Effects of bosentan in a homogeneous population of SSc subjects with an early or active SSc nailfold capillaroscopic pattern

The effect of bosentan on digital ulcers (DU) was studied in two randomized
placebo-controlled trials (RAPIDS-1 and RAPIDS-2). A limitation of these
studies was the heterogeneous study population. More importantly, there were no
endpoints that assessed changes in vasculopathy and / or perfusion. Laser
Doppler imaging has been shown to effectively demonstrate blood flow
restrictions in the hands of patients with systemic sclerosis (SSc) (Rosato et
al., 2010).

In the HOME study, which was carried out in 2011, the effect of bosentan in SSc
patients with a predefined restriction of blood flow in the hands was studied.
During this study, it was observed that there was no direct correlation between
a reduced blood flow and the extent of DU disease. Therefore, inclusion was not
directly correlated with severity of disease, resulting in a hereogeneous study
population.

Nailfold capillaroscopy (NFM) is a technique to visualize vasculopathy by
observing the capillaries in the nailfolds of the hands. Several studies have
recently shown a good correlation between NFM images and the risk for
development of DU (Smith et al., 2011; Sebastiani et al., 2011). NFM will
therefore be a good tool to include a homogeneous population of SSc patients.

HOME II will therefore assess the effect of bosentan on the blood flow in the
hands, in a defined cohort of SSc-DU patients with a history of DU within the
past 2 years, and a NFM early or active SSc pattern.

Primairy objective:
- Evaluate the effect of bosentan on the blood flow in the hands from baseline
to 12 weeks, measured by laser Doppler imaging, in SSc subjects with an early
or active SSc pattern, measured with nailfold capillaroscopy (NFM), with
ongoing digital ulcer disease and a history of DU disease in the past 2 years.

Secondary objectives:
- Evaluate the effect of bosentan on the blood flow of different regions (ROI
1, ROI 2 and ROI 3, see 7.6.2) in the hands from baseline to 12 weeks, 26 weeks
and 52 weeks;
- Evaluate the effect of bosentan on the hand function, pain perception and
quality of life from baseline to 12 weeks, 26 weeks and 52 weeks;
- Evaluate the effect of bosentan on the skin involvement measured with the
modified Rodnan skin score from baseline to 12 weeks, 26 weeks and 52 weeks;
- Evaluate the effect of bosentan on the development of new digital ulcers and
pitting scars from baseline to 12 weeks, 26 weeks and 52 weeks;
- Evaluate the effect of bosentan on DU risk score (measured by CSURI and PILD)
from baseline to 12 weeks, 26 weeks and 52 weeks;
- Evaluate the effect of bosentan on the blood flow in the hands, and in
different regions of the hands (ROI 1, ROI 2 and ROI 3), from baseline to 12
weeks, 26 weeks and 52 weeks in SSc-DU patients with no history of iloprost use;
- Evaluate the effect of bosentan on nailfold capillaries from baseline to 12
weeks, 26 weeks and 52 weeks, measured with NFM.

Open label, non comparative study.

Patients that will be included in the study will start bosentan treatment as
described in the summary of product characteristics. After 12 weeks of
treatment the investigator/treating physician decides, together with the
patient, if the bosentan treatment will be continued (for as long as needed).

The patients will visit the hospital 4 times (after 0, 12, 26 and 52 weeks) as
a result of participating in this study. During all visits, the NFM will be
performed, the blood flow in the hands will be measured by Laser Doppler
imaging and the patient is asked to complete two questionnaires (selected
components of the SHAQ and the EQ 5D). The investigator also completes a
questionnaire at each visit (modified Rodnan Skin Score).

Besides the known risks of treatment with bosentan there are no significant
risks to participation in this study and the burden is minimal, compared to the
advantage the patient might experience from treatment with bosentan.