- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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