A Phase 3 interventional study of Hydroxyurea in Sickle Cell Anemia, sponsored by Children's Hospital Medical Center, Cincinnati. Terminated. Open to participants aged 4 Years to 15 Years. Per ClinicalTrials.gov, last updated 2020-07-22.
Sponsored by Children's Hospital Medical Center, Cincinnati · Phase 3, Interventional, and Prevention
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.
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.
1,733 studies on the registry are indexed under Anemia; 246 are open to participants now.
This study's enrollment of 159 is above the median of 94 across 1,291 interventional studies indexed under Anemia.
Browse Anemia studies →Children's Hospital Medical Center, Cincinnati is the lead sponsor of 661 studies on the registry; 134 are open to participants now.
Of its 54 completed or terminated interventional studies of FDA-regulated products, 30 (56%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Standard Therapy of monthly transfusions
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)
Also known as: Hydroxycarbamide, Hydrea, Droxia
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).
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
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
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
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
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
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
Neuropsychological Decline
This outcome will be measured using standardized neurocognitive tests at baseline and exit.
Time frame: 24 months
Growth and Development
This outcome will be measured by capturing height and weight monthly and conducting an annual pubertal assessment.
Time frame: 24 months
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
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
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
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
Number of Participants With Serious Adverse Events
Time frame: 24 Months
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
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
| Milestone | Standard Therapy | Treatment Arm |
|---|---|---|
| Started | 61 | 60 |
| Completed | 42 | 41 |
| Not completed | 19 | 19 |
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.
| cm/sec | Treatment Arm | Standard Therapy |
|---|---|---|
| Difference in TCD Time-averaged Mean Velocity (TAMV) on the Index Side | 138 (135 to 142) | 143 (140 to 146) |
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.
Results for this outcome have not been posted.
This secondary outcome measure will compare standard to alternative therapy for primary stroke events (a) primary ischemic stroke; b) primary hemorrhagic stroke
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
This secondary objective will compare standard to alternative therapy for hepatic iron overload.
| ng per mL | Standard Therapy | Treatment Arm |
|---|---|---|
| Change of Baseline in Hepatic Iron Overload as Assessed by Serum Ferritin | -38 ± 2095 | -1805 ± 1651 |
Standard Quality of Life measure will be taken during specific time points as well as one newly developed Sickle Cell Disease-specific test.
Results for this outcome have not been posted.
This outcome will be measured using Barthel Index testing at the beginning, middle, and end of the treatment period.
Results for this outcome have not been posted.
This outcome will be measured using standardized neurocognitive tests at baseline and exit.
Results for this outcome have not been posted.
This outcome will be measured by capturing height and weight monthly and conducting an annual pubertal assessment.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
This measure will be performed on a monthly basis throughout the trial by recording the CBC and retic count.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
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.
Results for this outcome have not been posted.
Results for this outcome have not been posted.
This secondary objective will compare standard to alternative therapy for hepatic iron overload.
| mg FE per g dry weight liver | Standard Therapy | Treatment Arm |
|---|---|---|
| Change of Baseline in Hepatic Iron Overload as Assessed by Liver Iron Concentration | 2.4 ± 8.7 | -1.9 ± 4.2 |
Collected over 2 years. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Standard Therapy | — | 6/61 (9.8%) | 53/61 (86.9%) |
| Treatment Arm | — | 9/60 (15%) | 58/60 (96.7%) |
| Event | Standard Therapy | Treatment Arm |
|---|---|---|
| Vaso-occlusive PainBlood and lymphatic system disorders | 1/61 | 5/60 |
| FeverInfections and infestations | 1/61 | 4/60 |
| Acute Chest SyndromeRespiratory, thoracic and mediastinal disorders | 2/61 | 4/60 |
| HeadacheNervous system disorders | 0/61 | 1/60 |
| CholelithiasisHepatobiliary disorders | 1/61 | 1/60 |
| Intracranial AneurysmNervous system disorders | 1/61 | 0/60 |
| Splenomeagaly/SplenectomySurgical and medical procedures | 1/61 | 0/60 |
| Event | Standard Therapy | Treatment Arm |
|---|---|---|
| Hemoglobin DecreasedInvestigations | 25/61 | 32/60 |
| Sickle Cell Anemia with CrisisBlood and lymphatic system disorders | 9/61 | 24/60 |
| HeadacheNervous system disorders | 19/61 | 22/60 |
| Upper Respiratory Tract InfectionInfections and infestations | 14/61 | 18/60 |
| Neutrophil Count DecreasedInvestigations | 0/61 | 15/60 |
| Aspartate AminotranseraseInvestigations | 9/61 | 14/60 |
| Reticulocyte Count DecreasedInvestigations | 0/61 | 12/60 |
| Alanine AminotranferaseInvestigations | 12/61 | 7/60 |
| Blood Bilirubin IncreasedInvestigations | 12/61 | 3/60 |
| PyrxiaGeneral disorders | 7/61 | 10/60 |
| Age, Categorical(Participants) | Standard Therapy | Treatment Arm | Total |
|---|---|---|---|
| <=18 years | 61 | 60 | 121 |
| Between 18 and 65 years | 0 | 0 | 0 |
| >=65 years | 0 | 0 | 0 |
| Age, Continuous(years) | Standard Therapy | Treatment Arm | Total |
|---|---|---|---|
| Mean | 9.5 ± 2.6 | 9.7 ± 3.2 | 9.6 ± 2.9 |
| Sex: Female, Male(Participants) | Standard Therapy | Treatment Arm | Total |
|---|---|---|---|
| Female | 42 | 29 | 71 |
| Male | 19 | 31 | 50 |
| Ethnicity (NIH/OMB)(Participants) | Standard Therapy | Treatment Arm | Total |
|---|---|---|---|
| Hispanic or Latino | 3 | 3 | 6 |
| Not Hispanic or Latino | 58 | 57 | 115 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Race (NIH/OMB)(Participants) | Standard Therapy | Treatment Arm | Total |
|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 0 |
| Asian | 0 | 0 | 0 |
| Native Hawaiian or Other Pacific Islander | 0 | 0 | 0 |
| Black or African American | 58 | 57 | 115 |
| White | 0 | 1 | 1 |
| More than one race | 3 | 2 | 5 |
| Unknown or Not Reported | 0 | 0 | 0 |
| Region of Enrollment(participants) | Standard Therapy | Treatment Arm | Total |
|---|---|---|---|
| Canada | 4 | 5 | 9 |
| United States | 57 | 55 | 112 |
| Age at Index TCD(years) | Standard Therapy | Treatment Arm | Total |
|---|---|---|---|
| Mean | 5.7 ± 2.0 | 5.0 ± 1.8 | 5.4 ± 1.9 |
| Duration of Transfusions(years) | Standard Therapy | Treatment Arm | Total |
|---|---|---|---|
| Mean | 3.8 ± 1.8 | 4.5 ± 2.8 | 4.1 ± 2.4 |
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Plan to share: No
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Children's Hospital Medical Center, Cincinnati