| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Interstitial Lung Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| Interstitial Lung Disease |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066393 |
| E.1.2 | Term | Respiratory bronchiolitis-associated interstitial lung disease |
| E.1.2 | System Organ Class | 100000004855 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The trial will assess the safety and tolerability of long-term treatment with nintedanib in
pediatric patients with clinically significant fibrosing ILD.
The primary objective is to estimate the incidence of treatment emergent adverse events over
the whole trial. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
HRCT substudy:
only at selected sites in the United States (US) for patients who already participated in the similar substudy in the parent trial
Details of the planned HRCT analyses and endpoints will be described in a specific Statistical Analysis Plan (SAP) for the substudy and are considered exploratory. |
|
| E.3 | Principal inclusion criteria |
For new patients:
1. Children and adolescents 6 to 17 years old at Visit 2.
2. Signed and dated written informed consent and assent, where applicable, in accordance with ICH-GCP and local legislation prior to admission to the trial.
3. Male or female patients. Female of childbearing potential (WOCBP1) 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 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.
4. Patients with evidence of fibrosing ILD on HRCT within 12 months of Visit 1 as assessed by the investigator and confirmed by central review.
5. Patients with FVC % predicted ≥25% at Visit 2.
6. 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
o a 5-10% relative decline in FVC% predicted accompanied by worsening symptoms, or
o a ≥10% relative decline in FVC % predicted, or
o increased fibrosis on HRCT, or
o other measures of clinical worsening attributed to progressive lung disease
For roll-over patients from the InPedILD™ study:
Only criteria 2 and 3 listed for new patients are applicable with the following additional inclusion criterion:
7. Patients who completed the InPedILD™ trial as planned and who did not permanently prematurely discontinue study treatment.
For patients who discontinued treatment permanently in 1199-0337 but are potentially eligible:
Criteria for new patients are applicable except criteria 4, and 6 |
|
| E.4 | Principal exclusion criteria |
For new patients:
1. AST and/or ALT >1.5 x ULN at Visit 1.
2. Bilirubin >1.5 x ULN at Visit 1.
3. eGFR <30 mL/min calculated by Schwartz formula at Visit 1
4. Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic impairment) at Visit 1.
5. Other investigational therapy received within 1 month or 5 half-lives (whichever is shorter but ≥1 week) prior to Visit 2 except investigational therapy received in InPedILD™ trial.
6. Significant pulmonary arterial hypertension (PAH) defined by any of the following:
a. Previous clinical or echocardiographic evidence of significant right heart failure
b. History of right heart catheterization showing a cardiac index ≤2 l/min/m²
c. PAH requiring parenteral therapy with epoprostenol/treprostinil
7. In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
8. Cardiovascular diseases, any of the following:
a. Severe hypertension, uncontrolled under treatment, within 6 months of Visit 1.
Uncontrolled hypertension is defined as
i. 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) (please refer to Appendix 10.5)
ii. In adolescents 13 to 17 years old: systolic blood pressure ≥140 mm Hg or
diastolic blood pressure ≥90 mm Hg (please refer to Appendix 10.5)
b. Myocardial infarction within 6 months of Visit 1
c. Unstable cardiac angina within 6 months of Visit 1
9. Bleeding risk, any of the following:
a. Known genetic predisposition to bleeding
b. Patients who require
i. Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin inhibitors, heparin, hirudin)
ii. High dose antiplatelet therapy
c. History of haemorrhagic central nervous system (CNS) event within 12 months of Visit 1
d. Any of the following within 3 months of Visit 1:
i. Haemoptysis or haematuria
ii. Active gastro-intestinal (GI) bleeding or GI – ulcers
iii. Major injury or surgery (investigator’s judgment)
e. Any of the following coagulation parameters at Visit 1:
i. International normalized ratio (INR) >2
ii. Prolongation of prothrombin time (PT) by >1.5 x ULN
iii. Prolongation of activated partial thromboplastin time (aPTT) by >1.5 x ULN
10. History of thrombotic event (including stroke and transient ischemic attack) within 12 months of Visit 1.
11. Known hypersensitivity to the trial medication or its components (i.e. soya lecithin).
12. Patients with documented allergy to peanut or soya.
13. 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.
14. Life expectancy for any concomitant disease other than ILD <2.5 years (investigator assessment).
15. Female patients who are pregnant, nursing, or who plan to become pregnant while in the trial.
16. Patients not able or willing to adhere to trial procedures, including intake of study medication.
17. Patients who must or wish to take any drug considered likely to interfere with the safe conduct of the trial according to investigator’s benefit-risk assessment for the individual patient
18. 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.
19. Patients <13.5 kg of weight at Visit 1 (same threshold to be used for male and female patients).
For roll-over patients from the InPedILD™ study:
Only criteria 11, 12, 13, 15, 16, 17 and 19, listed for new patients are applicable with the following additional exclusion criterion:
20. Patient not compliant in parent trial (InPedILD™), with trial medication or trial visits, according to investigator’s judgement. Roll-over patients may qualify for participation even though other exclusion criteria may have been met during the participation in InPedILD™, if the investigator’s benefit-risk assessment for the individual patient remains favourable.
For patients who discontinued treatment permanently in 1199-0337 but are potentially eligible:
All exclusion criteria for new patients are applicable with following additional exclusion criterion:
21. Patients who experienced drug-related adverse events during parent trial leading to permanent study treatment discontinuation. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1) The primary endpoint is the incidence of treatment emergent adverse events over the whole trial. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Canada |
| Czechia |
| Denmark |
| Finland |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Mexico |
| Netherlands |
| Norway |
| Poland |
| Portugal |
| Russian Federation |
| Spain |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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