Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Children's Hospital Boston
University of Texas Southwestern Medical Center
Children's Healthcare of Atlanta
Children's Hospital of Philadelphia
The Hospital for Sick Children
Children's Research Institute
Columbia University
St. Jude Children's Research Hospital
Rainbow Babies Hospital
University of South Alabama
Medical University of South Carolina
Cohen Children's Medical Center
University of Alabama at Birmingham
University of Miami
University of Mississippi Medical Center
Wayne State University
Children's Hospital of The King's Daughters
Nemours Children's Clinic
Duke University
East Carolina University
Children's Hospitals and Clinics of Minnesota
Ann & Robert H Lurie Children's Hospital of Chicago
Texas Children's Hospital
State University of New York - Downstate Medical Center
Information provided by (Responsible Party):
Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier:
NCT01425307
First received: August 19, 2011
Last updated: January 27, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention Phase
Sickle Cell Anemia
Drug: Hydroxyurea
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: TCD With Transfusions Changing to Hydroxyurea (TWiTCH): A Phase III Randomized Clinical 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

Resource links provided by NLM:


Further study details as provided by Children's Hospital Medical Center, Cincinnati:

Primary Outcome Measures:
  • TCD Mean Velocity at 24 months on the index side [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]
    The primary endpoint for the TWiTCH trial will be maximum TCD time-averaged mean velocity on the index side. The index side is the side with the higher mean (averaged over baseline evaluations) of the maximum (over arteries on that side) TCD time-averaged velocity. Values of the primary endpoint will be obtained at clinic visits during baseline and during the 24-month treatment period. An abnormally high TCD is defined as TCD V≥200 cm/sec, or abnormally high TCDi V ≥ 185cm/sec, or TCD maximum V ≥ 250 cm/sec.


Secondary Outcome Measures:
  • TCD time-averaged mean velocity on the non-index side [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]
    This secondary endpoint for the TWiTCH trial will be maximum TCD time-averaged mean velocity on the non-index side. The non-index side is the side with the lower mean (averaged over baseline evaluations) of the maximum (over arteries on that side) TCD time-averaged velocity. Values of the secondary endpoint will be obtained at clinic visits during baseline and during the 24-month treatment period.

  • Primary stroke events [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]
    This secondary outcome measure will compare standard to alternative therapy for primary stroke events (a) primary ischemic stroke; b) primary hemorrhagic stroke

  • Non-stroke neurological events [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]
    This secondary objective will compare standard to alternative treatment for the incidence of non-stroke neurological events. Data for this outcome will be collected through entry and exit neurological exams.

  • Hepatic iron overload [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]
    This secondary objective will compare standard to alternative therapy for heaptic iron overload.

  • Effects on Quality of Life [ Time Frame: 30 months ] [ Designated as safety issue: No ]
    Standard Quality of Life measure will be taken during specific time points as well as one newly developed Sickle Cell Disease-specific test.

  • Functional status [ Time Frame: 30 months ] [ Designated as safety issue: No ]
    This outcome will be measured using Barthel Index testing at the beginning, middle, and end of the treatment period.

  • Neuropsychological decline [ Time Frame: 30 months ] [ Designated as safety issue: No ]
    This outcome will be measured using standardized neurocognitive tests at baseline and exit.

  • Growth and development [ Time Frame: 30 months ] [ Designated as safety issue: No ]
    This outcome will be measured by capturing height and weight monthly and conducting an annual pubertal assessment.

  • Transfusion events [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]
    This outcome will be recorded on every interval visit form through questions asking whether there have been transfusion complications. Any complication higher than a CTCAE grade 2 event will be reported as a SAE.

  • Hydroxyurea toxicities [ Time Frame: 30 Months ] [ Designated as safety issue: Yes ]
    This measure will be performed on a monthly basis throughout the trial by recording the CBC and retic count.

  • Phlebotomy complications [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]
    This outcome will be recorded on every interval visit form through questions asking whether there have been phlebotomy complications. Any complication higher than a CTCAE grade 2 event will be reported as a SAE.

  • Liver MRI complications [ Time Frame: 30 months ] [ Designated as safety issue: Yes ]
    This outcome will be recorded through questions asking whether there have been Liver MRI complications at baseline, middle, and end of treatment. Any complication higher than a CTCAE grade 2 event will be reported as a SAE.

  • Safety endpoints of adverse events and clinical laboratory values [ Time Frame: 30 Months ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 148
Study Start Date: August 2011
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
No Intervention: Standard Therapy
Standard Therapy of monthly transfusions
Experimental: Treatment Arm
Hydroxyurea will be provided as capsules or liquid
Drug: Hydroxyurea
Capsules (300 mg, 400 mg, or 500 mg) taken once daily liquid formulation (100 mg/mL)
Other Names:
  • Hydroxycarbamide
  • Hydrea
  • Droxia

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

Ages Eligible for Study:   4 Years to 15 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01425307

Locations
United States, Texas
Baylor College of Medicine
Houston, Texas, United States, 77030
Sponsors and Collaborators
Children's Hospital Medical Center, Cincinnati
Children's Hospital Boston
University of Texas Southwestern Medical Center
Children's Healthcare of Atlanta
Children's Hospital of Philadelphia
The Hospital for Sick Children
Children's Research Institute
Columbia University
St. Jude Children's Research Hospital
Rainbow Babies Hospital
University of South Alabama
Medical University of South Carolina
Cohen Children's Medical Center
University of Alabama at Birmingham
University of Miami
University of Mississippi Medical Center
Wayne State University
Children's Hospital of The King's Daughters
Nemours Children's Clinic
Duke University
East Carolina University
Children's Hospitals and Clinics of Minnesota
Ann & Robert H Lurie Children's Hospital of Chicago
Texas Children's Hospital
State University of New York - Downstate Medical Center
Investigators
Principal Investigator: Russell E. Ware, MD, PhD Children's Hospital Medical Center, Cincinnati
  More Information

No publications provided

Responsible Party: Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier: NCT01425307     History of Changes
Other Study ID Numbers: H-28572 TWiTCH, R01HL095647
Study First Received: August 19, 2011
Last Updated: January 27, 2014
Health Authority: United States: Food and Drug Administration
United States: Federal Government

Keywords provided by Children's Hospital Medical Center, Cincinnati:
Phase III
Sickle cell anemia
Abnormally high Transcranial Doppler velocities.
Reduce risk of primary stroke
Pediatric patients
Chelation therapy

Additional relevant MeSH terms:
Anemia
Anemia, Sickle Cell
Hematologic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hemoglobinopathies
Genetic Diseases, Inborn
Hydroxyurea
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antisickling Agents
Hematologic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors

ClinicalTrials.gov processed this record on October 01, 2014