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) (InPedILD®)

• ClinicalTrials.gov Identifier: NCT04093024
• Recruitment Status: Completed
• First Posted: September 17, 2019
• Results First Posted: January 31, 2023
• Last Update Posted: April 25, 2023
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Lung Diseases, Interstitial	Drug: Nintedanib; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 39 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: December 3, 2019
• Actual Primary Completion Date: May 24, 2022
• Actual Study Completion Date: May 24, 2022

Arms and Interventions

Arm	Intervention/treatment
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.	Drug: Nintedanib; Capsule; Other Name: Ofev®
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.	Drug: Placebo; Capsule

Outcome Measures

Primary Outcome Measures :

1. 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.

2. 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 Outcome Measures :

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 [ Time Frame: 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 at least one treatment-emergent pathological finding of the epiphyseal growth plate imaging (Magnetic Resonance Imaging (MRI)s/x-rays) were analyzed cumulatively and based on central review.
2. Number of Participants With Treatment-emergent Pathological Findings on Dental Examination or Imaging up to Week 24 [ Time Frame: Dental examination: at Week 12 and Week 24; Dental imaging: at Week 24 ]
   Number of participants with treatment-emergent pathological findings on dental examination (clinical examination) based on dentist assessment or imaging (panoramic x-ray) based on central review were analyzed. Number of participants with treatment-emergent pathological findings on dental imaging were analyzed cumulatively.
3. Number of Participants With at Least One Treatment-emergent Pathological Findings on Dental Examination or Imaging up to Week 52 [ Time Frame: 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 pathological findings on dental examination (clinical examination) based on dentist assessment or imaging (panoramic x-ray) based on central review were analyzed. Number of participants with treatment-emergent pathological findings on dental imaging were analyzed cumulatively.
4. Number of Participants With Treatment-emergent Adverse Events Over the Whole Trial [ Time Frame: From first drug administration until the last drug intake, up to 92 weeks ]
   Treatment-emergent was defined as: Adverse events with onset or worsening on or after date of treatment start until last drug intake + residual effect period was considered as treatment-emergent and was included in the analysis. Adverse events were counted under the treatment as randomized for the double-blind period.
5. Absolute Change From Baseline in Height at Week 24 [ Time Frame: 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 24 was measured with a stadiometer 3 times at each time point. The average of these 3 measurements was taken per time point.

   Absolute change from baseline in height at Week 24 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

6. Absolute Change From Baseline in Height at Week 52 [ Time Frame: 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 height at Week 52 was measured with a stadiometer 3 times at each time point. The average of these 3 measurements was taken per time point.

   Absolute change from baseline in height at Week 52 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

7. Absolute Change From Baseline in Height at Week 76 [ Time Frame: Measurements were assessed at Week 0 and at Week 76 ]

   Absolute change from baseline in height at Week 76 was measured with a stadiometer 3 times at each time point. The average of these 3 measurements was taken per time point.

   MMRM has been calculated but did not provide estimates for this time point due to low sample size. Thus, change in height from baseline to Week 76 was analyzed descriptively only.

8. Absolute Change From Baseline in Sitting Height at Week 24 [ Time Frame: 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 sitting height at Week 24 was measured with a stadiometer 3 times at each time point. The average of these 3 measurements was taken per time point.

   Absolute change from baseline in sitting height at Week 24 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

9. Absolute Change From Baseline in Sitting Height at Week 52 [ Time Frame: Measurements were assessed at Week 0 and at Week 52 ]

   Absolute change from baseline in sitting height at Week 52 was measured with a stadiometer 3 times at each time point. The average of these 3 measurements was taken per time point.

   MMRM has been calculated but did not provide estimates for this time point due to low sample size. Thus, change in sitting height from baseline to Week 52 was analyzed descriptively only.

10. Absolute Change From Baseline in Sitting Height at Week 76 [ Time Frame: Measurements were assessed at Week 0 and at Week 76 ]

    Absolute change from baseline in sitting height at Week 76 was measured with a stadiometer 3 times at each time point. The average of these 3 measurements was take per time point.

    MMRM has been calculated but did not provide estimates for this time point due to low sample size. Thus, change in sitting height from baseline to Week 76 was analyzed descriptively only.

11. Absolute Change From Baseline in Leg Length at Week 24 - Left [ Time Frame: 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 left leg length at Week 24 was assessed by measuring the distance between the anterior iliac spine and the medial malleolus 3 times at each leg and each time point. The average of these 3 measurements was taken per time point.

    Absolute change from baseline in left leg length at Week 24 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

12. Absolute Change From Baseline in Leg Length at Week 52 - Left [ Time Frame: 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 left leg length at Week 52 was assessed by measuring the distance between the anterior iliac spine and the medial malleolus 3 times at each leg and each time point. The average of these 3 measurements was taken per time point.

