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

• Sponsor: Children's Hospital Medical Center, Cincinnati (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01425307
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), Boston Children's Hospital (Other), University of Texas Southwestern Medical Center (Other), Children's Healthcare of Atlanta (Other), Children's Hospital of Philadelphia (Other), The Hospital for Sick Children (Other), Children's National Research Institute (Other), Columbia University (Other), St. Jude Children's Research Hospital (Other), University Hospitals Cleveland Medical Center (Other), University of South Alabama (Other), Medical University of South Carolina (Other), University of Alabama at Birmingham (Other), University of Miami (Other), University of Mississippi Medical Center (Other), Wayne State University (Other), Children's Hospital of The King's Daughters (Other), Nemours Children's Clinic (Other), Duke University (Other), East Carolina University (Other), Children's Hospitals and Clinics of Minnesota (Other), Ann & Robert H Lurie Children's Hospital of Chicago (Other), Baylor College of Medicine (Other), State University of New York - Downstate Medical Center (Other), Steven and Alexandra Cohen Children's Medical Center (Other)
• Enrollment: 159
• Arms: 2
• Duration (Months): 51

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Sickle Cell Anemia	Drug: Hydroxyurea	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 159 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• 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 Start Date: Aug 1, 2011
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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

3. 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.

4. 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.

5. 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.

6. Functional Status [24 months]

   This outcome will be measured using Barthel Index testing at the beginning, middle, and end of the treatment period.

7. Neuropsychological Decline [24 months]

   This outcome will be measured using standardized neurocognitive tests at baseline and exit.

8. Growth and Development [24 months]

   This outcome will be measured by capturing height and weight monthly and conducting an annual pubertal assessment.

9. 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.

10. 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.

11. 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.

12. 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.

13. Number of Participants With Serious Adverse Events [24 Months]

14. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years to 15 Years
• Sexes Eligible for Study: All
• Accepts 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).

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Children's Hospital Medical Center, Cincinnati
• 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

Investigators

• Principal Investigator: Russell E. Ware, MD, PhD, Children's Hospital Medical Center, Cincinnati

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Hospital Medical Center, Cincinnati
• ClinicalTrials.gov Identifier: NCT01425307
• Other Study ID Numbers: H-28572 TWiTCH; R01HL095647
• First Posted: Aug 30, 2011
• Last Update Posted: Jul 22, 2020
• Last Verified: May 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• 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; Hydroxyurea

Study Results

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 Detail	159 were enrolled. 121 met eligibility criteria and randomized to treatment.

Arm/Group Title	Standard Therapy	Treatment Arm
Arm/Group Description	Standard Therapy of monthly transfusions	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)
Period Title: Overall Study
STARTED	61	60
COMPLETED	42	41
NOT COMPLETED	19	19

Baseline Characteristics

Arm/Group Title	Standard Therapy	Treatment Arm	Total
Arm/Group Description	Standard Therapy of monthly transfusions	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)	Total of all reporting groups
Overall Participants	61	60	121
Age (Count of Participants)
<=18 years	61 100%	60 100%	121 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9.5 (2.6)	9.7 (3.2)	9.6 (2.9)
Sex: Female, Male (Count of Participants)
Female	42 68.9%	29 48.3%	71 58.7%
Male	19 31.1%	31 51.7%	50 41.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 4.9%	3 5%	6 5%
Not Hispanic or Latino	58 95.1%	57 95%	115 95%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	58 95.1%	57 95%	115 95%
White	0 0%	1 1.7%	1 0.8%
More than one race	3 4.9%	2 3.3%	5 4.1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Canada	4 6.6%	5 8.3%	9 7.4%
United States	57 93.4%	55 91.7%	112 92.6%
Age at Index TCD (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	5.7 (2.0)	5.0 (1.8)	5.4 (1.9)
Duration of Transfusions (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	3.8 (1.8)	4.5 (2.8)	4.1 (2.4)

Outcome Measures

1. Primary Outcome

Title	Difference in TCD Time-averaged Mean Velocity (TAMV) on the Index Side
Description	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).

