A double blind, randomised, placebo-controlled trial evaluating efficacy and safety of oral nintedanib treatment for at least 52 weeks in patients with Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD)

As no approved SSc-ILD treatment is available, and internal organ fibrosis,
especially lung
fibrosis, leads to severe loss of function and ultimately results in death,
there is a high unmet
medical need to stop the fibrotic remodeling and thus prevent loss of organ
function.
As a common practice, immunosuppressive agents (e.g. mycophenolate mofetil,
cyclophosphamide, methotrexate, azathioprine, prednisone) are widely used to
address the
organ-specific manifestations. Currently no approved treatment is available
addressing the
interstitial lung manifestation of the disease.
Based upon the mechanism of action and the similarities of pathophysiology
resulting in the
same pro-fibrotic cascade described in both SSc-ILD and IPF (P14-07919), the
pharmacological rationale for multiple tyrosine kinase inhibition in SSc-ILD is
sound and
promising. Pre-clinical evidence of anti-fibrotic activity of nintedanib in SSc
and clinical
evidence in IPF with an acceptable safety profile support the rationale of
performing a trial in
patients with SSc-ILD.
SSc-ILD is expected to be a co-manifestation with varying degrees of
involvement of skin
and other organs. From a mechanistic point of view and based on preclinical
data, an effect of
nintedanib on manifestations of the disease outside of the lung, for example
skin effects, is
also expected.
The rationale to conduct this Phase III trial in SSc-ILD can be summarized as
follows:
High unmet medical need
Preclinical evidence for efficacy in SSc and SSc-ILD
Anti-fibrotic efficacy of nintedanib proven in IPF patients (similar pattern
regarding
lung fibrosis)
From a mechanistic point of view, treatment with nintedanib may also be
beneficial
on the disease outside of the lung, for example skin.

The objective of the trial is to assess the efficacy and safety of nintedanib
in the treatment of
SSc with ILD at a dose of 150 mg bid compared to placebo.

multi-centre, multi-national, prospective, double blind, randomised, placebo
controlled.

56 to 104 weeks of treatment, witht nintedanib 150 mg twice daily or placebo
150 mg twice daily.

Blood samples (every visit), pregnancy test in blood or urine (every visit), PK
assessment (2 visits), ECG (4 visits), filling in 6 questionnaires (4 visits),
maintaining menses calendar (every visit), filling in PK card (12 times over 6
days), mRSS assessment (7 visits), digital ulcer assessment (7 visits),
autoantibody assessment (3 visits), biomarker blood sample (4 visits),
farmacogenomic blood sample (1 visit), SpO2 test (4 visit), spirometry (12
visits), DLCO test (5 visits), echo of the hart (2 visits). If necessary a HRCT
scan; when no HRCT is available, less than 1 year old.

The risks of treatment with nintedanib have been well delineated in patients
with the fibrotic lung disease IPF. These risks are primarily related to the
gastrointestinal tract (nausea, vomiting, diarrhoea, abdominal pain), and are
usually managed with supportive therapy and
with temporary or permanent dose reduction to 100 mg bid. In some cases,
temporary interruption or permanent drug discontinuation is necessary. A
reduction in appetite and weight decrease has also been reported in patients
treated with nintedanib. Patients with SSc may already suffer from
gastrointestinal symptoms and will be monitored for such events. Parenteral fed
patients will be excluded from the trial. Increases in liver enzymes and
bilirubin have been reported with the use of nintedanib and liver enzymes and
must be followed closely during treatment (see also Section 4.2.1.2).
Nintedanib must be dose-reduced, or interrupted in the event of hepatic
toxicity and further treatment withheld until recovery of the abnormal
laboratory parameters.
Risk associated to the HRCT: The more radiation received over the course of a
life, the greater risk of having cancerous tumors or of inducing changes in
genes. The changes in genes possibly could cause abnormalities or disease in
your future offspring. The radiation in this study is not expected to greatly
increase these risks, but the exact increase in such risks is not known. You
also may feel uncomfortable in the described tunnel. However, the scanner is
open at both ends, and an intercom allows you to talk with the trial doctor and
the staff. The scan can be stopped at any time at your request, but the scan
may not be complete.