The main objective of the trial is to assess the safety and tolerability of long-term treatment with nintedanib in pediatric patients with clinically significant fibrosing ILD.See section 2.1 and 2.2 of the protocol.
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Respiratoire bronchiolitis-geassocieerde interstitiële longziekte
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is the incidence of treatment emergent adverse events over
the whole trial.
See section 2.1 of the protocol.
Secondary outcome
N/A
Background summary
Childhood interstitial lung disease (chILD) is a term used to describe diffuse
lung disease in children with non-specific respiratory symptoms. It consists of
a heterogeneous group of rare respiratory diseases associated with varying
morbidity and mortality. Although many of the ILDs present in children can also
be found in adults, some chILDs are specific to paediatric populations and
involve different pathophysiology.
There are no currently approved therapies for the treatment of ILD in children.
Based on the mode of action of nintedanib and its demonstrated effects in adult
IPF and other chronic fibrosing ILDs with progressive phenotype, the use of
nintedanib in fibrotic ILDs in children was considered to be of potential
benefit.
In the Phase III trial, InPedILD® (BI trial 1199-0337; EudraCT no.
2018-004530-14), the parent trial to this open label study, the dose-exposure
relationship and safety of nintedanib in children and adolescents with
fibrosing ILD is investigated and information on the efficacy is collected as
well.
If, the benefit/risk assessment based on the data of the InPedILD® trial
justifies further exposure to nintedanib, all patients still on treatment will
be offered to participate in this open label trial InPedILD®-ON (BI trial
1199-0378). Rollover of eligible patients from InPedILD® study to the current
trial is planned to occur without treatment interruption, whenever possible.
The rationale of this open label trial is to collect additional safety and
efficacy data of nintedanib in children and adolescents with clinically
significant fibrosing ILD for at least 2 years (applies to patients rolling
over from the parent trial) or until alternative treatment options become
available or are made available (applies to new patients and to roll-over
patients after 2 years).
See section 1.1 of the protocol.
Study objective
The main objective of the trial is to assess the safety and tolerability of
long-term treatment with nintedanib in pediatric patients with clinically
significant fibrosing ILD.
See section 2.1 and 2.2 of the protocol.
Study design
This is a multi-centre, multi-national, not randomised, open label clinical
trial.
The patient population will include two cohorts:
1. Patients rolling over from the InPedILD® study and 2. Patients newly
enrolled in the study.
Patients will be enrolled (screened) in the trial once they have signed the
informed consent.
The roll-over patients will be screened (visit 1) on the same day as their
first day of the treatmentperiod (visit 2) and the end of treatment (EoT) visit
from InPedILD® 1199-0337. These 3 visits will be combined on one day to prevent
treatment interruption. Common procedures from the EoT from 1199-0337 and visit
1/ visit 2, will not be repeated. For medical reasons, the screening period for
roll-over patients can last up to 8 weeks after the EoT from InPedILD®.
For new patients, the screening period can last up to 12 weeks.
After their eligibility has been confirmed at screening, patients will patients
will be requested to stay in the trial with nintedanib for a minimum of 6
months to approximately 2 years.
Roll-over patients will receive treatment with nintedanib at their last dose of
study medication in the parent trial, unless the patient*s weight has changed.
For new patients, the starting dose will be assigned based on the patient*s
weight.
During treatment period, dose is adjusted based on patient*s weight. Dose
reduction to the next lower dose is possible to manage adverse events.
The end of the trial will take place approximately when the last roll-over
patient reaches 2 years of treatment in the follow-up study ensuring that
nintedanib or alternative treatment options will be available for all remaining
patients (roll-over and/or new patients) outside the trial at this time (this
is expected to happen in in third quarter 2024). This can be earlier, if there
are alternative treatment options become or are made available.
Calculated for 2 years, the patient will have approximately 13 scheduled visits.
See section 3.1 of the protocol.
Intervention
Children and young adolescent:
13.5 kg to <23.0 kg receive 50mg or 25mg nintedanib 2x a day
23.0 kg to <33.5 kg receive 75mg or 50mg nintedanib 2x a day
33.5 kg to <57.5 kg receive 100mg or 75mg nintedanib 2x a day
>=57.5 kg receive 150mg or 100mg nintedanib 2x a day
Patients will receive the medication dose as indicated above. The lower dose is
to manage adverse events. For roll over patients, they will receive the same
dose as they received for the parent trial, unless their weight has changed. If
dose already reduced in InPedILD® or if dose reduction is needed at visit 2. In
these cases, no further reduction will be possible. The lowest possible dose in
this study is 25mg nintedanib 2x a day.
See section 4.1 of the protocol.
Study burden and risks
Burden
- Patient will be asked to participate for a minimum 6 months to approximately
2 years (approximately 6-13 scheduled visits). The length of the study varies
depending on when the patient starts participating and when nintedanib or
alternative treatment options become available outside of this trial. Patients
will be asked to follow the visits according to protcol.
