International Biometric Society
STATISTICAL ISSUES ARISING IN THE TRANSCRANIAL DOPPLER VELOCITY WITH TRANSFUSIONS
CHANGING TO HYDROXYUREA (TWITCH) TRIAL
Barry R. Davis, MD, PhD, Peng Wei, PhD, Sara Pressel, MS, Robert Adams, MD, PhD,
Russell Ware, MD, PhD
University of Texas School of Public Health, Houston, Texas, USA (BRD, PW, SP); Medical
University of South Carolina, Charleston, South Carolina, USA (RA), Cincinnati Children’s
Hospital Medical Center, Cincinnati, Ohio, USA (RW)
The Transcranial Doppler (TCD) Velocity With Transfusions Changing to Hydroxyurea
(TWiTCH) trial is a Phase III multicenter randomized controlled clinical trial. The primary goal
is to compare 24 months of hydroxyurea treatment to transfusion therapy in children with
sickle cell anemia and abnormally high (≥200 cm/sec) TCD velocities, who currently receive
chronic transfusions to reduce the risk of primary stroke. The primary hypothesis is that after
adjustment for baseline differences, the hydroxyurea treatment arm’s mean TCD velocity at
24 months will be less than the transfusion treatment arm’s plus 15cm/sec, in which case,
the hydroxyurea treatment arm would be considered non-inferior to the transfusion treatment
arm.
TWiTCH was designed to randomize 118 patients in a 1:1 fashion to provide 90% power to
test the non-inferiority hypothesis under reasonable scenarios. This sample size includes
adjustment for dropout and crossovers to ensure that at least 100 patients complete the 24month post-randomization follow-up period. TWiTCH successfully ended randomization in
August 2013 with 121 patients.
Several interesting clinical trials and statistical issues arose in the design and conduct of the
trial. This presentation will review some of these issues including (1) primary endpoint based
on a linear mixed model of longitudinal measurement of TCD velocities; (2) non-inferiority
design with an "acceptable" difference between TCD velocities; (3) interim monitoring; and
(4) statistical monitoring of TCDs. This TCD monitoring is used to detect, and appropriately
address, TWiTCH patients who develop a “TCD alert,” which occurs when a subject’s mean
TCD velocity, during the on-treatment period is too high, too low or has substantially changed
from baseline and requires some action (e.g., increased monitoring or change in therapy).
International Biometric Conference, Florence, ITALY, 6 – 11 July 2014