Trial Outcomes & Findings for Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) Follow-up Observational Study II Protocol (NCT NCT01783990)

Last Updated: 2020-08-20

Results Overview

The change in splenic function from the randomized control trial baseline measurement was one of the primary outcomes. The change in splenic function (worse vs not-worse) was compared between the randomized treatment groups (hydroxyurea vs placebo). The change in splenic function from baseline (before treatment initiation) to age 10 years (a visit when child turned 10 years old) was defined as worse if it changed from normal to decreased or absent, or decreased to absent; and not worse if it changed from decreased to decreased, normal to normal, decreased to normal, absent to absent, or absent to decreased.

Recruitment status

COMPLETED

Target enrollment

150 participants

Primary outcome timeframe

baseline and when child turned 10 years old

Results posted on

2020-08-20

Participant Flow

Participant milestones

Participant milestones
Measure	Active Complete blood counts (CBCs), reticulocytes, differential, lactate dehydrogenase (LDH), bilirubin and alanine transaminases (ALTs), cystatin C, blood urea nitrogen (BUN), Creatinine, fetal hemoglobin (HbF), pit counts, Howell Jolly Body (HJB), and urine microalbumin:creatinine ratio were collected at study entry, annually, and exit to Follow-Up Study II. Variable-diversity-joining (VDJ) and a stored blood sample were collected at study entry and study exit. Additional tests that include liver/spleen scan, abdominal sonogram, pulmonary function testing, magnetic resonance imaging (MRI) / magnetic resonance angiography (MRA), cardiac echocardiogram, or neuropsychology testing were collected once during the study when the child was 10 years old.	Passive Complete blood counts (CBCs), reticulocytes, differential, lactate dehydrogenase (LDH), bilirubin and alanine transaminases (ALTs), cystatin C, blood urea nitrogen (BUN), Creatinine, fetal hemoglobin (HbF), pit counts, Howell Jolly Body (HJB), variable-diversity-joining (VDJ), urine microalbumin:creatinine ratio and a stored blood sample were collected at study entry and exit to Follow-Up Study II. Additional tests that include liver/spleen scan, abdominal sonogram, pulmonary function testing, MRI/MRA, cardiac echocardiogram, or neuropsychology testing were collected as part of clinical care.
Overall Study STARTED	130	20
Overall Study COMPLETED	125	18
Overall Study NOT COMPLETED	5	2

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) Follow-up Observational Study II Protocol

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Active n=130 Participants Blood and urine specimens, and questionnaires related to the child's health status. * Liver Spleen Scan * Abdominal Ultrasound * Brain magnetic resonance imaging (MRI) / magnetic resonance angiography (MRA) * Cardiac Echocardiogram/Pulmonary Function Testing * Transcranial Doppler * Neuropsychology Testing (Vineland, Wechsler Intelligence Scale for Children (WISC-IV), Connor Continuous Performance Test 2nd Edition (CPT II) and Pediatric Quality of Life Inventory(PedsQOL)) Patients could be on or off hydroxyurea at the start of Follow-Up Study II, and could change treatment during the study.	Passive n=20 Participants Information from usual clinical care of sickle cell disease. We will collect information from routine tests ordered by the child's clinical sickle cell doctors. Patients could be on or off hydroxyurea at the start of Follow-Up Study II, and could change treatment during the study.	Total n=150 Participants Total of all reporting groups
Age, Categorical <=18 years	130 Participants n=99 Participants	20 Participants n=107 Participants	150 Participants n=206 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Age, Categorical >=65 years	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Age, Continuous	8.16 Years STANDARD_DEVIATION 1.13 • n=99 Participants	8.06 Years STANDARD_DEVIATION 1.26 • n=107 Participants	8.15 Years STANDARD_DEVIATION 1.14 • n=206 Participants
Sex: Female, Male Female	70 Participants n=99 Participants	14 Participants n=107 Participants	84 Participants n=206 Participants
Sex: Female, Male Male	60 Participants n=99 Participants	6 Participants n=107 Participants	66 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=99 Participants	1 Participants n=107 Participants	6 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	125 Participants n=99 Participants	19 Participants n=107 Participants	144 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Asian	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Black or African American	122 Participants n=99 Participants	18 Participants n=107 Participants	140 Participants n=206 Participants
Race (NIH/OMB) White	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) More than one race	4 Participants n=99 Participants	0 Participants n=107 Participants	4 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	4 Participants n=99 Participants	2 Participants n=107 Participants	6 Participants n=206 Participants
Region of Enrollment United States	130 participants n=99 Participants	20 participants n=107 Participants	150 participants n=206 Participants

PRIMARY outcome

Timeframe: baseline and when child turned 10 years old

Population: All subjects who had age 10 years and baseline spleen function measurement.

