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)

NCT04093024 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: 1199-03372018-004530-14
• Study Type: interventional
• Target: 39
• Locations: 21 countries
• Sites: 43

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

Outcome Measures

Primary Outcomes (2)

• Area Under the Plasma Concentration-time Curve at Steady State (AUCτ,ss) Based on Sampling at Steady State (at Week 2 and Week 26)

  Area under the plasma concentration-time curve at steady state (AUCt,ss) based on sampling at steady state (at Week 2 and Week 26) after multiple oral administration of Nintedanib by age group over all treatments. Values of samples taken at Week 2 (for randomised Nintedanib participants) and at Week 26 (for randomised placebo participants) were used. Missing values at Week 2 of randomised Nintedanib participants were replaced with values taken at Week 26.

  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

• Number of Participants With Treatment-emergent Adverse Events During the Double-blind Period

  Treatment-emergent was defined as: Adverse events with onset or worsening on or after date of treatment start until end of double-blind period (defined as the day before first intake of open-label nintedanib or last double-blind drug intake + residual effect period, whichever is earlier) were considered as treatment-emergent and were included in the analysis. Adverse events were counted under the treatment as randomized for the double-blind period.

  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 (32)

• Number of Participants With at Least One Treatment-emergent Pathological Finding of Epiphyseal Growth Plate on Imaging up to Week 24, and Week 52

  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)

• Number of Participants With Treatment-emergent Pathological Findings on Dental Examination or Imaging up to Week 24

  Dental examination: at Week 12 and Week 24; Dental imaging: at Week 24

• Number of Participants With at Least One Treatment-emergent Pathological Findings on Dental Examination or Imaging up to Week 52

  Dental examination: at Week 12, 24, 34, and Week 52; Dental imaging: at Week 24 and at Week 52.

• Number of Participants With Treatment-emergent Adverse Events Over the Whole Trial

  From first drug administration until the last drug intake, up to 92 weeks

• Absolute Change From Baseline in Height at Week 24

  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

Study Arms (2)

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

EXPERIMENTAL

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.

Drug: Nintedanib

DBP+OLNP: Randomised placebo

PLACEBO COMPARATOR

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.

Drug: Placebo

Interventions

Nintedanib DRUG

Capsule

Also known as: Ofev®

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

Placebo DRUG

Capsule

DBP+OLNP: Randomised placebo

Eligibility Criteria

• Age: 6 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• Boehringer Ingelheim: lead

Study Sites (43)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Riley Hospital for Children at Indiana University Health

Indianapolis, Indiana, 46202, United States

Location

Children's Mercy Hospitals and Clinics

Kansas City, Missouri, 64108, United States

Location

Weill Cornell Medicine

New York, New York, 10021, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

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

Pittsburgh, Pennsylvania, 15224, United States

Location

Vanderbilt University Medical Center

Nashville, Tennessee, 37232, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

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

CABA, C1245AAM, Argentina

Location

Hospital de Niños Dr. Ricardo Gutierrez

CABA, C1425EFD, Argentina

Location

INSARES

Mendoza, M5500CCG, Argentina

Location

Women's and Children's Hospital

North Adelaide, South Australia, 5006, Australia

Location

Brussels - UNIV HUDERF

Brussels, 1020, Belgium

Location

Serviços Medicos Respirar Sul Fluminense

Barra Mansa, 27323240, Brazil

Location

Centro de Pesquisa Clinica do Instituto da Crianca - HCFMUSP

São Paulo, 5403-900, Brazil

Location

BC Children's Hospital

Vancouver, British Columbia, V6H 3N1, Canada

Location

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Teaching Hospital Motol, Oncology Clinic

Prague, 150 06, Czechia

Location

Aarhus University Hospital

Aarhus N, 8200, Denmark

Location

Tampere University Hospital

Tampere, 33520, Finland

Location

HOP Intercommunal

Créteil, 94010, France

Location

HOP Armand-Trousseau

Paris, 75571, France

Location

General Hospital of Thessaloniki "Ippokrateio"

Thessaloniki, 54642, Greece

Location

Semmelweis University

Budapest, 1122, Hungary

Location

Azienda Ospedaliera Meyer

Florence, 50139, Italy

Location

Azienda Ospedaliera Universitaria di Padova

Padua, 35128, Italy

Location

Osp. Pediatrico Bambin Gesù

Roma, 00165, Italy

Location

Clinical Research Institute S.C.

Tlalnepantla, 54055, Mexico

Location

Oslo Universitetssykehus HF, Rikshospitalet

Oslo, N-0372, Norway

Location

Independent Public Teaching Children's Hospital

Warsaw, 02091, Poland

Location

CHULC, EPE - Hospital Dona Estefânia

Lisbon, 1169-045, Portugal

Location

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

Lisbon, 1649-035, Portugal

Location

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

Moscow, 117198, Russia

Location

State Novosibirsk Regional Clinical Hospital

Novosibirsk, 630087, Russia

Location

St. Petersburg State Pediatric University

Saint Petersburg, 194100, Russia

Location

Hospital Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Virgen del Rocío

Seville, 41013, Spain

Location

Regional Children Clinical Hospital, Pulmonology, Kharkiv

Kharkiv, 61093, Ukraine

Location

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

Kyiv, 03680, Ukraine

Location

Regional clinical children hospital, Zaporizhya

Zaporizhya, 69063, Ukraine

Location

Birmingham Children's Hospital

Birmingham, B4 6NH, United Kingdom

Location

King's College Hospital

London, SE5 9RS, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 36041751 DERIVED

• 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.

  PMID: 34164554 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Lung Diseases, Interstitial

Interventions

nintedanib

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases

Limitations and Caveats

In the protocol it was planned to communicate the end of trial (EoT) once 30 participants had completed pharmacokinetic (PK) sampling at Week 26 or prematurely discontinued the trial and PK data was confirmed as adequate. When the EoT was communicated, no participant had reached Week 100 yet, thus Week 100 time points were not assessable and the trial was completed as per protocol.

Results Point of Contact

• Title: Boehringer Ingelheim, Call Center
• Organization: Boehringer Ingelheim

clintriage.rdg@boehringer-ingelheim.com

1-800-243-0127

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 16, 2019
• First Posted: September 17, 2019
• Study Start: December 3, 2019
• Primary Completion: May 24, 2022
• Study Completion: May 24, 2022
• Last Updated: July 9, 2024
• Results First Posted: January 31, 2023

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

GR (1); NO (1); RU (3); UA (3); HU (1); GB (2); ME (1); ES (2); CA (2); BE (1); AR (3); US (9); PT (2); FI (1); CZ (1); AU (1); DK (1); BR (2); PL (1); IT (3); FR (2)