    Absolute change from baseline in left leg length at Week 52 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

13. Absolute Change From Baseline in Leg Length at Week 76 - Left [ Time Frame: 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 left leg length at Week 76 was assessed by measuring the distance between the anterior iliac spine and the medial malleolus 3 times at each leg and each time point. The average of these 3 measurements was taken per time point.

    Absolute change from baseline in left leg length at Week 76 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

14. Absolute Change From Baseline in Leg Length at Week 24 - Right [ Time Frame: 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 right leg length at Week 24 was assessed by measuring the distance between the anterior iliac spine and the medial malleolus 3 times at each leg and each time point. The average of these 3 measurements was taken per time point.

    Absolute change from baseline in right leg length at Week 24 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

15. Absolute Change From Baseline in Leg Length at Week 52 - Right [ Time Frame: 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 right leg length at Week 52 was assessed by measuring the distance between the anterior iliac spine and the medial malleolus 3 times at each leg and each time point. The average of these 3 measurements was taken per time point.

    Absolute change from baseline in right leg length at Week 52 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

16. Absolute Change From Baseline in Leg Length at Week 76 - Right [ Time Frame: 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 right leg length at Week 76 was assessed by measuring the distance between the anterior iliac spine and the medial malleolus 3 times at each leg and each time point. The average of these 3 measurements was taken per time point.

    Absolute change from baseline in right leg length at Week 76 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

17. Absolute Change From Baseline in Forced Vital Capacity (FVC) % Predicted at Week 24 [ Time Frame: 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 ]

    Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. The predicted values were calculated according to the Global Lungs Initiative (GLI) 2012 equations.

    Absolute change from baseline in Forced Vital Capacity (FVC) % predicted at Week 24 in the treated set(TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

18. Absolute Change From Baseline in Forced Vital Capacity (FVC) % Predicted at Week 52 [ Time Frame: 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 ]

    Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. The predicted values were calculated according to the Global Lungs Initiative (GLI) 2012 equations.

    Absolute change from baseline in Forced Vital Capacity (FVC) % predicted at Week 52 in the treated set(TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

19. Absolute Change From Baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 24 - Parent Report [ Time Frame: MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below ]

    The PedsQL™ questionnaires consists of 23 items (i) and 4 dimensions: physical (8i), emotional (5i), social (5i) and school (5i) functioning. A 5-point Likert response scale (0 = never (worst outcome) to 4=almost always (best outcome)) was used except for the Young Child Report, where a 3-point scale (0=not at all (worst outcome) to 4=a lot (best outcome)) was used. Items were reverse-scored and linearly transformed to a 0-100 scale (0 = 100 to 4 = 0). Higher scores indicated better health-related quality of life. To create total scores, the mean was computed.

    Absolute change from baseline in PedsQL™ reported by parents was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

20. Absolute Change From Baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 52 - Parent Report [ Time Frame: MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below ]

    The PedsQL™ questionnaires consists of 23 items (i) and 4 dimensions: physical (8i), emotional (5i), social (5i) and school (5i) functioning. A 5-point Likert response scale (0 = never (worst outcome) to 4=almost always (best outcome)) was used except for the Young Child Report, where a 3-point scale (0=not at all (worst outcome) to 4=a lot (best outcome)) was used. Items were reverse-scored and linearly transformed to a 0-100 scale (0 = 100 to 4 = 0). Higher scores indicated better health-related quality of life. To create total scores, the mean was computed.

    Absolute change from baseline in PedsQL™ reported by parents was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

21. Absolute Change From Baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 24 - Participant Report [ Time Frame: MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below ]

    The PedsQL™ questionnaires consists of 23 items (i) and 4 dimensions: physical (8i), emotional (5i), social (5i) and school (5i) functioning. A 5-point Likert response scale (0 = never (worst outcome) to 4=almost always (best outcome)) was used except for the Young Child Report, where a 3-point scale (0=not at all (worst outcome) to 4=a lot (best outcome)) was used. Items were reverse-scored and linearly transformed to a 0-100 scale (0 = 100 to 4 = 0). Higher scores indicated better health-related quality of life. To create total scores, the mean was computed.

    Absolute change from baseline in PedsQL™ was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

22. Absolute Change From Baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 52 - Participant Report [ Time Frame: MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below ]

    The PedsQL™ questionnaires consists of 23 items (i) and 4 dimensions: physical (8i), emotional (5i), social (5i) and school (5i) functioning. A 5-point Likert response scale (0 = never (worst outcome) to 4=almost always (best outcome)) was used except for the Young Child Report, where a 3-point scale (0=not at all (worst outcome) to 4=a lot (best outcome)) was used. Items were reverse-scored and linearly transformed to a 0-100 scale (0 = 100 to 4 = 0). Higher scores indicated better health-related quality of life. To create total scores, the mean was computed.