Outcome measures

Outcome measures
Measure	Randomized to Hydroxyurea n=58 Participants Subjects randomized to Hydroxyurea in the randomized phase III clinical trial.	Randomized to Placebo n=50 Participants Subjects randomized to Placebo in the randomized phase III clinical trial.
Change in Qualitative Spleen Function From Randomized Control Trial Baseline Measurement - Compared Between Children Randomized to Hydroxyurea vs Placebo Splenic function - worse from baseline	26 Participants	28 Participants
Change in Qualitative Spleen Function From Randomized Control Trial Baseline Measurement - Compared Between Children Randomized to Hydroxyurea vs Placebo Splenic function - not worse from baseline	32 Participants	22 Participants

PRIMARY outcome

Timeframe: baseline and when child turned 10 years old

Population: All subjects who were known to be on hydroxyurea vs. off hydroxyurea at age 10 years, and had age 10 years and baseline spleen function measurement.

The change in splenic function from the randomized control trial baseline measurement was one of the primary outcomes. The change in splenic function (worse vs not-worse) was compared between children who were known to be on hydroxyurea vs. off hydroxyurea at the time of the visit. The change in splenic function from baseline (before treatment initiation) to age 10 years (a visit when child turned 10 years old) was defined as worse if it changed from normal to decreased or absent, or decreased to absent; and not worse if it changed from decreased to decreased, normal to normal, decreased to normal, absent to absent, or absent to decreased.

Outcome measures

Outcome measures
Measure	Randomized to Hydroxyurea n=88 Participants Subjects randomized to Hydroxyurea in the randomized phase III clinical trial.	Randomized to Placebo n=17 Participants Subjects randomized to Placebo in the randomized phase III clinical trial.
Change in Qualitative Spleen Function From Randomized Control Trial Baseline Measurement - Compared Between Children on Hydroxyurea vs Off Hydroxyurea at Study Visit Splenic function - worse from baseline	43 Participants	9 Participants
Change in Qualitative Spleen Function From Randomized Control Trial Baseline Measurement - Compared Between Children on Hydroxyurea vs Off Hydroxyurea at Study Visit Splenic function - not worse from baseline	45 Participants	8 Participants

PRIMARY outcome

Timeframe: Baseline and End of follow-up II study (up to 13 years from randomization date)

Population: All subjects who had end of study and baseline pitted cell measurement.

The change in the percentage of pitted cell from randomized control trial baseline measurement was one of the primary outcomes. The change in the percentage of pitted cell was compared between the randomized treatment groups (hydroxyurea vs placebo).

Outcome measures

Outcome measures
Measure	Randomized to Hydroxyurea n=70 Participants Subjects randomized to Hydroxyurea in the randomized phase III clinical trial.	Randomized to Placebo n=68 Participants Subjects randomized to Placebo in the randomized phase III clinical trial.
Change in the Percentage of Pitted Cell From Randomized Control Trial Baseline Measurement - Compared Between Children Randomized to Hydroxyurea vs Placebo	-1.60 Percentage of pitted cell Interval -5.0 to -0.6	-1.75 Percentage of pitted cell Interval -6.25 to -0.4

PRIMARY outcome

Timeframe: Baseline and End of follow-up II study (up to 13 years from randomization date)

Population: All subjects who were known to be on hydroxyurea vs. off hydroxyurea at the end of study visit, and had end of study and baseline pitted cell count measurement.

The change in the percentage of pitted cell from the randomized control trial baseline measurement was one of the primary outcomes. The change in the percentage of pitted cell was compared between children who were known to be on hydroxyurea vs. off hydroxyurea at the time of the visit.

Outcome measures

Outcome measures
Measure	Randomized to Hydroxyurea n=116 Participants Subjects randomized to Hydroxyurea in the randomized phase III clinical trial.	Randomized to Placebo n=22 Participants Subjects randomized to Placebo in the randomized phase III clinical trial.
Change in the Percentage of Pitted Cell From Randomized Control Trial Baseline Measurement - Compared Between Children on Hydroxyurea vs Off Hydroxyurea at Study Visit	-1.80 Percentage of pitted cell Interval -6.4 to -0.4	-0.80 Percentage of pitted cell Interval -5.0 to -0.3

PRIMARY outcome

Timeframe: Baseline and End of follow-up II study (up to 13 years from randomization date)

Population: All subjects who had end of follow-up study II and baseline howell jolly body count measurement.

The change in Howell Jolly Body from the randomized control trial baseline measurement was one of the primary outcomes. The change in Howell Jolly Body was compared between the randomized treatment groups (hydroxyurea vs placebo).

Outcome measures

Outcome measures
Measure	Randomized to Hydroxyurea n=65 Participants Subjects randomized to Hydroxyurea in the randomized phase III clinical trial.	Randomized to Placebo n=62 Participants Subjects randomized to Placebo in the randomized phase III clinical trial.
Change in Howell Jolly Body (HJB) From Randomized Control Trial Baseline Measurement - Compared Between Children Randomized to Hydroxyurea vs Placebo	2719.88 Number of HJB per 10⁶ red blood cell Interval 1373.9 to 4080.5	2248.55 Number of HJB per 10⁶ red blood cell Interval 908.88 to 3758.11

PRIMARY outcome

Timeframe: Baseline and End of follow-up II study (up to 13 years from randomization date)

Population: All subjects who were known to be on hydroxyurea vs. off hydroxyurea at the end of study visit, and had end of study and baseline Howell Jolly Body count measurement.

