILD® study:

Only criteria 2 and 3 listed for new patients are applicable with the following additional inclusion criterion:

• Patients who completed the InPedILD® trial as planned and who did not permanently prematurely discontinue study treatment.

For patients who prematurely discontinued treatment permanently in 1199-0337 but are potentially eligible and for completed patients from parent trial not able to roll over into the extension trial within 12 weeks following their End of Treatment Visit in the parent trial:

Inclusion criteria

for new patients are applicable except criteria 4, and 6 (as eligibility for these criteria has been confirmed already in 1199-0337 and does not need to be repeated) and also except inclusion criterion 1 for completed patients from parent trial not able to roll over within 12 weeks following their End of Treatment Visit in the parent trial.

Exclusion criteria

For new patients:

• Aspartate Aminotransferase (AST) and/or Alanine Aminotransferase (ALT) >1.5 x Upper limit of normal (ULN) at Visit 1.
• Bilirubin >1.5 x ULN at Visit 1.
• Estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73 m² at Visit 1
• Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment) at Visit 1.
• Other investigational therapy received within 1 month or 5 half-lives (whichever is shorter but ≥1 week) prior to Visit 2 except investigational therapy received in InPedILD® trial.
• 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
• In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
• Cardiovascular diseases, any of the following:

• Severe hypertension, uncontrolled under treatment, within 6 months of Visit 1. Uncontrolled hypertension is defined as

• In children 6 to ≤12 years old: ≥95th percentile + 12 mm Hg or ≥140/90 mm Hg (whichever is lower) (systolic or diastolic blood pressure equal to or greater than the calculated target value). Not applicable in France.
• In adolescents 13 to 17 years old: systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg. Not applicable in France.
• 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
• 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 (investigator's judgment)
• Any of the following coagulation parameters at Visit 1:

• International normalized ratio (INR) >2
• Prolongation of prothrombin time (PT) by >1.5 x ULN
• Prolongation of activated partial thromboplastin time (aPTT) by >1.5 x ULN
• 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 documented allergy to peanut or soya.
• 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 any concomitant disease other than ILD <2.5 years (investigator assessment).
• Female patients who are pregnant, nursing, or who plan to become pregnant while in the trial.
• Patients not able or willing to adhere to trial procedures, including intake of study medication.
• Patients who must or wish to take any drug considered likely to interfere with the safe conduct of the trial according to investigator's benefit-risk assessment for the individual patient
• Patients with any diagnosed growth disorder such as growth hormone deficiency or any genetic disorder that is associated with short stature (e.g. Turner Syndrome, Noonan Syndrome, Russell-Silver Syndrome) and/or treatment with growth hormone therapy within 6 months before Visit 2. Patients with short stature considered by the investigator to be due to glucocorticoid therapy may be included.
• Patients <13.5 kg of weight at Visit 1 (same threshold to be used for male and female patients).

For roll-over patients from the InPedILD® study:

Only criteria 11, 12, 13, 15, 16, 17 and 19, listed for new patients are applicable with the following additional exclusion criterion:

• Patient not compliant in parent trial (InPedILD®), with trial medication or trial visits, according to investigator's judgement. Roll-over patients may qualify for participation even though other exclusion criteria may have been met during the participation in InPedILD®, if the investigator's benefit-risk assessment for the individual patient remains favorable.

For patients who prematurely discontinued treatment permanently in 1199-0337 but are potentially eligible and for completed patients from parent trial not able to roll over into the extension trial within 12 weeks following their End of Treatment Visit in the parent trial:

All exclusion criteria for new patients are applicable. In addition, the following additional exclusion criterion is applicable for patients who prematurely discontinued treatment permanently in 1199-0337:

• Patients who experienced drug-related adverse events during parent trial leading to permanent study treatment discontinuation.