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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04093024

Registration number

NCT04093024

Ethics application status

Date submitted

16/09/2019

Date registered

17/09/2019

Date last updated

9/07/2024

Titles & IDs

Public title

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)

Scientific 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

Secondary ID [1]

2018-004530-14

Secondary ID [2]

1199-0337

Universal Trial Number (UTN)

Trial acronym

InPedILD®

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Lung Diseases, Interstitial

Condition category

Condition code

Respiratory

Other respiratory disorders / diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Treatment: Drugs - Nintedanib
Treatment: Drugs - Placebo

Experimental: 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.

Placebo comparator: 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.

Treatment: Drugs: Nintedanib
Capsule

Treatment: Drugs: Placebo
Capsule

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Control group

Outcomes

Primary outcome [1]

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

Timepoint [1]

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

Primary outcome [2]

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

Timepoint [2]

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 outcome [1]

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

Timepoint [1]

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)

Secondary outcome [2]

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

Timepoint [2]

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

Secondary outcome [3]

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

Timepoint [3]

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

Secondary outcome [4]

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

Timepoint [4]

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

Secondary outcome [5]

Absolute Change From Baseline in Height at Week 24

Timepoint [5]

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

Secondary outcome [6]

Absolute Change From Baseline in Height at Week 52

Timepoint [6]

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

Secondary outcome [7]

Absolute Change From Baseline in Height at Week 76

Timepoint [7]

Measurements were assessed at Week 0 and at Week 76

Secondary outcome [8]

Absolute Change From Baseline in Sitting Height at Week 24

Timepoint [8]

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.

Secondary outcome [9]

Absolute Change From Baseline in Sitting Height at Week 52

Timepoint [9]

Measurements were assessed at Week 0 and at Week 52

Secondary outcome [10]

Absolute Change From Baseline in Sitting Height at Week 76

Timepoint [10]

Measurements were assessed at Week 0 and at Week 76

Secondary outcome [11]

Absolute Change From Baseline in Leg Length at Week 24 - Left

Timepoint [11]

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

Secondary outcome [12]

Absolute Change From Baseline in Leg Length at Week 52 - Left

Timepoint [12]

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

Secondary outcome [13]

Absolute Change From Baseline in Leg Length at Week 76 - Left

Timepoint [13]

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

Secondary outcome [14]

Absolute Change From Baseline in Leg Length at Week 24 - Right

Timepoint [14]

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

Secondary outcome [15]

Absolute Change From Baseline in Leg Length at Week 52 - Right

Timepoint [15]

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

Secondary outcome [16]

Absolute Change From Baseline in Leg Length at Week 76 - Right

Timepoint [16]

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

Secondary outcome [17]

Absolute Change From Baseline in Forced Vital Capacity (FVC) % Predicted at Week 24

Timepoint [17]

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

Secondary outcome [18]

Absolute Change From Baseline in Forced Vital Capacity (FVC) % Predicted at Week 52

Timepoint [18]

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

Secondary outcome [19]

Absolute Change From Baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 24 - Parent Report

Timepoint [19]

MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below

Secondary outcome [20]

Absolute Change From Baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 52 - Parent Report

Timepoint [20]

MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below

Secondary outcome [21]

Absolute Change From Baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 24 - Participant Report

Timepoint [21]

MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below

Secondary outcome [22]

Absolute Change From Baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 52 - Participant Report

Timepoint [22]

MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below

Secondary outcome [23]

Absolute Change From Baseline in Oxygen Saturation (SpO2) on Room Air at Rest at Week 24

Timepoint [23]

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

Secondary outcome [24]

Absolute Change From Baseline in Oxygen Saturation (SpO2) on Room Air at Rest at Week 52

Timepoint [24]

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

Secondary outcome [25]

Absolute Change From Baseline in 6 Minutes (Min) Walk Distance at Week 24

Timepoint [25]

MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below

Secondary outcome [26]

Absolute Change From Baseline in 6 Minutes (Min) Walk Distance at Week 52

Timepoint [26]

MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below

Secondary outcome [27]

Participants Acceptability Based on the Size of Capsules at Week 24 - Patient Question

Timepoint [27]

Acceptability was assessed at Week 24

Secondary outcome [28]

Participants Acceptability Based on the Size of Capsules at Week 24 - Investigator Question

Timepoint [28]

Acceptability was assessed at Week 24

Secondary outcome [29]

