Clinical trial NCT01425307: Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea
Official title: TCD With Transfusions Changing to Hydroxyurea (TWiTCH): A Phase III Randomized Trial to Compare Standard Therapy (Erythrocyte Transfusions) With Alternative Therapy (Hydroxyurea) for the Maintenance of Lowered TCD Velocities in Pediatric Subjects With Sickle Cell Anemia and Abnormal Pre-treatment TCD Velocities
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Sickle Cell Anemia
Keywords: Phase III
Sickle cell anemia
Abnormally high Transcranial Doppler velocities.
Reduce risk of primary stroke
Pediatric patients
Chelation therapy
Lead sponsor: Children's Hospital Medical Center, Cincinnati
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Boston Children's Hospital
name: University of Texas Southwestern Medical Center
name: Children's Healthcare of Atlanta
name: Children's Hospital of Philadelphia
name: The Hospital for Sick Children
name: Children's National Research Institute
name: Columbia University
name: St. Jude Children's Research Hospital
name: University Hospitals Cleveland Medical Center
name: University of South Alabama
name: Medical University of South Carolina
name: University of Alabama at Birmingham
name: University of Miami
name: University of Mississippi Medical Center
name: Wayne State University
name: Children's Hospital of The King's Daughters
name: Nemours Children's Clinic
name: Duke University
name: East Carolina University
name: Children's Hospitals and Clinics of Minnesota
name: Ann & Robert H Lurie Children's Hospital of Chicago
name: Baylor College of Medicine
name: State University of New York - Downstate Medical Center
name: Steven and Alexandra Cohen Children's Medical Center
First posted: 2011-08-30
Enrollment: 159
Sex: ALL
Minimum age (years): 4
Maximum age (years): 15
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The primary goal of the Phase III TWiTCH trial is to compare 24 months of alternative therapy (hydroxyurea) to standard therapy (transfusions) for pediatric subjects with sickle cell anemia and abnormally high (≥200 cm/sec) Transcranial Doppler (TCD) velocities, who currently receive chronic transfusions to reduce the risk of primary stroke. For the alternative treatment regimen (hydroxyurea) to be declared non-inferior to the standard treatment regimen (transfusions), after adjusting for baseline differences, the hydroxyurea-treated group must have a mean TCD velocity similar to that observed with transfusion prophylaxis.

Detailed description: Despite the clear results of the STOP and the follow-up STOP II trials, the use of chronic erythrocyte transfusions for primary stroke prevention in children with Sickle Cell Anemia (SCA) remains controversial for many practicing hematologists, as well as for patients and families. Transfusions have proven clinical efficacy in preventing first stroke in children with SCA and abnormal TCD velocities, but their indefinite use may still be difficult to justifY.

The risk of transfusion acquired iron overload is now recognized as a serious consequence of chronic erythrocyte transfusions in children with SCA. After one to two years of monthly transfusions, virtually every patient will have excess hepatic iron deposition that warrants intervention with chelation therapy. The effectiveness of iron chelation has not yet been realized, despite the availability of the oral chelator deferasirox (Exjade®), due to its lack of palatability and increasing recognition of serious drug-related toxicities including renal and hepatic dysfunction. Simply put, indefinite erythrocyte transfusions cannot be viewed as adequate and acceptable long-term therapy for primary stroke prevention in SCA. There is an urgent need to develop an equivalent effective alternative therapy for the prevention of primary stroke in children with SCA, specifically one that better manages iron overload and improves quality of life.

Eligibility criteria: Inclusion Criteria:

1. Pediatric subjects with severe forms of sickle cell anemia (HbSS, HbSβ0 thalassemia,HbSOArab)
2. Age range of 4.0-15.99 years, inclusive, at the time of enrollment
3. Documented index (pre-treatment) abnormally high TCD Velocity by Transcranial Doppler ultrasonography. An abnormally high index TCD is defined as TCD V greater than or equal to 200 cm/sec, or abnormally high TCDi V greater than or equal to185cm/sec, or TCD maximum V greater than or equal to 250 cm/sec.
4. At least 12 months of chronic monthly erythrocyte transfusions since the index abnormal TCD examination
5. Adequate monthly erythrocyte transfusions with average HbS less than or equal to 45% (the upper limit of the established academic community standard) for the past 6 months before enrollment
6. Parent or guardian willing and able to provide informed consent with verbal or written assent from the child
7. Ability to comply with study related treatments, evaluations, and follow-up

Exclusion Criteria:

