EXpanding Treatment for Existing Neurological Disease (EXTEND): An Open-Label Phase II Clinical Trial of Hydroxyurea Treatment in Sickle Cell Anemia.
BACKGROUND
Cerebral vasculopathy in sickle cell anemia (SCA) begins in childhood and features intracranial arterial stenosis with high risk of ischemic stroke. Stroke risk can be reduced by transcranial doppler (TCD) screening and chronic transfusion therapy; however, this approach is impractical in many developing countries. Accumulating evidence supports the use of hydroxyurea for the prevention and treatment of cerebrovascular disease in children with SCA. Recently we reported that hydroxyurea significantly reduced the conversion from conditional TCD velocities to abnormal velocities; whether hydroxyurea can be used for children with newly diagnosed severe cerebrovascular disease in place of starting transfusion therapy remains unknown.


OBJECTIVE
The primary objective of the EXpanding Treatment for Existing Neurological Disease (EXTEND) trial is to investigate the effect of open label hydroxyurea on the maximum time-averaged mean velocity (TAMV) after 18 months of treatment compared to the pre-treatment value. Secondary objectives include the effects of hydroxyurea on serial TCD velocities, the incidence of neurological and non-neurological events, quality of life (QOL), body composition and metabolism, toxicity and treatment response, changes to brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), genetic and serologic markers of disease severity, and cognitive and pulmonary function.


METHODS
This prospective Phase II trial will enroll children with SCA in Jamaica, between the ages of 2 and 17 years, with either conditional (170-199 cm/sec) or abnormal (≥ 200 cm/sec) TCD velocities. Oral hydroxyurea will be administered daily and escalated to the maximum tolerated dose (MTD). Participants will be seen in the Sickle Cell Unit (SCU) in Kingston, Jamaica monthly until achieving MTD, and then every 3 months. TCD will be performed every 6 months.


RESULTS
Currently, 43 participants have been enrolled out of a projected 50. There was one withdrawal due to immigration, with no permanent screen failures. Of the 43 enrolled, 37 participants have initiated study treatment.


CONCLUSIONS
This trial investigates the effects of hydroxyurea treatment at MTD in children with conditional or abnormal TCD velocities before transfusion therapy and may represent an important advance towards establishing a suitable non-transfusion protocol for stroke prevention in children with SCA. The trial outcomes will have profound significance in developing countries where the disease burden is highest.


BACKGROUND
ClinicalTrials.gov NCT02556099; https://clinicaltrials.gov/ct2/show/NCT02556099 (Archived by WebCite at http://www.webcitation.org/6k1yMAa9G).
Sickle Cell Unit, Tropical Medicine Research Institute, University of the West Indies, Kingston, Jamaica. angela.rankinemullings@uwimona.edu.jm.
Angela E
http://orcid.org/0000-0002-3535-0911
AE
Rankine-Mullings
Courtney R
http://orcid.org/0000-0002-7058-211X
CR
Little
Marvin E
http://orcid.org/0000-0003-4005-9384
ME
Reid
Deanne P
http://orcid.org/0000-0002-0428-1829
DP
Soares
Carolyn
http://orcid.org/0000-0002-5199-9235
C
Taylor-Bryan
Jennifer M
http://orcid.org/0000-0002-0939-1648
JM
Knight-Madden
Susan E
http://orcid.org/0000-0002-0043-5333
SE
Stuber
Asha V
http://orcid.org/0000-0001-9555-3967
AV
Badaloo
Karen
http://orcid.org/0000-0002-9046-4444
K
Aldred
Margaret E
http://orcid.org/0000-0001-7985-5850
ME
Wisdom-Phipps
Teresa
http://orcid.org/0000-0002-4473-5821
T
Latham
Russell E
http://orcid.org/0000-0001-9582-0594
RE
Ware
Doppler; anemia; child; sickle cell; stroke; transcranial; ultrasonography