Trial Outcomes & Findings for Hydroxyurea to Prevent Brain Injury in Sickle Cell Disease (NCT NCT01389024)

Last Updated: 2024-07-10

Results Overview

A composite of abnormally elevated cerebral blood flow velocity as measured by transcranial Doppler ultrasound, silent cerebral infarct, or stroke.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

28 participants

Primary outcome timeframe

3 years

Results posted on

2024-07-10

Participant Flow

28 participants were consented for the study. 18 were fully screened including an MRI of the brain. 12 participants were randomized to the two arms of the study.

Participant milestones

Participant milestones
Measure	Placebo Sucrose placebo 0.2 ml/kg/day increased to max of 0.35 ml/kg/day Placebo: Sucrose solution 0.2 ml/kg/day by mouth once a day with blinded dose escalation of 0.05 ml/kg/day to match the frequency of dose escalation in the hydroxyurea arm.	Hydroxyurea Treatment with hydroxyurea 20 mg/kg/day increased by 5 mg/kg every 8 weeks to maximum of 35 mg/kg/day or hematologic toxicity or absolute neutrophil count (ANC) \<4000 Hydroxyurea: Hydroxyurea solution 100 mg/ml with a starting dose of 20 mg/kg/day by mouth once daily and escalation by 5 mg/kg/day every 8 weeks until hematological toxicity, an absolute neutrophil count of 2000 to 4000/ul, or a maximum dose of 35 mg/kg/day.
Overall Study STARTED	6	6
Overall Study COMPLETED	5	5
Overall Study NOT COMPLETED	1	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Sucrose placebo 0.2 ml/kg/day increased to max of 0.35 ml/kg/day Placebo: Sucrose solution 0.2 ml/kg/day by mouth once a day with blinded dose escalation of 0.05 ml/kg/day to match the frequency of dose escalation in the hydroxyurea arm.	Hydroxyurea Treatment with hydroxyurea 20 mg/kg/day increased by 5 mg/kg every 8 weeks to maximum of 35 mg/kg/day or hematologic toxicity or absolute neutrophil count (ANC) \<4000 Hydroxyurea: Hydroxyurea solution 100 mg/ml with a starting dose of 20 mg/kg/day by mouth once daily and escalation by 5 mg/kg/day every 8 weeks until hematological toxicity, an absolute neutrophil count of 2000 to 4000/ul, or a maximum dose of 35 mg/kg/day.
Overall Study Withdrawal by Subject	1	0
Overall Study Lost to Follow-up	0	1

