SPECIAL EMPHASIS PANEL - CONCEPT DEVELOPMENT
PEDIATRIC HYDROXYUREA PHASE III CLINICAL TRIAL
APRIL 12, 1996, BETHESDA, MARYLAND


A Special Emphasis Panel (SEP) sponsored by the Sickle Cell Disease 
Scientific Research Group of the Division of Blood Diseases and 
Resources, National Heart, Lung, and Blood Institute (NHLBI), National 
Institutes of Health met at the Rockledge II Building in Bethesda, 
Maryland, on April 12, 1996. The purpose of the meeting was: 
(1) to discuss the status of the Multicenter Study of Hydroxyurea 
in Sickle Cell Anemia (MSH) Clinical Trial; (2) to discuss the status 
of the current phase II Pediatric Hydroxyurea Safety and Dosing Study 
(PED HUG); and (3) to make recommendations to the NHLBI as to what 
clinical trial should come next in children with sickle cell anemia (Hb SS). 

The MSH Trial was a prospective, randomized, double blind, placebo 
controlled trial designed to test the hypothesis that hydroxyurea is 
effective in decreasing the rate of painful episodes in individuals 
with Hb SS over the age of 18. In January, 1995, the MSH Trial was 
ended 4 months early when interim analyses demonstrated that 
hydroxyurea was effective in decreasing the rates of painful episodes, 
acute chest syndrome, hospitalizations, and transfusions by approximately 
50%. The data based on the interim analyses were published in the New 
England Journal of Medicine, 332:1317-1322, 1995 by Charache, et al.
The PED HUG study is an open label safety and dosing study of hydroxyurea
in severely affected children with sickle cell anemia between the ages 
of 5 and 15 who experienced 3 or more painful episodes in the year prior 
to enrollment. This study began recruitment in January, 1995. The SEP 
reviewed progress in the PED HUG study, which is scheduled to end in 
early 1997. This study will collect clinical outcome data and hydroxyurea
pharmacokinetic data on approximately 50 children enrolled at four NHLBI 
sponsored Comprehensive Sickle Cell Centers around the United States.

Until the MSH Trial, hydroxyurea had been used primarily as a 
chemotherapeutic agent to treat myeloproliferative disorders such as 
polycythemia vera. Since hydroxyurea acts upon rapidly growing cells, 
there is some concern about the long term risks of its use in children. 
In addition, although rare, cancers and leukemias have been reported 
in sickle cell anemia children and adults. The SEP members discussed the 
leukemogenic potential of hydroxyurea. In the Polycythemia Study Group, 
non-randomized subjects who have received hydroxyurea have a higher rate 
of leukemia that is not statistically significant when compared to
historical controls treated by phlebotomy. The SEP members agreed that a 
risk-benefit analysis must be obtained in carefully controlled pediatric 
hydroxyurea studies before wide spread use of this agent in severely 
affected sickle cell anemia children can be widely recommended.

The SEP members reviewed the Food and Drug Administration (FDA) revised 
rules for Pediatric Use drug labelling issued on December 13, 1994. 
Under these revised rules, once a drug has been found to be efficacious 
in adults, extending approval to children is considerably simplified. 
A New Drug Application (NDA) for subsequent pediatric use requires only 
additional pharmacokinetic data in children if the disease process in 
children is not pathogenetically different from that seen in adults. The 
SEP members agreed that once hydroxyurea is approved for the indication 
of decreasing painful episodes in severely affected adult sickle cell 
anemia patients, the PED HUG data could be used to apply for on label 
use of hydroxyurea for the indication of decreasing painful episodes, 
acute chest syndrome, hospitalizations, and transfusions in children. 

The SEP members then considered what unanswered questions remain to be 
explored concerning hydroxyurea use in children with sickle cell anemia, 
and whether these questions are best answered in the setting of a 
double blind, placebo controlled randomized clinical trial. The SEP 
members made the following recommendations to the NHLBI.

1. If the PED HUG Trial demonstrates that hydroxyurea is safe and
potentially effective in decreasing the rate of painful episodes in 
severely affected children with sickle cell anemia, a randomized, 
double blind placebo controlled trial with painful episodes as the 
primary endpoint should not be done because the pathophysiology of 
painful episodes is not different in children and adults.

2. A randomized, double blind placebo controlled trial of hydroxyurea 
in young children with Hb SS to test for the prevention of chronic end 
organ damage is the next logical step to be undertaken when the PED HUG 
is completed. The trial should be designed to demonstrate the efficacy 
of hydroxyurea in preventing the onset of chronic end organ damage in 
children. The panel recommended that such a study be undertaken in Hb SS
children who are recruited at one year of age. The children should be 
evaluated for changes in brain function, pulmonary function, renal 
function, splenic function, growth and developmental milestones, and 
quality of life.

3. The SEP members discussed the possibility of comparing hydroxyurea 
to another established treatment. The NHLBI is currently supporting the 
Stroke Prevention Trial in Sickle Cell Anemia (STOP), which is testing 
the efficacy of chronic transfusions to prevent first time stroke in 
children with Hb SS who are found to be at increased risk based upon 
abnormal transcranial doppler studies. The SEP discussed a comparison of
hydroxyurea to chronic transfusion therapy. However, since the efficacy 
of chronic transfusion therapy in pediatric stroke prevention will not 
be known until STOP is completed in 1999, the NHLBI will not support a 
comparison of hydroxyurea to transfusions until that time.

Participants:
     Frances Gill, M.D. (chair), Philadelphia, PA
     Gary Cutter, Ph.D., Denver, CO
     Cage Johnson, M.D., Los Angeles, CA
     Susan Shurin, M.D., Cleveland, OH
     Naomi Luban, M.D., Washington, D.C.
     Oswaldo Castro, M.D., Washington, D.C.
     Griffin Rodgers, M.D., Bethesda, MD
     Myron Waclawiw, Ph.D., Bethesda, MD
     Duane R. Bonds, M.D., Bethesda, MD

May 1996