Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea

NCT01425307 | Terminated Phase 3 Results DMC

• 2 other identifiers: H-28572 TWiTCHR01HL095647
• Study Type: interventional
• Target: 159
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Sickle Cell Anemia

Keywords

Phase III; Sickle cell anemia; Abnormally high Transcranial Doppler velocities.; Reduce risk of primary stroke; Pediatric patients; Chelation therapy

Outcome Measures

Primary Outcomes (1)

• Difference in TCD Time-averaged Mean Velocity (TAMV) on the Index Side

  The primary endpoint for the TWiTCH trial was the difference between the treatment groups of the maximum TCD TAMV on the index side, calculated from a mixed model. 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 TAMV on the index site were obtained at clinic visits during baseline and during the treatment period.

  Since the study was terminated early, time frame is from beginning of treatment until end of treatment (up to 24 Months).

Secondary Outcomes (14)

• TCD Time-averaged Mean Velocity on the Non-index Side

  24 months

• Primary Stroke Events

  24 months

• Non-stroke Neurological Events

  24 months

• Change of Baseline in Hepatic Iron Overload as Assessed by Serum Ferritin

  Baseline and 24 months

• Effects on Quality of Life

  24 months

Study Arms (2)

Standard Therapy

NO INTERVENTION

Standard Therapy of monthly transfusions

Treatment Arm

EXPERIMENTAL

Hydroxyurea will be provided as capsules or liquid

Drug: Hydroxyurea

Interventions

Hydroxyurea DRUG

Capsules (300 mg, 400 mg, or 500 mg) taken once daily liquid formulation (100 mg/mL)

Also known as: Hydroxycarbamide, Hydrea, Droxia

Treatment Arm

Eligibility Criteria

• Age: 4 Years - 15 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Pediatric subjects with severe forms of sickle cell anemia (HbSS, HbSβ0 thalassemia,HbSOArab)
• Age range of 4.0-15.99 years, inclusive, at the time of enrollment
• 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.
• At least 12 months of chronic monthly erythrocyte transfusions since the index abnormal TCD examination
• 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
• Parent or guardian willing and able to provide informed consent with verbal or written assent from the child
• Ability to comply with study related treatments, evaluations, and follow-up

You may not qualify if:

• Completed overt clinical stroke or TIA
• Inability to obtain TCD velocities due to anatomical abnormalities such as a) Inadequate bone windows b) Previous revascularization procedures (e.g., EDAS)
• Known severe vasculopathy or moya-moya disease on brain MRA
• 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
• Current participation in other therapeutic clinical trials
• 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.
• Any condition or chronic illness, such as a positive tuberculin (PPD) test, which in the opinion of the CI makes participation ill-advised.
• Inability or unwillingness to complete required screening and exit studies, including TCD ultrasonography, brain MRI/MRA, liver MRI and blood tests.
• A sibling enrolled in TWiTCH
• Pregnancy or unwillingness to use a medically acceptable form of contraception if sexually active (male OR female).

Sponsors & Collaborators

• Children's Hospital Medical Center, Cincinnati: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Boston Children's Hospital: collaborator
• University of Texas Southwestern Medical Center: collaborator
• Children's Healthcare of Atlanta: collaborator
• Children's Hospital of Philadelphia: collaborator
• The Hospital for Sick Children: collaborator
• Children's National Research Institute: collaborator
• Columbia University: collaborator
• St. Jude Children's Research Hospital: collaborator
• University Hospitals Cleveland Medical Center: collaborator
• University of South Alabama: collaborator
• Medical University of South Carolina: collaborator
• University of Alabama at Birmingham: collaborator
• University of Miami: collaborator
• University of Mississippi Medical Center: collaborator
• Wayne State University: collaborator
• Children's Hospital of The King's Daughters: collaborator
• Nemours Children's Clinic: collaborator
• Duke University: collaborator
• East Carolina University: collaborator
• Children's Hospitals and Clinics of Minnesota: collaborator
• Ann & Robert H Lurie Children's Hospital of Chicago: collaborator
• Baylor College of Medicine: collaborator
• State University of New York - Downstate Medical Center: collaborator
• Steven and Alexandra Cohen Children's Medical Center: collaborator

Related Publications (1)

• 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.

  PMID: 26670617 DERIVED

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

Hydroxyurea

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Urea; Amides; Organic Chemicals

Limitations and Caveats

Further analysis is required to verify that the Adverse Events are accurately represented.

Results Point of Contact

• Title: Barry Robert Davis
• Organization: The University of Texas School of Public Health

barry.r.davis@uth.tmc.edu

713-500-9515

Study Officials

• Russell E. Ware, MD, PhD

  Children's Hospital Medical Center, Cincinnati

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 19, 2011
• First Posted: August 30, 2011
• Study Start: August 1, 2011
• Primary Completion: March 1, 2015
• Study Completion: November 1, 2015
• Last Updated: July 22, 2020
• Results First Posted: April 11, 2017

Record last verified: 2017-05

Data Sharing

• IPD Sharing: Will not share