Baseline Characteristics

Hydroxyurea to Prevent Brain Injury in Sickle Cell Disease

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Hydroxyurea n=6 Participants Treatment with hydroxyurea 20 mg/kg/day increased by 5 mg/kg every 8 weeks to maximum of 35 mg/kg/day or hematologic toxicity or ANC \<4000 Hydroxyurea: Hydroxyurea solution 100 mg/ml with a starting dose of 20 mg/kg/day by mouth once daily and escalation by 5 mg/kg/day every 8 weeks until hematological toxicity, an absolute neutrophil count of 2000 to 4000/ul, or a maximum dose of 35 mg/kg/day.	Placebo n=6 Participants Sucrose placebo 0.2 ml/kg/day increased to max of 0.35 ml/kg/day Placebo: Sucrose solution 0.2 ml/kg/day by mouth once a day with blinded dose escalation of 0.05 ml/kg/day to match the frequency of dose escalation in the hydroxyurea arm.	Total n=12 Participants Total of all reporting groups
Age, Continuous	25.5 Months STANDARD_DEVIATION 11.6 • n=5 Participants	19.7 Months STANDARD_DEVIATION 10.2 • n=7 Participants	22.6 Months STANDARD_DEVIATION 10.8 • n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	4 Participants n=7 Participants	6 Participants n=5 Participants
Sex: Female, Male Male	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants n=5 Participants	6 Participants n=7 Participants	12 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	6 Participants n=5 Participants	5 Participants n=7 Participants	11 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Weight at screening	12.8 kg STANDARD_DEVIATION 2.2 • n=5 Participants	12.4 kg STANDARD_DEVIATION 4.8 • n=7 Participants	12.6 kg STANDARD_DEVIATION 3.6 • n=5 Participants
Hemoglobin Phenotype Hb-SS	6 Participants n=5 Participants	5 Participants n=7 Participants	11 Participants n=5 Participants
Hemoglobin Phenotype Hgb S-β0 thalassemia	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
White blood cell count	15,228 cells/mm^3 STANDARD_DEVIATION 3,250 • n=5 Participants	14,442 cells/mm^3 STANDARD_DEVIATION 7,242 • n=7 Participants	14,835 cells/mm^3 STANDARD_DEVIATION 5,368 • n=5 Participants
Hemoglobin	7.8 g/dL STANDARD_DEVIATION 0.9 • n=5 Participants	8.3 g/dL STANDARD_DEVIATION 1.1 • n=7 Participants	8.1 g/dL STANDARD_DEVIATION 1.0 • n=5 Participants
Mean corpuscular volume	82.9 fL STANDARD_DEVIATION 5.1 • n=5 Participants	79.2 fL STANDARD_DEVIATION 9.9 • n=7 Participants	81.1 fL STANDARD_DEVIATION 7.7 • n=5 Participants
Mean corpuscular hemoglobin concentration	34.3 g/dL STANDARD_DEVIATION 1.6 • n=5 Participants	33.6 g/dL STANDARD_DEVIATION 1.3 • n=7 Participants	34.0 g/dL STANDARD_DEVIATION 1.5 • n=5 Participants
Reticulocyte count	17.7 % STANDARD_DEVIATION 8.8 • n=5 Participants	16.0 % STANDARD_DEVIATION 7.2 • n=7 Participants	16.9 % STANDARD_DEVIATION 7.7 • n=5 Participants
Platelet count	417,333 platelets per mm^3 STANDARD_DEVIATION 105,742 • n=5 Participants	319,833 platelets per mm^3 STANDARD_DEVIATION 88,087 • n=7 Participants	368,583 platelets per mm^3 STANDARD_DEVIATION 105,839 • n=5 Participants
Bilirubin	2.6 mg/dL STANDARD_DEVIATION 1.2 • n=5 Participants	2.0 mg/dL STANDARD_DEVIATION 0.9 • n=7 Participants	2.3 mg/dL STANDARD_DEVIATION 1.1 • n=5 Participants
Creatinine	0.25 mg/dL STANDARD_DEVIATION 0.08 • n=5 Participants	0.22 mg/dL STANDARD_DEVIATION 0.04 • n=7 Participants	0.24 mg/dL STANDARD_DEVIATION 0.06 • n=5 Participants
Transcranial Doppler (TCD) TAMMV	127.5 cm/sec STANDARD_DEVIATION 23.9 • n=5 Participants	109.8 cm/sec STANDARD_DEVIATION 18.3 • n=7 Participants	118.7 cm/sec STANDARD_DEVIATION 22.3 • n=5 Participants

PRIMARY outcome

Timeframe: 3 years

A composite of abnormally elevated cerebral blood flow velocity as measured by transcranial Doppler ultrasound, silent cerebral infarct, or stroke.