Participants Acceptability Based on the Number of Capsules at Week 24 - Patient Question

Timepoint [29]

Acceptability was assessed at Week 24

Secondary outcome [30]

Number of Participants With Occurrence of First Respiratory-related Hospitalization Over the Whole Trial

Timepoint [30]

From first drug administration until the last drug intake + 28 days residual effect period (REP), up to 92.6 weeks

Secondary outcome [31]

Number of Participants With Occurrence of First Acute Interstitial Lung Disease (ILD) Exacerbation or Death Over the Whole Trial

Timepoint [31]

From first drug administration until the last drug intake + 28 days REP, up to 92.6 weeks

Secondary outcome [32]

Number of Participants With Occurrence of Death Over the Whole Trial

Timepoint [32]

From first drug administration until the last drug intake + 28 days REP, up to 92.6 weeks

Eligibility

Key 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).

Minimum age

6 Years

Maximum age

17 Years

Sex

Both males and females

Can healthy volunteers participate?

Key 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).

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Blinded (masking used)

Who is / are masked / blinded?

The people receiving the treatment/s

The people analysing the results/data

Intervention assignment

Parallel

Other design features

Phase

Phase 3

Type of endpoint/s

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Data analysis

Reason for early stopping/withdrawal

Other reasons

Date of first participant enrolment

Anticipated

Actual

3/12/2019

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

24/05/2022

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

Women's and Children's Hospital - North Adelaide

Recruitment postcode(s) [1]

5006 - North Adelaide

Recruitment outside Australia

Country [1]

United States of America

State/province [1]

California

Country [2]

United States of America

State/province [2]

Colorado

Country [3]

United States of America

State/province [3]

Indiana

Country [4]

United States of America

State/province [4]

Missouri

Country [5]

United States of America

State/province [5]

New York

Country [6]

United States of America

State/province [6]

Pennsylvania

Country [7]

United States of America

State/province [7]

Tennessee

Country [8]

United States of America

State/province [8]

Washington

Country [9]

Argentina

State/province [9]

Caba

Country [10]

Argentina

State/province [10]

Mendoza

Country [11]

Belgium

State/province [11]

Bruxelles

Country [12]

Brazil

State/province [12]

Barra Mansa

Country [13]

Brazil

State/province [13]

Sao Paulo

Country [14]

Canada

State/province [14]

British Columbia

Country [15]

Canada

State/province [15]

Ontario

Country [16]

Czechia

State/province [16]

Praha 5

Country [17]

Denmark

State/province [17]

Aarhus N

Country [18]

Finland

State/province [18]

Tampere

Country [19]

France

State/province [19]

Créteil

Country [20]

France

State/province [20]

Paris

Country [21]

Greece

State/province [21]

Thessaloniki

Country [22]

Hungary

State/province [22]

Budapest

Country [23]

Italy

State/province [23]

Firenze

Country [24]

Italy

State/province [24]

Padova

Country [25]

Italy

State/province [25]

Roma

Country [26]

Mexico

State/province [26]

Tlalnepantla

Country [27]

Norway

State/province [27]

Oslo

Country [28]

Poland

State/province [28]

Warsaw

Country [29]

Portugal

State/province [29]

Lisboa

Country [30]

Russian Federation

State/province [30]

Moscow

Country [31]

Russian Federation

State/province [31]

Novosibirsk

Country [32]

Russian Federation

State/province [32]

St. Petersburg

Country [33]

Spain

State/province [33]

Barcelona

Country [34]

Spain

State/province [34]

Sevilla

Country [35]

Ukraine

State/province [35]

Kharkiv

Country [36]

Ukraine

State/province [36]

Kyiv

Country [37]

Ukraine

State/province [37]

Zaporizhya

Country [38]

United Kingdom

State/province [38]

Birmingham

Country [39]

United Kingdom

State/province [39]

London

Funding & Sponsors

Primary sponsor type

Commercial sector/industry

Name

Boehringer Ingelheim

Address

Country

Ethics approval

Ethics application status

Summary

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).

Trial website

https://clinicaltrials.gov/study/NCT04093024

Trial related presentations / publications

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.

Public notes

Contacts

Principal investigator

Name

Address

Country

Phone

Fax

Contact person for public queries

Name

Address

Country

Phone

Fax

Contact person for scientific queries

Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT04093024

Trial Review

Registering a new trial?

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04093024