Clinical trial NCT04093024: 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)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Lung Diseases, Interstitial
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2019-09-17
Enrollment: 39
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).

Primary outcomes:
measure: Area Under the Plasma Concentration-time Curve at Steady State (AUCτ,ss) Based on Sampling at Steady State (at Week 2 and Week 26)
timeFrame: At Week 2 and at Week 26: at 5 minutes before and at 0, 1, 2, 3, 4, 6, and 8 hours post administration of the morning dose
measure: Number of Participants With Treatment-emergent Adverse Events During the Double-blind Period
timeFrame: From first drug administration until the earlier of (i) first intake of open-label nintedanib (exclusive) and (ii) last drug intake, up to 28 weeks
Secondary outcomes:
measure: Number of Participants With at Least One Treatment-emergent Pathological Finding of Epiphyseal Growth Plate on Imaging up to Week 24, and Week 52
timeFrame: Up to Week 24 (included values at Week 12 and Week 24); Up to Week 52 (included values at Week 12, 24, 36 and 52)
measure: Number of Participants With Treatment-emergent Pathological Findings on Dental Examination or Imaging up to Week 24
timeFrame: Dental examination: at Week 12 and Week 24; Dental imaging: at Week 24
measure: Number of Participants With at Least One Treatment-emergent Pathological Findings on Dental Examination or Imaging up to Week 52
timeFrame: Dental examination: at Week 12, 24, 34, and Week 52; Dental imaging: at Week 24 and at Week 52.
measure: Number of Participants With Treatment-emergent Adverse Events Over the Whole Trial
timeFrame: From first drug administration until the last drug intake, up to 92 weeks
measure: Absolute Change From Baseline in Height at Week 24
timeFrame: MMRM included measurements pre-administration at -4 weeks and at 0, 12, 24, 36, 52, 64, 76, and 88 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
measure: Absolute Change From Baseline in Height at Week 52
timeFrame: MMRM included measurements pre-administration at -4 weeks and at 0, 12, 24, 36, 52, 64, 76, and 88 weeks after first drug administration. MMRM values at Week 52 are reported in the table below
measure: Absolute Change From Baseline in Height at Week 76
timeFrame: Measurements were assessed at Week 0 and at Week 76
measure: Absolute Change From Baseline in Sitting Height at Week 24
timeFrame: MMRM included measurements pre-administration at -4 weeks and at 0, 12, 24, 36, 52, 64, 76, and 88 weeks after first drug administration. MMRM values at Week 24 are reported in the table below.
measure: Absolute Change From Baseline in Sitting Height at Week 52
timeFrame: Measurements were assessed at Week 0 and at Week 52
measure: Absolute Change From Baseline in Sitting Height at Week 76
timeFrame: Measurements were assessed at Week 0 and at Week 76
measure: Absolute Change From Baseline in Leg Length at Week 24 - Left
timeFrame: MMRM included measurements at 0, 12, 24, 36, 52, 64, and 76 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
measure: Absolute Change From Baseline in Leg Length at Week 52 - Left
timeFrame: MMRM included measurements at 0, 12, 24, 36, 52, 64, and 76 weeks after first drug administration. MMRM values at Week 52 are reported in the table below
measure: Absolute Change From Baseline in Leg Length at Week 76 - Left
timeFrame: MMRM included measurements at 0, 12, 24, 36, 52, 64, and 76 weeks after first drug administration. MMRM values at Week 76 are reported in the table below
measure: Absolute Change From Baseline in Leg Length at Week 24 - Right
timeFrame: MMRM included measurements at 0, 12, 24, 36, 52, 64, and 76 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
measure: Absolute Change From Baseline in Leg Length at Week 52 - Right
timeFrame: MMRM included measurements at 0, 12, 24, 36, 52, 64, and 76 weeks after first drug administration. MMRM values at Week 52 are reported in the table below
measure: Absolute Change From Baseline in Leg Length at Week 76 - Right
timeFrame: MMRM included measurements at 0, 12, 24, 36, 52, 64, and 76 weeks after first drug administration. MMRM values at Week 76 are reported in the table below
measure: Absolute Change From Baseline in Forced Vital Capacity (FVC) % Predicted at Week 24
timeFrame: MMRM included measurements pre-administration at -4 weeks and at 0, 2, 6, 12, 24, 26, 36, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
measure: Absolute Change From Baseline in Forced Vital Capacity (FVC) % Predicted at Week 52
timeFrame: MMRM included measurements pre-administration at -4 weeks and at 0, 2, 6, 12, 24, 26, 36, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below
measure: Absolute Change From Baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 24 - Parent Report
timeFrame: MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
measure: Absolute Change From Baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 52 - Parent Report
timeFrame: MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below
measure: Absolute Change From Baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 24 - Participant Report
timeFrame: MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
measure: Absolute Change From Baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 52 - Participant Report
timeFrame: MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below