Outcome Measure Data

Analysis Population Description

Intention-to-Treat

Arm/Group Title	Treatment Arm	Standard Therapy
Arm/Group Description	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)	Standard Therapy of monthly transfusions
Measure Participants	60	61
Mean (95% Confidence Interval) [cm/sec]	138	143

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Arm, Standard Therapy
	Comments	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.
	Type of Statistical Test	Non-Inferiority or Equivalence (legacy)
	Comments	We hypothesized that the Alternative arm mean TCD velocity at 24 months will be less than the Standard arm mean TCD velocity plus 15cm/sec. We used Lan-DeMets boundaries to control overall Type I error rate at α = 0.05. For looks at exactly 1/3, 2/3, and 100 percent of the completed subjects, the cumulative α were estimated to be 0.0001, 0.001, and 0.05, respectively.
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	P value for non inferiority was 8.82 X 10^-16
	Method	Mixed Models Analysis
	Comments	Linear mixed model
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.54
	Confidence Interval	(2-Sided) 95%; 0.10 to 8.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	TCD Time-averaged Mean Velocity on the Non-index Side
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Primary Stroke Events
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Non-stroke Neurological Events
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Change of Baseline in Hepatic Iron Overload as Assessed by Serum Ferritin
Description	This secondary objective will compare standard to alternative therapy for hepatic iron overload.
Time Frame	Baseline and 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard Therapy	Treatment Arm
Arm/Group Description	Standard Therapy of monthly transfusions	Hydroxyurea will be provided as capsules and liquid
Measure Participants	61	60
Mean (Standard Deviation) [ng per mL]	-38 (2095)	-1805 (1651)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Arm, Standard Therapy
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Effects on Quality of Life
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Functional Status
Description	This outcome will be measured using Barthel Index testing at the beginning, middle, and end of the treatment period.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Neuropsychological Decline
Description	This outcome will be measured using standardized neurocognitive tests at baseline and exit.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Growth and Development
Description	This outcome will be measured by capturing height and weight monthly and conducting an annual pubertal assessment.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Number of Participants With Transfusion Events
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Number of Participants With Hydroxyurea Toxicities
Description	This measure will be performed on a monthly basis throughout the trial by recording the CBC and retic count.
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

12. Secondary Outcome

Title	Number of Participants With Phlebotomy Complications
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Number of Participants With Liver MRI Complications
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

14. Secondary Outcome

Title	Number of Participants With Serious Adverse Events
Time Frame	24 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Secondary Outcome

Title	Change of Baseline in Hepatic Iron Overload as Assessed by Liver Iron Concentration
Description	This secondary objective will compare standard to alternative therapy for hepatic iron overload.
Time Frame	Baseline and 24 months

