Low dose iron chelation as TReatment of Oxidative stress in Sickle cell disease; TROS study

Chronic life-long intravascular hemolysis with the resulting excessive levels
of cell-free heme and iron is the major cause of increased production of
reactive oxygen species (ROS) in SCD resulting in oxidative stress. Oxidative
stress is a major pathophysiological factor in SCD playing a significant role
in the SCD-related microvascular dysfunction, vaso-occlusion, inflammation and
organ damage. If this oxidative stress could be reduced, outcomes of SCD
patients might be improved. In this study we want to investigate if we can
reduce oxidative stress by reducing one of the begin products resulting in
oxidative stress: fee iron. One of the main endpoints we want to investigate
is the point of sickling of red blood cells.

To study the safety and efficacy of deferasirox as treatment of oxidative
stress in adult subjects with sickle cell disease.

This will be an open-label pilot study, including 12 patients per dose group.
As the antioxidant capacity of deferasirox might be dose-dependent, we will
start with the highest dose of deferasirox (360 mg) deemed adequate for chronic
use without causing iron depletion in adult SCD patients. Depending on the
results (at least 3 of the 12 patients show a decrease of at least 25% in PoS
or one of the main secondary endpoints) we will continue, after a washout
period of at least 4 weeks, with another cohort of 12 patients in a dose of
deferasirox 180 mg. We will ask the responding patients of the first cohort to
participate again. Afresh, depending on the results, the study can continue
with the next group of 12 patients using 90 mg deferasirox per day. Again, the
responding patients might continue with the lower dose, after a washout period
of 4 weeks. The study will be closed if <3 patients show a response in at least
one of the endpoints.

If 4 or more patients show depletion of iron levels, we will directly continue
with a lower dose of deferasirox.

Once daily deferasirox in a maximum dose of 360 mg for 6 weeks. For
particapants with effect, there can be following periods of treatment for 6
weeks with a lower dose (180mg and 90mg).

We will only include adult patients who are able to make a clear decision about
participation in this study.

The risks of participation in this study are predicted to be very low.
Deferasirox is a drug that has been widely used for years with good safety
profile. The doses usually used are much higher 720 - 1430 mg daily than the
intended doses in this study (360 - 90 mg). We therefore do not expect to
encounter the previously described side effects such as diarrhoea, decreased
renal function, which are mostly dose-dependent. All potential side effects
will be closely monitored during study visits.

However, patients will have to take study medication once a day for a period of
6 weeks, beside their regular medication. Patients will have to visit the
outpatient clinic every two weeks which costs time. Travel expenses will be
covered. During these visits, questionaires will be taken, physical examination
will be performed and blood and urine samples will be collected.
-During each visit information about any positive or negative effect of study
medication will be discussed.
-The questionaires do not concern sensitive information and serve to inform
about pain and fatigue. The questionaires are shor, about 5-10 minutes every 2
weeks. Additionally, patients have to keep track of a pain score every day of
the study, this takes a few seconds per day.
-The physical examination is general and non-invasive and serves to recognize
side effects
-The amount of blood that is collected does not cause complaints in adults,
however the blood collection itself can give discomfort and a haematoma.

We are confident that the discomforts of this study do not outway the possible
effects and the knowledge that can be generated from this study.