Hydroxyurea to prevent brain injury in children with sickle cell disease (HU Prevent)-A randomized, placebo-controlled phase II feasibility/pilot study

被引：4

作者：

Casella, James F. ^{[1
]}

Furstenau, Dana K. ^{[1
]}

Adams, Robert J. ^{[2
]}

Brambilla, Donald J. ^{[3
]}

Lebensburger, Jeffrey D. ^{[4
]}

Fehr, James J. ^{[5
]}

Jordan, Lori C. ^{[6
]}

King, Allison A. ^{[7
,8
]}

Ichord, Rebecca N. ^{[9
]}

McKinstry, Robert C. ^{[10
]}

Kraut, Michael A. ^{[11
]}

Shaw, Dennis W. ^{[12
]}

White, Desiree A. ^{[13
]}

Whyte-Stewart, Donna A. ^{[14
]}

Avadhani, Radhika ^{[15
]}

Barron-Casella, Emily A. ^{[1
]}

Cannon, Alicia D. ^{[16
]}

Eaton, Cyd K. ^{[17
]}

Riekert, Kristin A. ^{[18
]}

Shay, Joanne E. ^{[19
]}

Smith-Seidel, Cynthia A. ^{[20
]}

Weiss, Diane C. ^{[1
]}

Ostapkovich, Noeleen D. ^{[15
]}

Vermillion, Krista ^{[21
]}

Treine, Kevin E. ^{[15
]}

Kingsbury, Claire E. ^{[1
]}

Strouse, John J. ^{[22
]}

Thompson, Richard E. ^{[23
]}

Hanley, Daniel F. ^{[15
]}

机构：

[1] Johns Hopkins Univ, Dept Pediat, Div Hematol, Sch Med, 720 Rutland Ave,Ross Res Bldg 1125, Baltimore, MD 21205 USA

[2] Med Univ South Carolina, Dept Neurol, Charleston, SC USA

[3] Res Triangle Inst RTI Int, Rockville, MD USA

[4] Univ Alabama Birmingham, Dept Pediat, Div Pediat Hematol Oncol, Birmingham, AL USA

[5] Stanford Univ Sch Med, Dept Anesthesiol Perioperat & Pain Med, Stanford, CA USA

[6] Vanderbilt Univ, Dept Pediat, Div Pediat Neurol, Med Ctr, Nashville, TN USA

[7] Washington Univ, Div Pediat Hematol Oncol, St Louis, MO USA

[8] St Louis Childrens Hosp, St Louis, MO USA

[9] Univ Penn, Childrens Hosp Philadelphia, Perelman Sch Med, Dept Neurol & Pediat, Philadelphia, PA USA

[10] Washington Univ, Mallinckrodt Inst Radiol, Sch Med, St Louis, MO USA

[11] Johns Hopkins Univ, Dept Radiol & Radiol Sci, Sch Med, Baltimore, MD USA

[12] Seattle Childrens Hosp, Dept Radiol, Seattle, WA USA

[13] Washington Univ St Louis, Dept Psychol & Brain Sci, St Louis, MO USA

[14] Food & Drug Adm FDA, Div Nonmalignant Hematol, Silver Spring, MD USA

[15] Johns Hopkins Univ, BIOS Clin Trials Coordinating Ctr, Dept Neurol & Neurosurg, Sch Med, Baltimore, MD USA

[16] Kennedy Krieger Inst, Dept Neuropsychol, Baltimore, MD USA

[17] Johns Hopkins Bayview, Biostat Epidemiol & Data Management Core, Med Ctr, Baltimore, MD USA

[18] Johns Hopkins Univ, Dept Med, Div Pulm & Crit Care Med, Sch Med, Baltimore, MD USA

[19] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD USA

[20] Martinsburg Vet Affairs Med Ctr VAMC, Dept Psychol, Martinsburg, WV USA

[21] Vanderbilt Univ, Vanderbilt Inst Clin & Translat Res VICTR, Med Ctr, Nashville, TN USA

[22] Duke Univ, Dept Med & Pediat, Sch Med, Durham, NC USA

[23] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA

来源：

AMERICAN JOURNAL OF HEMATOLOGY | 2024年 / 99卷 / 10期

关键词：

YOUNG-CHILDREN; CONTROLLED-TRIAL; ANEMIA; TRANSFUSIONS; ASSOCIATION; MANAGEMENT; ANESTHESIA; EXPOSURE; AGE;

D O I：

10.1002/ajh.27423

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Central nervous system (CNS) injury is common in sickle cell disease (SCD) and occurs early in life. Hydroxyurea is safe and efficacious for treatment of SCD, but high-quality evidence from randomized trials to estimate its neuroprotective effect is scant. HU Prevent was a randomized (1:1), double-blind, phase II feasibility/pilot trial of dose-escalated hydroxyurea vs. placebo for the primary prevention of CNS injury in children with HbSS or HbS-beta(0)-thalassemia subtypes of SCD age 12-48 months with normal neurological examination, MRI of the brain, and cerebral blood flow velocity. We hypothesized that hydroxyurea would reduce by 50% the incidence of CNS injury. Two outcomes were compared: primary-a composite of silent cerebral infarction, elevated cerebral blood flow velocity, transient ischemic attack, or stroke; secondary-a weighted score estimating the risk of suffering the consequences of stroke (the Stroke Consequences Risk Score-SCRS), based on the same outcome events. Six participants were randomized to each group. One participant in the hydroxyurea group had a primary outcome vs. four in the placebo group (incidence rate ratio [90% CI] 0.216 [0.009, 1.66], p = .2914) (similar to 80% reduction in the hydroxyurea group). The mean SCRS score was 0.078 (SD 0.174) in the hydroxyurea group, 0.312 (SD 0.174) in the placebo group, p = .072, below the p-value of .10 often used to justify subsequent phase III investigations. Serious adverse events related to study procedures occurred in 3/41 MRIs performed, all related to sedation. These results suggest that hydroxyurea may have profound neuroprotective effect in children with SCD and support a definitive phase III study to encourage the early use of hydroxyurea in all infants with SCD.

引用

页码：1906 / 1916

页数：11

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