    Absolute change from baseline in PedsQL™ was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

23. Absolute Change From Baseline in Oxygen Saturation (SpO₂) on Room Air at Rest at Week 24 [ Time Frame: 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 ]

    Oxygen saturation (SpO₂) was measured after minimum 5 minutes on room air by standard pulse oximetry at rest.

    Absolute change from baseline in SpO₂ at Week 24 in the treated set(TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

24. Absolute Change From Baseline in Oxygen Saturation (SpO₂) on Room Air at Rest at Week 52 [ Time Frame: 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 ]

    Oxygen saturation (SpO₂) was measured after minimum 5 minutes on room air by standard pulse oximetry at rest.

    Absolute change from baseline in SpO₂ at Week 52 in the treated set(TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.

25. Absolute Change From Baseline in 6 Minutes (Min) Walk Distance at Week 24 [ Time Frame: 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 24 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.
26. Absolute Change From Baseline in 6 Minutes (Min) Walk Distance at Week 52 [ Time Frame: 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 6 minutes (min) walk distance at Week 52 in the treated set(TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age-group and the fixed continuous effects of baseline at each visit, and random effect for participant. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within-participant measurements.
27. Participants Acceptability Based on the Size of Capsules at Week 24 - Patient Question [ Time Frame: Acceptability was assessed at Week 24 ]

    Acceptability is defined as the overall ability and willingness of the participant to use the medicinal product as intended.

    Acceptability based on the capsule size was assessed by a acceptability questionnaire (1 item with 3 categories as shown below) for participants. In case the participant was considered not old enough as per investigator judgment the caregiver could assist with the completion.

    In addition to the commercially available 100 milligram (mg) soft capsules (oblong shape, 6 millimeter (mm) diameter and 16 mm length) and 150 mg soft capsules (oblong shape, 7 mm diameter and 18 mm length), 25 mg Nintedanib soft capsules of smaller size (oval shape, 5 mm diameter and 8 mm length) were provided in this trial for participants who were assigned to a dose smaller than 100 mg or were unable to swallow the larger 100 mg or 150 mg capsules.

28. Participants Acceptability Based on the Size of Capsules at Week 24 - Investigator Question [ Time Frame: Acceptability was assessed at Week 24 ]

    Acceptability is defined as the overall ability and willingness of the participant to use the medicinal product as intended.

    Acceptability based on the capsule size was assessed by a acceptability questionnaire (1 item with 3 categories as shown below) for investigators.

    In addition to the commercially available 100 milligram (mg) soft capsules (oblong shape, 6 millimeter (mm) diameter and 16 mm length) and 150 mg soft capsules (oblong shape, 7 mm diameter and 18 mm length), 25 mg Nintedanib soft capsules of smaller size (oval shape, 5 mm diameter and 8 mm length) were provided in this trial for participants who were assigned to a dose smaller than 100 mg or were unable to swallow the larger 100 mg or 150 mg capsules.

29. Participants Acceptability Based on the Number of Capsules at Week 24 - Patient Question [ Time Frame: Acceptability was assessed at Week 24 ]

    Acceptability is defined as the overall ability and willingness of the participant to use the medicinal product as intended.

    Acceptability based on the number of capsule was assessed by a acceptability questionnaire (1 item with 3 categories as shown below) for participants. In case the participant was considered not old enough as per investigator judgment the caregiver could assist with the completion.

    In addition to the commercially available 100 milligram (mg) soft capsules (oblong shape, 6 millimeter (mm) diameter and 16 mm length) and 150 mg soft capsules (oblong shape, 7 mm diameter and 18 mm length), 25 mg Nintedanib soft capsules of smaller size (oval shape, 5 mm diameter and 8 mm length) were provided in this trial for participants who were assigned to a dose smaller than 100 mg or were unable to swallow the larger 100 mg or 150 mg capsules. Medication dosage was based on the participant's body weight and number of capsules per administration ranged from 2 to >6 capsules.

30. Number of Participants With Occurrence of First Respiratory-related Hospitalization Over the Whole Trial [ Time Frame: 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 respiratory-related hospitalization over the whole trial.

    The number of participants with first respiratory-related hospitalization is reported instead of a metric summarizing the time-to-event data with unit of time, as the numbers resulting from the Kaplan-Meier-analysis were even below the first quartile.

31. Number of Participants With Occurrence of First Acute Interstitial Lung Disease (ILD) Exacerbation or Death Over the Whole Trial [ Time Frame: From first drug administration until the last drug intake + 28 days 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. The number of participants with first acute ILD exacerbation is reported instead of a metric summarizing the time-to-event data with unit of time, as the numbers resulting from the Kaplan-Meier-analysis were even below the first quartile.
32. Number of Participants With Occurrence of Death Over the Whole Trial [ Time Frame: 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 over the whole trial was computed. The number of participants with occurrence of death is reported instead of a metric summarizing the time-to-event data with unit of time, as the numbers resulting from the Kaplan-Meier-analysis were even below the first quartile.

