The effect of GBT440 on cerebral perfusion and oxygenation (GBT440-MRI side study)

Our laboratory has demonstrated that CBF is increased to maintain oxygen
delivery in patients with anemia2,3. However, this compensatory cerebral
vasodilation may not be without costs. Blood vessels have limited capacity to
dilate4. The proportion that CBF can be increased under metabolic stress,
relative to the baseline flow, is known as the cerebrovascular reserve (CVR).
CVR is typically 40%-70% in healthy control subjects, but is much lower in
subjects with anemia because of their already increased resting brain blood
flow4. A decreased CVR does not directly cause damage, but it leaves the brain
vulnerable to ischemic insults because the brain*s oxygen reserve capacities (a
combination of increased flow and extraction) can no longer compensate for
decreased oxygen delivery or increased metabolic demand. This two-hit
hypothesis is supported by studies linking acute anemic events to strokes in
sickle cell patients5. Nighttime desaturations, which are relatively minor but
repetitive, cause strokes over years6,7.
GBT440 is a new compound that stabilizes hemoglobin in its oxy-form thereby
correcting the oxygen affinity to normal values. In a phase 1 and 2 studies it
has been demonstrated that GBT440 is safe and is able to reduce the hemolytic
rate in patients with SCD resulting in a significant rise in hemoglobin
concentration. In addition, GBT440 has demonstrated to reduce the number of
circulating sickled red cells and plasma levels of specific markers of vascular
distress such as ICAM and sP-selectin.

1. To assess the effect of increased hematocrit on cerebral perfusion as
depicted by CBF and CVR.
2. To determine the effect of GBT440 on oxygen saturation of the cerebral
vasculature and the oxygen local consumption.
3. Determine the dose response relation of GBT440 on the above parameters.
4. To determine the effect on shear stress of GBT440.

In current studies, we have built up ample experience with all mentioned MRI
techniques and we consider ourselves as one of the few labs in the world that
can perform these technically demanding measurements non-invasively using MRI.
Patients will be analyzed by MRI after inclusion in the HOPE trial before the
start of the study medication and 3 months after initiation of study
medication. Since patients will be randomized between high dose GBT440, low
dose GBT440 and placebo, three groups will be analyzed with respect to the
effect of GBT440 on cerebral perfusion.
The following measurements of the cerebral perfusion will be performed by MRI:
1. CBF will be measured by PCASL in SCD.
2. CVR will be assess by the administration of acetazolamide which is a
carbonic anhydrase inhibitor that produces a powerful cerebral vasodilatory
effect comparable to 5% inhaled CO2.8,9
3. Cerebral oxygen utilization is measured by MRI technique by T2 relaxation
under spin tagging (TRUST).

MRI is harmless, the ACZ injection has been declared safe and venapunction is
routine in patients wtih SCD.

Parameters obtained by blood drawn in this study will be used clinically as
well. Presumably, participation is associated with minimal burden and risks. As
cranial MRI is not routinely performed in adults with SCD, coincidental
findings are potentially beneficial. The studied population represents the
group of patients with the highest disease severity, and is therefore
representable.