The main objective of the study is to evaluate dose-exposure and safety of nintedanib in children and adolescents with fibrosing ILD. Additional efficacy and safety endpoints will be collected to explore potential long-term effects.Please see…
ID
Source
Brief title
Condition
- Other condition
Synonym
Health condition
Interstitiale longziekten met significante fribrotisering
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints:
* PK: AUC*,ss based on sampling at steady state (at week 2 and week 26);
* N (%) of patients with treatment-emergent adverse events at week 24.
Please see protocol section 2.1
Secondary outcome
Secondary endpoints:
* N (%) of patients with treatment-emergent pathological findings of epiphyseal
growth plate on imaging at week 24, and week 52*;
* N (%) of patients with treatment-emergent pathological findings on dental
examination or imaging at week 24, and week 52*;
* N (%) of patients with treatment-emergent adverse events over the whole trial;
* Change in height, sitting height, leg length from baseline at week 24, and
week 52*.
* Change in Forced Vital Capacity (FVC) % predicted from baseline at week 24,
and week 52*;
* Absolute change from baseline in Pediatric Quality of Life Questionnaire*
(PedsQL*) at week 24, and week 52*;
* Change in oxygen saturation (SpO2) on room air at rest from baseline at week
24, and week 52*;
* Change in 6-min walk distance from baseline at week 24, and week 52*;
* Patient acceptability based on the size of capsules at week 24;
* Patient acceptability based on the number of capsules at week 24;
* Time to first respiratory-related hospitalization over the whole trial;
* Time to first acute Interstitial Lung Disease (ILD) exacerbation or death
over the whole trial;
* Time to death over the whole trial;
*52 weeks time point will not be available for all patients.
Please see section 2.1 and 2.2 from the protocol.
Background summary
Childhood interstitial lung disease (chILD) comprises a complex and
heterogeneous spectrum of rare respiratory disorders affecting infants and
children associated with varying prognosis.
Similar to adults with ILD, some of whom can develop a progressive phenotype
characterized by worsening symptoms, lung function decline and increased
morbidity, some patients with chILD develop chronic lung fibrosis that is
associated with significant morbidity and mortality.
There are currently no approved therapies for the treatment of fibrosing
interstitial lung disease associated with any of these conditions in children.
Please see Section 1.1
Study objective
The main objective of the study is to evaluate dose-exposure and safety of
nintedanib in children and adolescents with fibrosing ILD. Additional efficacy
and safety endpoints will be collected to explore potential long-term effects.
Please see section 2.1 and 2.2
Study design
This is a multi-centre, multi-national, prospective, double blind, randomised,
placebo-controlled clinical 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 years old) with clinically significant fibrosing
interstitial lung disease.
After the assessment of all in- and exclusion criteria, each eligible patient
will be randomised to treatment groups according to a randomisation plan in a
2:1 ratio (nintedanib:placebo).
The study will include two database locks (DBL 1 and DBL 2). The first DBL will
be announced once 30 patients (at least 20 adolescents aged 12-17 years) have
completed PK sampling at 26 weeks, or prematurely discontinued the trial
(last-patient-last-visit-primary-endpoint). At this timepoint patient
recruitment will close.
After the EoT visit, patients will enter a 4-week follow-up period, unless they
subsequently roll-over into the open label extension trial. The open label
extension trial (1199-0378) will be initiated if supported by the benefit-risk
assessment from DBL 1
Please see chapter 3 and 4.1
Intervention
Children:
13.5 kg to <23.0 kg receive 50 mg Nintedanib/placebo twice a day
23.0 kg to <33.5 kg receive 75 mg Nintedanib/placebo twice a day
33.5 kg to <57.5 kg receive 100 mg Nintedanib/placebo twice a day
*57.5 kg receive 150 mg Nintedanib/placebo twice a day
After the assessment of all in- and exclusion criteria, each eligible patient
will be randomised to treatment groups according to a randomisation plan in a
2:1 ratio (nintedanib:placebo).
Please see protocol section 4.1
Study burden and risks
During the first 52 weeks the patient will come 9 times to the hospital. In the
second year this will be every 12 weeks until the end of the study. 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.
At approximately 13 visits, blood will be drawn from the patient. This will be
between 6,5 ml and 13,5 ml per visit.
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. Imaging of the
physes in the knee will be done with an MRI about 8 times. 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. Also the teeth will be monitored by
panoramic X-ray (8x) and regular dental check-ups 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 3 times per protocol. Twice the patients are
asked to complete a questionnaire about the IMP acceptability and fort he 2 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 benefit-risk of nintedanib in the target population is
considered acceptable. The planned trial procedures and the associated-risk are
deemed acceptable as they allow for timely identification of potential risks,
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. should be considered to manage adverse events.
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.
Please see protocol sections: 1.4, 3.1, 4.1 and Section 5. Also, see the table
of contents.
Comeniusstraat 6
Alkmaar 1817MS
NL
Comeniusstraat 6
Alkmaar 1817MS
NL
Listed location countries
Age
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 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 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.
-Patients with evidence of fibrosing ILD on HRCT within 12 months of Visit 1 as
assessed by the investigator and confirmed by central review.
-Patients with FVC % predicted *25% at Visit 2.
-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
AST and/or ALT and/or bilirubin >1.5 x ULN, and/or creatinine clearance
<30 mL/min (Schwartz formula), and/or 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, any cardiovascular disease excluded by
protocol, history of thrombotic event within 12 months of Visit 1, other
disease that may interfere with testing procedures or trial participation, or
may put the patient at risk; bleeding risk; life expectancy for any concomitant
disease other than ILD <2.5 years (investigator assessment); any diagnosed
growth disorder or any genetic disorder associated with short stature and/or
treatment with growth hormone therapy within 6 months before Visit 2; <13.5
kg of weight at Visit 1.
Design
Recruitment
Medical products/devices used
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 | EUCTR2018-004530-14-NL |
| CCMO | NL71187.018.19 |
| Other | Op dit moment nog niet bekend |