measure: Absolute Change From Baseline in Oxygen Saturation (SpO₂) on Room Air at Rest at Week 24
timeFrame: MMRM included measurements pre-administration at -4 weeks and at 0, 2, 6, 12, 24, 26, 36, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
measure: Absolute Change From Baseline in Oxygen Saturation (SpO₂) on Room Air at Rest at Week 52
timeFrame: MMRM included measurements pre-administration at -4 weeks and at 0, 2, 6, 12, 24, 26, 36, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below
measure: Absolute Change From Baseline in 6 Minutes (Min) Walk Distance at Week 24
timeFrame: MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
measure: Absolute Change From Baseline in 6 Minutes (Min) Walk Distance at Week 52
timeFrame: MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below
measure: Participants Acceptability Based on the Size of Capsules at Week 24 - Patient Question
timeFrame: Acceptability was assessed at Week 24
measure: Participants Acceptability Based on the Size of Capsules at Week 24 - Investigator Question
timeFrame: Acceptability was assessed at Week 24
measure: Participants Acceptability Based on the Number of Capsules at Week 24 - Patient Question
timeFrame: Acceptability was assessed at Week 24
measure: Number of Participants With Occurrence of First Respiratory-related Hospitalization Over the Whole Trial
timeFrame: From first drug administration until the last drug intake + 28 days residual effect period (REP), up to 92.6 weeks
measure: Number of Participants With Occurrence of First Acute Interstitial Lung Disease (ILD) Exacerbation or Death Over the Whole Trial
timeFrame: From first drug administration until the last drug intake + 28 days REP, up to 92.6 weeks
measure: Number of Participants With Occurrence of Death Over the Whole Trial
timeFrame: From first drug administration until the last drug intake + 28 days REP, up to 92.6 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Indianapolis
country: United States
facility: Riley Hospital for Children at Indiana University Health
state: Indiana
city: Kansas City
country: United States
facility: Children's Mercy Hospitals and Clinics
state: Missouri
city: New York
country: United States
facility: Weill Cornell Medicine
state: New York
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Caba
country: Argentina
facility: Hospital de Pediatría " Prof. Dr. Juan P. Garrahan"
city: Caba
country: Argentina
facility: Hospital de Niños Dr. Ricardo Gutierrez
city: Mendoza
country: Argentina
facility: INSARES
city: North Adelaide
country: Australia
facility: Women's and Children's Hospital
state: South Australia
city: Bruxelles
country: Belgium
facility: Brussels - UNIV HUDERF
city: Barra Mansa
country: Brazil
facility: Serviços Medicos Respirar Sul Fluminense
city: Sao Paulo
country: Brazil
facility: Centro de Pesquisa Clinica do Instituto da Crianca - HCFMUSP
city: Vancouver
country: Canada
facility: BC Children's Hospital
state: British Columbia
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Praha 5
country: Czechia
facility: Teaching Hospital Motol, Oncology Clinic
city: Aarhus N
country: Denmark
facility: Aarhus University Hospital
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Créteil
country: France
facility: HOP Intercommunal
city: Paris
country: France
facility: HOP Armand-Trousseau
city: Thessaloniki
country: Greece
facility: General Hospital of Thessaloniki "Ippokrateio"
city: Budapest
country: Hungary
facility: Semmelweis University
city: Firenze
country: Italy
facility: Azienda Ospedaliera Meyer
city: Padova
country: Italy
facility: Azienda Ospedaliera Universitaria di Padova
city: Roma
country: Italy
facility: Osp. Pediatrico Bambin Gesù
city: Tlalnepantla
country: Mexico
facility: Clinical Research Institute S.C.
city: Oslo
country: Norway
facility: Oslo Universitetssykehus HF, Rikshospitalet
city: Warsaw
country: Poland
facility: Independent Public Teaching Children's Hospital
city: Lisboa
country: Portugal
facility: CHULC, EPE - Hospital Dona Estefânia
city: Lisboa
country: Portugal
facility: Centro Hospitalar Universitário de Lisboa Norte, EPE - Hospital Santa Maria
city: Moscow
country: Russian Federation
facility: Children's Hematology,Oncology&Immunology na Rogachev,Moscow
city: Novosibirsk
country: Russian Federation
facility: State Novosibirsk Regional Clinical Hospital
city: St. Petersburg
country: Russian Federation
facility: St. Petersburg State Pediatric University
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocío
city: Kharkiv
country: Ukraine
facility: Regional Children Clinical Hospital, Pulmonology, Kharkiv
city: Kyiv
country: Ukraine
facility: Institute of Phthisiology and Pulmonology n. a. F.G.Yanovsky
city: Zaporizhya
country: Ukraine
facility: Regional clinical children hospital, Zaporizhya
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
city: London
country: United Kingdom
facility: King's College Hospital
Study officials:
References:
citation: Deterding R, Griese M, Deutsch G, Warburton D, DeBoer EM, Cunningham S, Clement A, Schwerk N, Flaherty KR, Brown KK, Voss F, Schmid U, Schlenker-Herceg R, Verri D, Dumistracel M, Schiwek M, Stowasser S, Tetzlaff K, Clerisme-Beaty E, Young LR. Study design of a randomised, placebo-controlled trial of nintedanib in children and adolescents with fibrosing interstitial lung disease. ERJ Open Res. 2021 Jun 21;7(2):00805-2020. doi: 10.1183/23120541.00805-2020. eCollection 2021 Apr.