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
Overview
- Phase
- Phase 3
- Intervention
- Nintedanib
- Conditions
- Lung Diseases, Interstitial
- Sponsor
- Boehringer Ingelheim
- Enrollment
- 39
- Locations
- 43
- Primary Endpoint
- Area Under the Plasma Concentration-time Curve at Steady State (AUCτ,ss) Based on Sampling at Steady State (at Week 2 and Week 26)
- Status
- Completed
- Last Updated
- last year
Overview
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).
Investigators
Eligibility Criteria
Inclusion Criteria
- •Children and adolescents 6 to 17 years old at Visit
- •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
- •\[Note: Predicted normal values will be calculated according to GLI (Global Lung Initiative)\]
- •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
Exclusion Criteria
- •Aspartate Aminotransferase (AST) and/or Alanine Aminotransferase (ALT)\>1.5 x Upper Level of Normal (ULN) at Visit
- •Bilirubin \>1.5 x ULN at Visit
- •Creatinine clearance \<30 mL/min calculated by Schwartz formula at Visit
- •\[Note: Laboratory parameters from Visit 1 have to satisfy the laboratory threshold values as shown above. Visit 2 laboratory results will be available only after randomization. In case at Visit 2 the results do no longer satisfy the entry criteria, the Investigator has to decide whether it is justified that the patient remains on study drug. The justification for decision needs to be documented. Laboratory parameters that are found to be abnormal at Visit 1 are allowed to be re-tested (once) if it is thought to be a measurement error (i.e. there was no abnormal result of this test in the recent history of the patient and there is no related clinical sign) or the result of a temporary and reversible medical condition, once that condition is resolved.\]
- •Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment) at Visit
- •Previous treatment with nintedanib.
- •Other investigational therapy received within 1 month or 5 half-lives (whichever is shorter but ≥1 week) prior to Visit
- •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
Arms & Interventions
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.
Intervention: Nintedanib
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.
Intervention: Placebo
Outcomes
Primary Outcomes
Area Under the Plasma Concentration-time Curve at Steady State (AUCτ,ss) Based on Sampling at Steady State (at Week 2 and Week 26)
Time Frame: 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
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.
Number of Participants With Treatment-emergent Adverse Events During the Double-blind Period
Time Frame: 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
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.
Secondary Outcomes
- Absolute Change From Baseline in Height at Week 52(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)
- Absolute Change From Baseline in Sitting 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.)
- Absolute Change From Baseline in Leg Length at Week 52 - Left(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)
- 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.)
- Absolute Change From Baseline in Leg Length at Week 24 - Left(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)
- Absolute Change From Baseline in Leg Length at Week 76 - Right(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)
- 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)
- Absolute Change From Baseline in Height at Week 76(Measurements were assessed at Week 0 and at Week 76)
- Absolute Change From Baseline in Sitting Height at Week 52(Measurements were assessed at Week 0 and at Week 52)
- Absolute Change From Baseline in Sitting Height at Week 76(Measurements were assessed at Week 0 and at Week 76)
- Absolute Change From Baseline in Forced Vital Capacity (FVC) % Predicted at Week 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 24 are reported in the table below)
- Absolute Change From Baseline in Forced Vital Capacity (FVC) % Predicted at Week 52(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)
- Absolute Change From Baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 24 - Parent Report(MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below)
- Absolute Change From Baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 52 - Parent Report(MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below)
- Absolute Change From Baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 24 - Participant Report(MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below)
- Absolute Change From Baseline in Leg Length at Week 76 - Left(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)
- Absolute Change From Baseline in Leg Length at Week 24 - Right(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)
- Absolute Change From Baseline in Leg Length at Week 52 - Right(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)
- Absolute Change From Baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 52 - Participant Report(MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below)
- Absolute Change From Baseline in Oxygen Saturation (SpO₂) on Room Air at Rest at Week 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 24 are reported in the table below)
- Absolute Change From Baseline in Oxygen Saturation (SpO₂) on Room Air at Rest at Week 52(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)
- Absolute Change From Baseline in 6 Minutes (Min) Walk Distance at Week 24(MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below)
- Absolute Change From Baseline in 6 Minutes (Min) Walk Distance at Week 52(MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below)
- Participants Acceptability Based on the Size of Capsules at Week 24 - Patient Question(Acceptability was assessed at Week 24)
- Participants Acceptability Based on the Size of Capsules at Week 24 - Investigator Question(Acceptability was assessed at Week 24)
- Participants Acceptability Based on the Number of Capsules at Week 24 - Patient Question(Acceptability was assessed at Week 24)
- Number of Participants With Occurrence of First Respiratory-related Hospitalization Over the Whole Trial(From first drug administration until the last drug intake + 28 days residual effect period (REP), up to 92.6 weeks)
- Number of Participants With Occurrence of First Acute Interstitial Lung Disease (ILD) Exacerbation or Death Over the Whole Trial(From first drug administration until the last drug intake + 28 days REP, up to 92.6 weeks)
- Number of Participants With Occurrence of Death Over the Whole Trial(From first drug administration until the last drug intake + 28 days REP, up to 92.6 weeks)