Eligibility Criteria

• Ages Eligible for Study: 6 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Locations

United States, California

Children's Hospital Los Angeles

Los Angeles, California, United States, 90027

United States, Colorado

Children's Hospital Colorado

Aurora, Colorado, United States, 80045

United States, Indiana

Riley Hospital for Children at Indiana University Health

Indianapolis, Indiana, United States, 46202

United States, Missouri

Children's Mercy Hospitals and Clinics

Kansas City, Missouri, United States, 64108

United States, New York

Weill Cornell Medicine

New York, New York, United States, 10021

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

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

Pittsburgh, Pennsylvania, United States, 15224

United States, Tennessee

Vanderbilt University Medical Center

Nashville, Tennessee, United States, 37232

United States, Washington

Seattle Children's Hospital

Seattle, Washington, United States, 98105

Argentina

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

Caba, Argentina, C1245AAM

Hospital de Niños Dr. Ricardo Gutierrez

Caba, Argentina, C1425EFD

INSARES

Mendoza, Argentina, M5500CCG

Australia, South Australia

Women's and Children's Hospital

North Adelaide, South Australia, Australia, 5006

Belgium

Brussels - UNIV HUDERF

Bruxelles, Belgium, 1020

Brazil

Serviços Medicos Respirar Sul Fluminense

Barra Mansa, Brazil, 27323240

Centro de Pesquisa Clinica do Instituto da Crianca - HCFMUSP

Sao Paulo, Brazil, 5403-900

Canada, British Columbia

BC Children's Hospital

Vancouver, British Columbia, Canada, V6H 3N1

Canada, Ontario

The Hospital for Sick Children

Toronto, Ontario, Canada, M5G 1X8

Czechia

Teaching Hospital Motol, Oncology Clinic

Praha 5, Czechia, 150 06

Denmark

Aarhus University Hospital

Aarhus N, Denmark, 8200

Finland

Tampere University Hospital

Tampere, Finland, 33520

France

HOP Intercommunal

Créteil, France, 94010

HOP Armand-Trousseau

Paris, France, 75571

Greece

General Hospital of Thessaloniki "Ippokrateio"

Thessaloniki, Greece, 54642

Hungary

Semmelweis University

Budapest, Hungary, 1122

Italy

Azienda Ospedaliera Meyer

Firenze, Italy, 50139

Azienda Ospedaliera Universitaria di Padova

Padova, Italy, 35128

Osp. Pediatrico Bambin Gesù

Roma, Italy, 00165

Mexico

Clinical Research Institute S.C.

Tlalnepantla, Mexico, 54055

Norway

Oslo Universitetssykehus HF, Rikshospitalet

Oslo, Norway, N-0372

Poland

Independent Public Teaching Children's Hospital

Warsaw, Poland, 02091

Portugal

CHULC, EPE - Hospital Dona Estefânia

Lisboa, Portugal, 1169-045

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

Lisboa, Portugal, 1649-035

Russian Federation

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

Moscow, Russian Federation, 117198

State Novosibirsk Regional Clinical Hospital

Novosibirsk, Russian Federation, 630087

St. Petersburg State Pediatric University

St. Petersburg, Russian Federation, 194100

Spain

Hospital Vall d'Hebron

Barcelona, Spain, 08035

Hospital Virgen del Rocío

Sevilla, Spain, 41013

Ukraine

Regional Children Clinical Hospital, Pulmonology, Kharkiv

Kharkiv, Ukraine, 61093

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

Kyiv, Ukraine, 03680

Regional clinical children hospital, Zaporizhya

Zaporizhya, Ukraine, 69063

United Kingdom

Birmingham Children's Hospital

Birmingham, United Kingdom, B4 6NH

King's College Hospital

London, United Kingdom, SE5 9RS

Sponsors and Collaborators

Boehringer Ingelheim

  Study Documents (Full-Text)

Documents provided by Boehringer Ingelheim:

Study Protocol  [PDF] June 14, 2021

Statistical Analysis Plan  [PDF] March 9, 2022

More Information

Additional Information:

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT04093024
• Other Study ID Numbers: 1199-0337; 2018-004530-14 ( EudraCT Number )
• First Posted: September 17, 2019
• Results First Posted: January 31, 2023
• Last Update Posted: April 25, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Plan Description

Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents, except for the following exclusions:

1. studies in products where Boehringer Ingelheim is not the license holder;
2. studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials;
3. studies conducted in a single center or targeting rare diseases (because of limitations with anonymization).

For more details refer to: https://www.mystudywindow.com/msw/datasharing

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Lung Diseases; Lung Diseases, Interstitial; Respiratory Tract Diseases; Nintedanib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action