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)
Condition: Lung Diseases, Interstitial
MeSH terms: Lung Diseases; Lung Diseases, Interstitial
Intervention: Nintedanib; Placebo
Intervention description: Capsule; Capsule
Intervention MeSH terms: Nintedanib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 39.0
Sex: All
Minimum age: 6 Years
Maximum age: 17 Years
Healthy volunteers: No

Summary:

      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).
    

Eligibility criteria:

        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).