1. Completed overt clinical stroke or TIA
2. Inability to obtain TCD velocities due to anatomical abnormalities such as a) Inadequate bone windows b) Previous revascularization procedures (e.g., EDAS)
3. Known severe vasculopathy or moya-moya disease on brain MRA
4. Inability to receive or tolerate chronic red blood cell (RBC) transfusion therapy, due to any of the following: a) Multiple RBC alloantibodies making cross-matching difficult or impossible b) RBC autoantibodies making cross-matching difficult or impossible c) Religious objection to transfusions that preclude their chronic use d) Non-compliance with transfusions over the past 6 months before enrollment (temporary exclusion)
5. Inability to take or tolerate daily oral hydroxyurea, including a) Known allergy to hydroxyurea therapy b) Positive serology to HIV infection c) Malignancy d) Current lactation e) Previous stem cell transplant or other myelosuppressive therapy
6. Clinical and laboratory evidence of hypersplenism (temporary exclusions): a) Palpable splenomegaly greater than 5cm below the left costal margin AND b) Transfusion requirement greater than 250 mL/kg over the previous 12 months
7. Abnormal laboratory values at initial evaluation (temporary exclusions): a) Pre-transfusion hemoglobin concentration less than 8.0 gm/dL b) WBC count less than 3.0 x 10\^9/L c) Absolute neutrophil count (ANC) less than 1.5 x 10\^9/L d) Platelet count less than 100 x 10\^9/L e) Serum creatinine more than twice the upper limit for age OR greater than or equal to 1.0 mg/dL
8. Current participation in other therapeutic clinical trials
9. Current use of other therapeutic agents for sickle cell disease (e.g., arginine, decitabine, magnesium). Subjects must have been off hydroxyurea for at least 3- months prior to enrollment.
10. Any condition or chronic illness, such as a positive tuberculin (PPD) test, which in the opinion of the CI makes participation ill-advised.
11. Inability or unwillingness to complete required screening and exit studies, including TCD ultrasonography, brain MRI/MRA, liver MRI and blood tests.
12. A sibling enrolled in TWiTCH
13. Pregnancy or unwillingness to use a medically acceptable form of contraception if sexually active (male OR female).

Primary outcomes:
measure: Difference in TCD Time-averaged Mean Velocity (TAMV) on the Index Side
timeFrame: Since the study was terminated early, time frame is from beginning of treatment until end of treatment (up to 24 Months).
Secondary outcomes:
measure: TCD Time-averaged Mean Velocity on the Non-index Side
timeFrame: 24 months
measure: Primary Stroke Events
timeFrame: 24 months
measure: Non-stroke Neurological Events
timeFrame: 24 months
measure: Change of Baseline in Hepatic Iron Overload as Assessed by Serum Ferritin
timeFrame: Baseline and 24 months
measure: Effects on Quality of Life
timeFrame: 24 months
measure: Functional Status
timeFrame: 24 months
measure: Neuropsychological Decline
timeFrame: 24 months
measure: Growth and Development
timeFrame: 24 months
measure: Number of Participants With Transfusion Events
timeFrame: 24 months
measure: Number of Participants With Hydroxyurea Toxicities
timeFrame: 24 Months
measure: Number of Participants With Phlebotomy Complications
timeFrame: 24 months
measure: Number of Participants With Liver MRI Complications
timeFrame: 24 months
measure: Number of Participants With Serious Adverse Events
timeFrame: 24 Months
measure: Change of Baseline in Hepatic Iron Overload as Assessed by Liver Iron Concentration
timeFrame: Baseline and 24 months
Other outcomes:
Locations:
Study officials:
affiliation: Children's Hospital Medical Center, Cincinnati
name: Russell E. Ware, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ware RE, Davis BR, Schultz WH, Brown RC, Aygun B, Sarnaik S, Odame I, Fuh B, George A, Owen W, Luchtman-Jones L, Rogers ZR, Hilliard L, Gauger C, Piccone C, Lee MT, Kwiatkowski JL, Jackson S, Miller ST, Roberts C, Heeney MM, Kalfa TA, Nelson S, Imran H, Nottage K, Alvarez O, Rhodes M, Thompson AA, Rothman JA, Helton KJ, Roberts D, Coleman J, Bonner MJ, Kutlar A, Patel N, Wood J, Piller L, Wei P, Luden J, Mortier NA, Stuber SE, Luban NLC, Cohen AR, Pressel S, Adams RJ. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet. 2016 Feb 13;387(10019):661-670. doi: 10.1016/S0140-6736(15)01041-7. Epub 2015 Dec 6.