A Study to Find Out How Nintedanib is Taken up in the Body and How Well it is Tolerated in Children and Adolescents With Interstitial Lung Disease (ILD)

A Double Blind, Randomised, Placebo-controlled Trial to Evaluate the Dose-exposure and Safety of Nintedanib Per os on Top of Standard of Care for 24 Weeks, Followed by Open Label Treatment With Nintedanib of Variable Duration, in Children and Adolescents (6 to 17 Year-old) With Clinically Significant Fibrosing Interstitial Lung Disease

The main objective of the study is to evaluate dose-exposure and safety of nintedanib in children and adolescents with fibrosing Interstitial Lung Disease (ILD).

Inclusion Criteria:

• Children and adolescents 6 to 17 years old at Visit 2.

• Signed and dated written informed consent and assent, where applicable, in accordance with International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial.

• Male or female patients. Female of childbearing potential (WOCBP) 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 International Conference on Harmonisation (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. A list of contraception methods meeting these criteria is provided in the parental information.

• 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. [Note: Predicted normal values will be calculated according to GLI (Global Lung Initiative)]

• 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).

Exclusion Criteria:

• Aspartate Aminotransferase (AST) and/or Alanine Aminotransferase (ALT)>1.5 x Upper Level of Normal (ULN) at Visit 1.

• Bilirubin >1.5 x ULN at Visit 1.

• Creatinine clearance <30 mL/min calculated by Schwartz 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) at Visit 1.

• Previous treatment with nintedanib.

• Other investigational therapy received within 1 month or 5 half-lives (whichever is shorter but ≥1 week) prior to Visit 2.

• 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)
    • In adolescents 13 to 17 years old: systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg

  • 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 (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 Interstitial Lung Disease (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 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).