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)

NCT ID: NCT04093024

Last Updated: 2024-07-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 39 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-12-03
• Study Completion Date: 2022-05-24

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).

Conditions

Lung Diseases, Interstitial

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Double-blind period (DBP) + open-label Nintedanib period (OLNP): Randomised Nintedanib

This arm shows Nintedanib randomised participants treated orally with Nintedanib in the DBP and OLNP twice daily with a dose interval of approximately 12 hours from one dose to the next dose.

Medication dosage was per administration 50 milligram (mg) [2 capsules with strength 25 mg],75 mg [3 capsules with strength 25 mg], 100 mg [1 capsule with strength 100 mg or 4 capsules with strength 25 mg] or 150 mg [1 capsule with strength 150 mg or 6 capsules with strength 25 mg] based on the participant's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the participant's weight had changed.

In this arm participants received Nintedanib in both periods (DBP + OLNP). Participants in this arm do not entail participants from the 'randomised to placebo' arms.

DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

OLNP: Planned was from first open-label Nintedanib intake to last open-label Nintedanib intake.

Group Type: EXPERIMENTAL

Nintedanib

Intervention Type: DRUG

Capsule

DBP+OLNP: Randomised placebo

Placebo randomised participants were treated orally with a Nintedanib matching placebo soft capsule twice daily in the double-blind period (DBP).

Participants who continued with the open-label Nintedanib period (OLNP) after the DBP switched to active Nintedanib treatment in the OLNP and were treated orally with Nintedanib twice daily.

Medication dosage was per administration 50 milligram (mg) [2 25 mg capsules (cap)],75 mg [3 25 mg cap], 100 mg [1 100 mg or 4 25 mg cap] or 150 mg [1 150 mg or 6 25 mg cap] based on the participant's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the participant's weight had changed.

The dose interval was approximately 12 hours between one and the next dose.

Here participants received placebo first (DBP) and then Nintedanib (OLNP). DBP: Planned was from first to last randomised blinded drug intake. OLNP: Planned was from first to last open-label Nintedanib intake.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Capsule

Interventions

Nintedanib

Capsule

Intervention Type: DRUG

Placebo

Capsule

Intervention Type: DRUG

Other Intervention Names

Ofev®

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).

• Minimum Eligible Age: 6 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Boehringer Ingelheim

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Children's Hospital Los Angeles

Los Angeles, California, United States

Children's Hospital Colorado

Aurora, Colorado, United States

Riley Hospital for Children at Indiana University Health

Indianapolis, Indiana, United States

Children's Mercy Hospitals and Clinics

Kansas City, Missouri, United States

Weill Cornell Medicine

New York, New York, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Vanderbilt University Medical Center

Nashville, Tennessee, United States

Seattle Children's Hospital

Seattle, Washington, United States

Hospital de Pediatría " Prof. Dr. Juan P. Garrahan"

CABA, , Argentina

Hospital de Niños Dr. Ricardo Gutierrez

CABA, , Argentina

INSARES

Mendoza, , Argentina

Women's and Children's Hospital

North Adelaide, South Australia, Australia

Brussels - UNIV HUDERF

Brussels, , Belgium

Serviços Medicos Respirar Sul Fluminense

Barra Mansa, , Brazil

Centro de Pesquisa Clinica do Instituto da Crianca - HCFMUSP

São Paulo, , Brazil

BC Children's Hospital

Vancouver, British Columbia, Canada

The Hospital for Sick Children

Toronto, Ontario, Canada

Teaching Hospital Motol, Oncology Clinic

Prague, , Czechia

Aarhus University Hospital

Aarhus N, , Denmark

Tampere University Hospital

Tampere, , Finland

HOP Intercommunal

Créteil, , France

HOP Armand-Trousseau

Paris, , France

General Hospital of Thessaloniki "Ippokrateio"

Thessaloniki, , Greece

Semmelweis University

Budapest, , Hungary

Azienda Ospedaliera Meyer

Florence, , Italy

Azienda Ospedaliera Universitaria di Padova

Padua, , Italy

Osp. Pediatrico Bambin Gesù

Roma, , Italy

Clinical Research Institute S.C.

Tlalnepantla, , Mexico

Oslo Universitetssykehus HF, Rikshospitalet

Oslo, , Norway

Independent Public Teaching Children's Hospital

Warsaw, , Poland

CHULC, EPE - Hospital Dona Estefânia

Lisbon, , Portugal

Centro Hospitalar Universitário de Lisboa Norte, EPE - Hospital Santa Maria

Lisbon, , Portugal

Children's Hematology,Oncology&Immunology na Rogachev,Moscow

Moscow, , Russia

State Novosibirsk Regional Clinical Hospital

Novosibirsk, , Russia

St. Petersburg State Pediatric University

Saint Petersburg, , Russia

Hospital Vall d'Hebron

Barcelona, , Spain

Hospital Virgen del Rocío

Seville, , Spain

Regional Children Clinical Hospital, Pulmonology, Kharkiv

Kharkiv, , Ukraine

Institute of Phthisiology and Pulmonology n. a. F.G.Yanovsky

Kyiv, , Ukraine

Regional clinical children hospital, Zaporizhya

Zaporizhya, , Ukraine

Birmingham Children's Hospital

Birmingham, , United Kingdom

King's College Hospital

London, , United Kingdom

Countries

United States; Argentina; Australia; Belgium; Brazil; Canada; Czechia; Denmark; Finland; France; Greece; Hungary; Italy; Mexico; Norway; Poland; Portugal; Russia; Spain; Ukraine; United Kingdom

References

Deterding R, Young LR, DeBoer EM, Warburton D, Cunningham S, Schwerk N, Flaherty KR, Brown KK, Dumistracel M, Erhardt E, Bertulis J, Gahlemann M, Stowasser S, Griese M; InPedILD trial investigators. Nintedanib in children and adolescents with fibrosing interstitial lung diseases. Eur Respir J. 2023 Feb 2;61(2):2201512. doi: 10.1183/13993003.01512-2022. Print 2023 Feb.

Reference Type: DERIVED

PMID: 36041751 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34164554 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.mystudywindow.com

Related Info

Other Identifiers

2018-004530-14

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

1199-0337

Identifier Type: -

Identifier Source: org_study_id