The change in Howell Jolly Body count from the randomized control trial baseline measurement was one of the primary outcomes. The change in Howell-Jolly Bodies was compared between children who were known to be on hydroxyurea vs. off hydroxyurea at the time of the visit.

Outcome measures

Outcome measures
Measure	Randomized to Hydroxyurea n=107 Participants Subjects randomized to Hydroxyurea in the randomized phase III clinical trial.	Randomized to Placebo n=20 Participants Subjects randomized to Placebo in the randomized phase III clinical trial.
Change in Howell Jolly Body (HJB) Count From Randomized Control Trial Baseline Measurement - Compared Between Children on Hydroxyurea vs Off Hydroxyurea	2645.43 Number of HJB per 10⁶ red blood cell Interval 1373.9 to 4010.52	1833.73 Number of HJB per 10⁶ red blood cell Interval 326.15 to 2713.72

Adverse Events

Randomized to Hydroxyurea

Serious events: 24 serious events

Other events: 0 other events

Deaths: 0 deaths

Randomized to Placebo

Serious events: 31 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Adverse event data not reported

Additional Information

Julie Miller

New England Research Institutes, Inc

Phone: 617-972-3197

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Serious adverse events
Measure	Randomized to Hydroxyurea n=77 participants at risk Subjects randomized to Hydroxyurea in the randomized phase III clinical trial. 150 subjects (130 in active and 20 in passive follow-up group) consented to follow-up II study. Of the 150 subjects, 77 subjects were randomized to the hydroxyurea treatment group during the randomized phase III clinical trial.	Randomized to Placebo n=73 participants at risk Subjects randomized to Placebo in the randomized phase III clinical trial. 150 subjects (130 in active and 20 in passive follow-up group) consented to follow-up II study. Of the 150 subjects, 73 subjects were randomized to the placebo treatment group during the randomized phase III clinical trial.
Respiratory, thoracic and mediastinal disorders Acute chest syndrome	20.8% 16/77 • Number of events 23 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	30.1% 22/73 • Number of events 36 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Blood and lymphatic system disorders Vaso-occlusive crisis	2.6% 2/77 • Number of events 4 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	4.1% 3/73 • Number of events 3 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Infections and infestations VOC. Acute hematogenous Osteomyelitis	0.00% 0/77 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	1.4% 1/73 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Nervous system disorders Stroke, TIA	1.3% 1/77 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	1.4% 1/73 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Eye disorders Binocular diplopia and new onset left esotropia	1.3% 1/77 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	0.00% 0/73 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Blood and lymphatic system disorders Pain Crisis	5.2% 4/77 • Number of events 7 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	6.8% 5/73 • Number of events 6 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Musculoskeletal and connective tissue disorders Pain	1.3% 1/77 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	0.00% 0/73 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Gastrointestinal disorders Pain	0.00% 0/77 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	1.4% 1/73 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Blood and lymphatic system disorders Splenic sequestration crisis	1.3% 1/77 • Number of events 2 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	1.4% 1/73 • Number of events 3 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Infections and infestations Pneumonia	2.6% 2/77 • Number of events 2 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	1.4% 1/73 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Hepatobiliary disorders Cholelithiasis	0.00% 0/77 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	2.7% 2/73 • Number of events 2 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Respiratory, thoracic and mediastinal disorders Bilateral infiltrates on chest x-ray.	1.3% 1/77 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	0.00% 0/73 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Blood and lymphatic system disorders Sickle cell anemia with crisis	1.3% 1/77 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	0.00% 0/73 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Hepatobiliary disorders Acute hepatic crisis with component of hepatic sequestration.	1.3% 1/77 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	0.00% 0/73 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Injury, poisoning and procedural complications Delayed hemolytic transfusion reaction	0.00% 0/77 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	1.4% 1/73 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.00% 0/77 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	1.4% 1/73 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lymphangioma	0.00% 0/77 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	1.4% 1/73 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Infections and infestations Osteomyelitis radial	1.3% 1/77 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	0.00% 0/73 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Infections and infestations Tonsilitis	0.00% 0/77 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	1.4% 1/73 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Infections and infestations Fever rhinovirus	1.3% 1/77 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	0.00% 0/73 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Respiratory, thoracic and mediastinal disorders Fever, cough, runny nose, sore throat and difficulty breathing.	1.3% 1/77 • Number of events 1 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	0.00% 0/73 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.
Blood and lymphatic system disorders Aplastic crisis	0.00% 0/77 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.	2.7% 2/73 • Number of events 2 • The date of consent to follow-up study II (FUS-II) through end of FUS-II, up to 4 years Serious adverse events (SAEs) were Death, Life-threatening event, Prolonged hospitalization (\>7 days), Splenic sequestration crisis, Stroke, transient ischemic attack (TIA), Acute chest syndrome, or intensive care unit (ICU) admissions which occurred during the first 5 days following performance of an active assessment study. Major events met the definition of SAE but didn't occur within 5 days following the performance of active assessment. These are included below as if they were SAEs.