Outcome measures

Outcome measures
Measure	Hydroxyurea n=6 Participants Treatment with hydroxyurea 20 mg/kg/day increased by 5 mg/kg every 8 weeks to maximum of 35 mg/kg/day or hematologic toxicity or ANC \<4000 Hydroxyurea: Hydroxyurea solution 100 mg/ml with a starting dose of 20 mg/kg/day by mouth once daily and escalation by 5 mg/kg/day every 8 weeks until hematological toxicity, an absolute neutrophil count of 2000 to 4000/ul, or a maximum dose of 35 mg/kg/day.	Placebo n=6 Participants Sucrose placebo 0.2 ml/kg/day increased to max of 0.35 ml/kg/day Placebo: Sucrose solution 0.2 ml/kg/day by mouth once a day with blinded dose escalation of 0.05 ml/kg/day to match the frequency of dose escalation in the hydroxyurea arm.
Number of Randomized Participants With Central Nervous System Complications	1 Participants	4 Participants

SECONDARY outcome

Timeframe: 3 years

Population: 18 participants underwent MRIs as part of screening. A total of 41 MRIs were performed including screening, annual or "for cause" MRIs. For this analysis, the overall number of participants analyzed is the total number of MRIs (41) performed. This outcome was not pre-specified to be collected by arm nor to evaluate treatment effect.

Number of MRIs resulting in serious adverse events. Participants can have multiple MRIs performed.

Outcome measures

Outcome measures
Measure	Hydroxyurea n=41 MRIs Treatment with hydroxyurea 20 mg/kg/day increased by 5 mg/kg every 8 weeks to maximum of 35 mg/kg/day or hematologic toxicity or ANC \<4000 Hydroxyurea: Hydroxyurea solution 100 mg/ml with a starting dose of 20 mg/kg/day by mouth once daily and escalation by 5 mg/kg/day every 8 weeks until hematological toxicity, an absolute neutrophil count of 2000 to 4000/ul, or a maximum dose of 35 mg/kg/day.	Placebo Sucrose placebo 0.2 ml/kg/day increased to max of 0.35 ml/kg/day Placebo: Sucrose solution 0.2 ml/kg/day by mouth once a day with blinded dose escalation of 0.05 ml/kg/day to match the frequency of dose escalation in the hydroxyurea arm.
Severe Adverse Events (SAE) Attributed to Study Procedures	3 MRIs	—

SECONDARY outcome

Timeframe: 3 years

Population: 18 participants underwent MRIs as part of screening. A total of 41 MRIs were performed including screening, annual or "for cause" MRIs. 29 of the 41 MRIs were performed with sedation. For this analysis, the overall number of participants analyzed was the total number of sedated (29) MRIs performed. The primary intent was only to look at the effects of sedated MRI. This outcome was not pre-specified to be collected by arm nor to evaluate treatment effect.

Number of sedated MRIs resulting in serious adverse events. Participants can have multiple MRIs performed.

Outcome measures

Outcome measures
Measure	Hydroxyurea n=18 Participants Treatment with hydroxyurea 20 mg/kg/day increased by 5 mg/kg every 8 weeks to maximum of 35 mg/kg/day or hematologic toxicity or ANC \<4000 Hydroxyurea: Hydroxyurea solution 100 mg/ml with a starting dose of 20 mg/kg/day by mouth once daily and escalation by 5 mg/kg/day every 8 weeks until hematological toxicity, an absolute neutrophil count of 2000 to 4000/ul, or a maximum dose of 35 mg/kg/day.	Placebo Sucrose placebo 0.2 ml/kg/day increased to max of 0.35 ml/kg/day Placebo: Sucrose solution 0.2 ml/kg/day by mouth once a day with blinded dose escalation of 0.05 ml/kg/day to match the frequency of dose escalation in the hydroxyurea arm.
Severe Adverse Events (SAE) Attributed to Sedated MRIs	3 MRIs	—

SECONDARY outcome

Timeframe: 6 months

We will evaluate the number of participants consented and fully screened that were randomized to hydroxyurea or placebo.