- Female patients will have to do a pregnancy test every 4-6 weeks. When they
do not have to come to the hospital, they can do a provided urine test at home.
The outcome will have to be administered in a patient diary.
- A maximum of 13 visits with blood sampling. In total, 100ml of blood per
patient will be drawn at scheduled visits over a participation of 2 years in
the study.
- 1x CT scan - when there is no CT scan available from within a year form the
screening date a new CT scan is done. This is
about 9,5 mSv per scan.
- Imaging of the physes in the knee will be done with an MRI around every 12
weeks in the first year of the study and thereafter around every 24 weeks.
If the patient does not consent with having an MRI done an X-ray is allowed per
protocol. An X-ray from the knee is about 0,01 mSv per time. When the physis is
closed, no more imaging of the knee is needed.
- The teeth will be monitored by panoramic X-ray (every around 24 weeks in the
first year and thereafter around every 48 weeks) and regular dental check-ups
(around every 12 weeks in the first year and thereafter around every 24weeks)
by a dentist. The amount of radiation that comes with a panoramic X-ray is
0,007 mSv per photo.
- The PedsQL and the 6 MWT are done a maximum of 6 times per protocol.
- The patients will be asked 2x to complete a questionnaire about the IMP
acceptability.
- For the 2x PK visits, patients will have to complete a diary about the 3 days
of IMP intake before this visits.
Risk/benefit *
Given the high unmet need for treatment options in paediatric fibrosing ILDs,
the established clinical benefit and known safety profile of nintedanib in
adults as well as the expected benefit of nintedanib in the paediatric
fibrosing ILD, the benefitrisk of nintedanib in the target population is
considered acceptable. Importantly, this open label trial InPedILD®-ON (BI
trial 1199-0378) will only be implemented if the benefit/risk assessment based
on the data of the InPedILD® trial justifies further exposure to nintedanib.
The planned trial procedures in this extension study, which is the same as for
the parent trial, and the associated-risk are therefore deemed acceptable.
Also, timely identification of potential risks allow for discontinuation of
treatment and possible reversal of adverse drug reactions.
Criteria for dose reduction
If a patient experiences a drug related adverse event, the dose can be reduced
as described in Table 4.1.2: 1. The original the dose can be re-started after
recovery.The dose can be reduced without prior interruption, i.e. immediately
stepping down from one dose to the next dose.
See protocol sections: flowchart, 1.4, 3.1, 4.1 and 5.
The use of Nintedanib post-study
The overall end of trial will take place approximately when last roll-over
patient reaches 2 years of treatment ensuring that nintedanib or alternative
treatment options will be available for all remaining patients (roll-over or
new patients) outside the trial. This is expected in the third quarter of 2024.
Should the patient in the Netherlands withdraw his/her consent from trial
participation before end of trial, then there is the possibility of
implementing a type of compassionate use for Nintedanib called
*Artsenverklaring*. This will be only given when Nintedanib is considered
beneficial for the patient and thus will be determined on a case-by-case basis
between the investigator and sponsor.
See section 1.3 and 3.1 of the protocol.
Basisweg 10
Amsterdam 1043 AP
NL
Basisweg 10
Amsterdam 1043 AP
NL
Listed location countries
Age
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. A
list of contraception methods meeting these criteria is provided in the parental
information and in CTP Section 4.2.2.3.
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
(e.g.
increased oxygen requirement, decreased diffusion capacity).
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 prematurely discontinued treatment permanently in 1199-0337
but are potentially
eligible and for completed patients from parent trial not able to roll-over
into the extension trial within 12 weeks following their End of Treatment visit:
Inclusion criteria for new patients are applicable except criteria 4, and 6 (as
eligibility for these criteria has been done in 1199-0337 and does not need to
be repeated) and also except inclusion criteria 1 for completed patients from
parent trial not able to roll over within 12 weeks following their End of
Treatment Visit in the parent trial.
See protocol section 3.3.2.
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. Estimated Glomerular Filtration Rate (eGFR) <30 mL/min /1.73m² 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)
7. In the opinion of the Investigator, other clinically significant pulmonary
abnormalities.
8. Cardiovascular diseases
9. Bleeding risk
10. History of thrombotic event 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 and/or treatment with
growth hormone therapy
within 6 months before Visit 2.
19. Patients <13.5 kg of weight at Visit 1
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. This should be
discussed with
sponsor before the roll-over of patient.
For patients who prematurely discontinued treatment permanently in 1199-0337
but are potentially
eligible and for completed patients from parent trial not able to roll-over
into the extension trial within 12 weeks following their End of Treatment visit:
All exclusion criteria for new patients are applicable. In addition, following
additional exclusion
criterion is applicable for patients who prematurely discontinued treatment
permanently in 1199-0337:
21. Patients who experienced drug-related adverse events during parent trial
leading to
permanent study treatment discontinuation.
See protocol section 3.3.3.
Design
Recruitment
Medical products/devices used
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-005554-23-NL |
| ClinicalTrials.gov | NCTnummerisnognietbekend |
| CCMO | NL79059.018.21 |