Sickle Cell Anemia
Conditions
Keywords
Phase III, Sickle cell anemia, Abnormally high Transcranial Doppler velocities., Reduce risk of primary stroke, Pediatric patients, Chelation therapy
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.
Interventions
DRUGHydroxyurea
Capsules (300 mg, 400 mg, or 500 mg) taken once daily liquid formulation (100 mg/mL)
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Boston Children's Hospital
University of Texas Southwestern Medical Center
Children's Healthcare of Atlanta
Children's Hospital of Philadelphia
The Hospital for Sick Children
Children's National Research Institute
Columbia University
St. Jude Children's Research Hospital
University Hospitals Cleveland Medical Center
University of South Alabama
Medical University of South Carolina
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
Baylor College of Medicine
State University of New York - Downstate Medical Center
Steven and Alexandra Cohen Children's Medical Center
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to 15 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in TCD Time-averaged Mean Velocity (TAMV) on the Index Side | Since the study was terminated early, time frame is from beginning of treatment until end of treatment (up to 24 Months). | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effects on Quality of Life | 24 months | 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 | 24 months | This outcome will be measured using Barthel Index testing at the beginning, middle, and end of the treatment period. |
| Primary Stroke Events | 24 months | 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 | 24 months | 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. |
| TCD Time-averaged Mean Velocity on the Non-index Side | 24 months | 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. |
| Neuropsychological Decline | 24 months | This outcome will be measured using standardized neurocognitive tests at baseline and exit. |
| Change of Baseline in Hepatic Iron Overload as Assessed by Serum Ferritin | Baseline and 24 months | This secondary objective will compare standard to alternative therapy for hepatic iron overload. |
| Number of Participants With Transfusion Events | 24 months | 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. |
| Number of Participants With Hydroxyurea Toxicities | 24 Months | This measure will be performed on a monthly basis throughout the trial by recording the CBC and retic count. |
| Number of Participants With Phlebotomy Complications | 24 months | 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. |
| Number of Participants With Liver MRI Complications | 24 months | 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. |
| Number of Participants With Serious Adverse Events | 24 Months | — |
| Change of Baseline in Hepatic Iron Overload as Assessed by Liver Iron Concentration | Baseline and 24 months | This secondary objective will compare standard to alternative therapy for hepatic iron overload. |
| Growth and Development | 24 months | This outcome will be measured by capturing height and weight monthly and conducting an annual pubertal assessment. |
Participant flow
Recruitment details
Phase 3 First Patient In: 16-Sep-2011; Last Patient Last Visit 10-Feb-2015 26 medical institutions in the United States of America and Canada
Pre-assignment details
159 were enrolled. 121 met eligibility criteria and randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Standard Therapy Standard Therapy of monthly transfusions | 61 |
| Treatment Arm Hydroxyurea will be provided as capsules or liquid
Hydroxyurea: Capsules (300 mg, 400 mg, or 500 mg) taken once daily or liquid formulation (100 mg/mL) | 60 |
| Total | 121 |
Baseline characteristics
| Characteristic | Standard Therapy | Treatment Arm | Total |
|---|---|---|---|
| Age at Index TCD | 5.7 years STANDARD_DEVIATION 2 | 5.0 years STANDARD_DEVIATION 1.8 | 5.4 years STANDARD_DEVIATION 1.9 |
| Age, Categorical <=18 years | 61 Participants | 60 Participants | 121 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 9.5 years STANDARD_DEVIATION 2.6 | 9.7 years STANDARD_DEVIATION 3.2 | 9.6 years STANDARD_DEVIATION 2.9 |
| Duration of Transfusions | 3.8 years STANDARD_DEVIATION 1.8 | 4.5 years STANDARD_DEVIATION 2.8 | 4.1 years STANDARD_DEVIATION 2.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 58 Participants | 57 Participants | 115 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 58 Participants | 57 Participants | 115 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Canada | 4 participants | 5 participants | 9 participants |
| Region of Enrollment United States | 57 participants | 55 participants | 112 participants |
| Sex: Female, Male Female | 42 Participants | 29 Participants | 71 Participants |
| Sex: Female, Male Male | 19 Participants | 31 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 53 / 61 | 58 / 60 |
| serious Total, serious adverse events | 6 / 61 | 9 / 60 |
Outcome results
Primary
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.
Time frame: Since the study was terminated early, time frame is from beginning of treatment until end of treatment (up to 24 Months).
Population: Intention-to-Treat
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment Arm | Difference in TCD Time-averaged Mean Velocity (TAMV) on the Index Side | 138 cm/sec |
| Standard Therapy | Difference in TCD Time-averaged Mean Velocity (TAMV) on the Index Side | 143 cm/sec |
Comparison: Participants were randomized at a central site, stratified by site with a block size of four, and an adaptive randomization scheme was used to balance the covariates of baseline age and TCD velocity. The treatment period lasted 24 months. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population.p-value: <0.0595% CI: [0.1, 8.98]Mixed Models Analysis
Secondary
Change of Baseline in Hepatic Iron Overload as Assessed by Liver Iron Concentration
This secondary objective will compare standard to alternative therapy for hepatic iron overload.
Time frame: Baseline and 24 months
Population: Participants with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Arm | Change of Baseline in Hepatic Iron Overload as Assessed by Liver Iron Concentration | 2.4 mg FE per g dry weight liver | Standard Deviation 8.7 |
| Standard Therapy | Change of Baseline in Hepatic Iron Overload as Assessed by Liver Iron Concentration | -1.9 mg FE per g dry weight liver | Standard Deviation 4.2 |
p-value: 0.0011t-test, 2 sided
Secondary
Change of Baseline in Hepatic Iron Overload as Assessed by Serum Ferritin
This secondary objective will compare standard to alternative therapy for hepatic iron overload.
Time frame: Baseline and 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment Arm | Change of Baseline in Hepatic Iron Overload as Assessed by Serum Ferritin | -38 ng per mL | Standard Deviation 2095 |
| Standard Therapy | Change of Baseline in Hepatic Iron Overload as Assessed by Serum Ferritin | -1805 ng per mL | Standard Deviation 1651 |
p-value: <0.0001t-test, 2 sided
Secondary
Effects on Quality of Life
Standard Quality of Life measure will be taken during specific time points as well as one newly developed Sickle Cell Disease-specific test.
Time frame: 24 months
Secondary
Functional Status
This outcome will be measured using Barthel Index testing at the beginning, middle, and end of the treatment period.
Time frame: 24 months
Secondary
Growth and Development
This outcome will be measured by capturing height and weight monthly and conducting an annual pubertal assessment.
Time frame: 24 months
Secondary
Neuropsychological Decline
This outcome will be measured using standardized neurocognitive tests at baseline and exit.
Time frame: 24 months
Secondary
Non-stroke Neurological Events
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.
Time frame: 24 months
Secondary
Number of Participants With Hydroxyurea Toxicities
This measure will be performed on a monthly basis throughout the trial by recording the CBC and retic count.
Time frame: 24 Months
Secondary
Number of Participants With Liver MRI Complications
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.
Time frame: 24 months
Secondary
Number of Participants With Phlebotomy Complications
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.
Time frame: 24 months
Secondary
Number of Participants With Serious Adverse Events
Time frame: 24 Months
Secondary
Number of Participants With Transfusion Events
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.
Time frame: 24 months
Secondary
Primary Stroke Events
This secondary outcome measure will compare standard to alternative therapy for primary stroke events (a) primary ischemic stroke; b) primary hemorrhagic stroke
Time frame: 24 months
Secondary
TCD Time-averaged Mean Velocity on the Non-index Side
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.
Time frame: 24 months