Phase 2 Trial Targets Increased Hydroxyurea Dosages to Curb Strokes in Children with Sickle Cell Disease

Malika Ammam, PhD avatar

by Malika Ammam, PhD |

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A Phase 2 clinical trial, aiming to assess the effects of hydroxyurea-based therapy at the maximum tolerated dose to prevent stroke in children with sickle cell anemia (SCA), began recently, and the outcomes are expected to highly impact children worldwide, particularly those living in developing countries where the disease is most prevalent.

The study describing the clinical trial is titled “EXpanding Treatment for Existing Neurological Disease (EXTEND): An Open-Label Phase II Clinical Trial of Hydroxyurea Treatment in Sickle Cell Anemia,” and it was published in JMIR Research Protocols.

Sickle Cell Disease (SCD), a group of inherited blood disorders, is considered a major public health issue worldwide, particularly in developing countries. The most common SCD type is known as sickle-cell anemia (SCA) characterized by abnormal hemoglobin, the oxygen-carrying protein found in blood. One of the most devastating complications of SCA is stroke, with some studies suggesting an incidence of 7.8% by age 14 and 11% by age 20.

Some reports documented that transcranial doppler (TCD) and chronic transfusion therapy might be effective screening tools to identify the risk of primary stroke in pediatric patients with SCA, but this method is impractical in numerous developing countries.

Growing evidence suggests that hydroxyurea provides neuroprotection and prevents cerebrovascular disease in SCA children by reducing TCD velocities. However, the consequences of the use of hydroxyurea in newly diagnosed children with severe cerebrovascular disease, instead of starting transfusion therapy, are still not clear.

The EXpanding Treatment for Existing Neurological Disease (EXTEND) trial (NCT02556099), currently recruiting participants, is designed to assess the effectiveness of hydroxyurea on the maximum time-averaged mean velocity in children with SCA after a period of 18 months of therapy with respect to the pre-treatment value.

The study also aims to examine how hydroxyurea affects the serial TCD velocities, neurological and non-neurological incidence events, quality of life, metabolism and body composition, treatment response and toxicity, as well as changes in the brain, genetic and serological markers, and cognitive and pulmonary parameters.

This Phase II study will include SCA children from Jamaica of 2 to 17 years old with TCD velocities of either conditional (170-199 cm/sec) or abnormal (greater than 200 cm/sec). The participants will receive daily doses of oral hydroxyurea, which then will be increased to the maximum tolerated dose (MTD). Monthly checkups of the participants will be performed at the Sickle Cell Unit in Kingston, Jamaica until reaching MTD, which then will be extended to every 3 months. The participants also will receive TCD every 6 months for comparative purposes.

Of of the planned 50 participants, a 43 participants have been enrolled; 37 of those have started the treatment.

“The EXTEND trial results will potentially have a large impact on the management of children with SCA on a worldwide scale. The study represents international collaborative research involving developing countries, which is a stated goal of the National Heart, Lung and Blood Institute and the subject of academic advocacy,” the authors concluded.

“Beyond the specific study objectives, the development of such collaborations between resource-rich countries and the developing world has the potential to be of considerable benefit to the health and well-being of patients with SCA in those developing nations,” they added.