Outcome Measure Data

Analysis Population Description

Participants with available data

Arm/Group Title	Standard Therapy	Treatment Arm
Arm/Group Description	Standard Therapy of monthly transfusions	Hydroxyurea will be provided as capsules and liquid
Measure Participants	52	58
Mean (Standard Deviation) [mg FE per g dry weight liver]	2.4 (8.7)	-1.9 (4.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Arm, Standard Therapy
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0011
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	2 years
Arm/Group Title	Standard Therapy		Treatment Arm
Arm/Group Description	Standard Therapy of monthly transfusions		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)
All Cause Mortality
	Standard Therapy		Treatment Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Standard Therapy		Treatment Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/61 (9.8%)		9/60 (15%)
Blood and lymphatic system disorders
Vaso-occlusive Pain	1/61 (1.6%)	3	5/60 (8.3%)	11
Hepatobiliary disorders
Cholelithiasis	1/61 (1.6%)	1	1/60 (1.7%)	1
Infections and infestations
Fever	1/61 (1.6%)	1	4/60 (6.7%)	4
Nervous system disorders
Headache	0/61 (0%)	0	1/60 (1.7%)	2
Intracranial Aneurysm	1/61 (1.6%)	1	0/60 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute Chest Syndrome	2/61 (3.3%)	3	4/60 (6.7%)	5
Surgical and medical procedures
Splenomeagaly/Splenectomy	1/61 (1.6%)	1	0/60 (0%)	0
Other (Not Including Serious) Adverse Events
	Standard Therapy		Treatment Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	53/61 (86.9%)		58/60 (96.7%)
Blood and lymphatic system disorders
Sickle Cell Anemia with Crisis	9/61 (14.8%)	28	24/60 (40%)	62
Gastrointestinal disorders
Abdominal Pain	7/61 (11.5%)	12	6/60 (10%)	7
Abdominal Pain Upper	3/61 (4.9%)	3	3/60 (5%)	4
Constipation	0/61 (0%)	0	4/60 (6.7%)	6
Gastritis	3/61 (4.9%)	4	0/60 (0%)	0
Nausea	0/61 (0%)	0	4/60 (6.7%)	7
Vomiting	4/61 (6.6%)	4	0/60 (0%)	0
General disorders
Pyrxia	7/61 (11.5%)	7	10/60 (16.7%)	10
Immune system disorders
Seasonal Allergy	0/61 (0%)	0	3/60 (5%)	3
Infections and infestations
Gastroenteritis	3/61 (4.9%)	3	3/60 (5%)	3
Gastrointestinal Viral Infection	3/61 (4.9%)	3	0/60 (0%)	0
Influenza	3/61 (4.9%)	4	7/60 (11.7%)	9
Pharyngitis	0/61 (0%)	0	5/60 (8.3%)	5
Pharyngitis Streptococcal	9/61 (14.8%)	12	9/60 (15%)	11
Pneumonia	3/61 (4.9%)	3	0/60 (0%)	0
Respiratory Syncytial Virus Infection	0/61 (0%)	0	3/60 (5%)	3
Sinusitis	0/61 (0%)	0	4/60 (6.7%)	4
Upper Respiratory Tract Infection	14/61 (23%)	21	18/60 (30%)	30
Urinary Tract Infection	6/61 (9.8%)	6	3/60 (5%)	4
Viral Infection	10/61 (16.4%)	11	9/60 (15%)	12
Viral Upper Respiratory Tract Infection	3/61 (4.9%)	3	3/60 (5%)	3
Injury, poisoning and procedural complications
Procedural Dizziness	0/61 (0%)	0	3/60 (5%)	3
Procedural Hypotension	0/61 (0%)	0	3/60 (5%)	3
Transfusion Reaction	5/61 (8.2%)	5	0/60 (0%)	0
Investigations
Alanine Aminotranferase	12/61 (19.7%)	16	7/60 (11.7%)	11
Aspartate Aminotranserase	9/61 (14.8%)	11	14/60 (23.3%)	16
Blood Bilirubin Increased	12/61 (19.7%)	37	3/60 (5%)	4
Blood Creatinine Increased	0/61 (0%)	0	7/60 (11.7%)	8
Coombs Direct Test Positive	7/61 (11.5%)	10	3/60 (5%)	4
Hemoglobin Decreased	25/61 (41%)	66	32/60 (53.3%)	76
Neutrophil Count Decreased	0/61 (0%)	0	15/60 (25%)	19
Platelet Count Decreased	0/61 (0%)	0	4/60 (6.7%)	4
Reticulocyte Count Decreased	0/61 (0%)	0	12/60 (20%)	16
Musculoskeletal and connective tissue disorders
Back Pain	3/61 (4.9%)	5	0/60 (0%)	0
Nervous system disorders
Headache	19/61 (31.1%)	38	22/60 (36.7%)	41
Migraine	3/61 (4.9%)	3	7/60 (11.7%)	9
Transient Ischemic Attack	3/61 (4.9%)	3	3/60 (5%)	3
Respiratory, thoracic and mediastinal disorders
Acute Chest Syndrome	4/61 (6.6%)	4	6/60 (10%)	6
Asthma	0/61 (0%)	0	3/60 (5%)	10
Cough	0/61 (0%)	0	4/60 (6.7%)	5
Epistaxis	3/61 (4.9%)	4	0/60 (0%)	0
Sleep Apnea Syndrome	3/61 (4.9%)	3	0/60 (0%)	0
Vascular disorders
Poor Venous Access	4/61 (6.6%)	4	0/60 (0%)	0

Limitations/Caveats

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

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.