Outcome measures

Outcome measures
Measure	Hydroxyurea n=18 Participants Treatment with hydroxyurea 20 mg/kg/day increased by 5 mg/kg every 8 weeks to maximum of 35 mg/kg/day or hematologic toxicity or ANC \<4000 Hydroxyurea: Hydroxyurea solution 100 mg/ml with a starting dose of 20 mg/kg/day by mouth once daily and escalation by 5 mg/kg/day every 8 weeks until hematological toxicity, an absolute neutrophil count of 2000 to 4000/ul, or a maximum dose of 35 mg/kg/day.	Placebo Sucrose placebo 0.2 ml/kg/day increased to max of 0.35 ml/kg/day Placebo: Sucrose solution 0.2 ml/kg/day by mouth once a day with blinded dose escalation of 0.05 ml/kg/day to match the frequency of dose escalation in the hydroxyurea arm.
Number of Participants Randomized	12 Participants	—

Adverse Events

Hydroxyurea

Serious events: 5 serious events

Other events: 5 other events

Deaths: 0 deaths

Placebo

Serious events: 6 serious events

Other events: 6 other events

Deaths: 0 deaths

Screen Fails

Serious events: 4 serious events

Other events: 3 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Hydroxyurea n=6 participants at risk Treatment with hydroxyurea 20 mg/kg/day increased by 5 mg/kg every 8 weeks to maximum of 35 mg/kg/day or hematologic toxicity or ANC \<4000 Hydroxyurea: Hydroxyurea solution 100 mg/ml with a starting dose of 20 mg/kg/day by mouth once daily and escalation by 5 mg/kg/day every 8 weeks until hematological toxicity, an absolute neutrophil count of 2000 to 4000/ul, or a maximum dose of 35 mg/kg/day.	Placebo n=6 participants at risk Sucrose placebo 0.2 ml/kg/day increased to max of 0.35 ml/kg/day Placebo: Sucrose solution 0.2 ml/kg/day by mouth once a day with blinded dose escalation of 0.05 ml/kg/day to match the frequency of dose escalation in the hydroxyurea arm.	Screen Fails n=16 participants at risk Patients who were consented and began screening, but were not randomized
General disorders Fever	66.7% 4/6 • Number of events 8 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	83.3% 5/6 • Number of events 13 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	18.8% 3/16 • Number of events 4 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).
Infections and infestations Parainfluenza	16.7% 1/6 • Number of events 1 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	0.00% 0/6 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	0.00% 0/16 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).
Musculoskeletal and connective tissue disorders Left Arm Weakness	16.7% 1/6 • Number of events 1 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	0.00% 0/6 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	0.00% 0/16 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).
Respiratory, thoracic and mediastinal disorders Acute Chest Syndrome	16.7% 1/6 • Number of events 2 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	16.7% 1/6 • Number of events 3 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	0.00% 0/16 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).
Respiratory, thoracic and mediastinal disorders Hypoxemia	16.7% 1/6 • Number of events 1 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	0.00% 0/6 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	0.00% 0/16 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).
Respiratory, thoracic and mediastinal disorders Laryngospasm	16.7% 1/6 • Number of events 1 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	0.00% 0/6 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	0.00% 0/16 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).
Surgical and medical procedures Tonsillectomy	16.7% 1/6 • Number of events 1 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	0.00% 0/6 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	0.00% 0/16 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).
Blood and lymphatic system disorders Splenic Sequestration	0.00% 0/6 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	33.3% 2/6 • Number of events 2 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	6.2% 1/16 • Number of events 2 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).
General disorders Pain	0.00% 0/6 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	16.7% 1/6 • Number of events 1 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	0.00% 0/16 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).
Musculoskeletal and connective tissue disorders Dactylitis	0.00% 0/6 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	0.00% 0/6 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	6.2% 1/16 • Number of events 1 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).
Renal and urinary disorders Urinary Retention	0.00% 0/6 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	0.00% 0/6 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).	6.2% 1/16 • Number of events 1 • 3 years Adverse events data was collected for all 28 consented participants during screening. 12 were randomized to the two arms of the study and collection of adverse reports was continued. Adverse events for the remainder of the consented participants who were followed only during screening were reported as a separate arm (non-randomized).

Other adverse events

Additional Information

Dr. James Casella

The Johns Hopkins University School of Medicine

Phone: 410-955-6132

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place