Pharmacokinetics of Oral Hydroxyurea Solution

Mean AUC 0-Infinity (hr\*ug/mL) pharmacokinetic parameters derived using the final population PK model.

Time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose on Day 1 and Day 2 (Week 20-36)

Population: PK population = 32 participants receiving at least one dose of 15mg/kg hydroxyurea and have at least one PK plasma sample above lower limit of quantification.

Model estimated Pharmacokinetic Parameter (PK population: n=32, having received at least one dose of study drug).

Time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose on Day 1 and Day 2 (Week 20-36)

Population: Clearance value for patient of 15.05 kg

Mean Cmax (ug/mL) pharmacokinetic parameter derived using the final population PK model.

Time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose on Day 1 and Day 2 (Week 20-36)

Population: PK population: n=32 safety population, having received at least one dose of study drug at 15mg/kg and one sample of PK plasma above the lower limit of quantification.

Mean Terminal Half-life (hours) pharmacokinetic parameter derived using the final population PK model.

Time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose on Day 1 and Day 2 (Week 20-36)

Population: PK Population n=32 where all subjects received at least one dose of 15 mg/kg hydroxyurea and have at least one sample of PK plasma above the lower limit of quantification.

Mean Tmax (h) pharmacokinetic parameter derived using the final population PK model.

Time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose on Day 1 and Day 2 (Week 20-36)

Population: PK population = 32 participants, who have received at least one dose at 15 mg/kg and have at least one sample of PK plasma above the lower limit of quantification

Model estimated Pharmacokinetic Parameter (PK population: n=32, having received at least one dose of study drug).

Time frame: 0, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 12 hours post-dose on Day 1 and Day 2 (Week 20-36)

Population: Volume of distribution for central and peripheral compartments for patient of 15.05 kg

Safety review for haematological toxicity (mild myelosuppression target: 1-3x10\^9/L)

Time frame: Baseline and Week 60 (or final visit); max 15 months on treatment

Population: Safety population = 32 participants, who received at least one dose of oral hydroxyurea.~Baseline value is the last non-missing assessment prior to first exposure of oral hydroxyurea.~Week 60 is the final study visit or withdrawal at which point oral hydroxyurea was halted.

Hospitalization Incidence for 12 Months Prior to and After First Dose of IMP (Safety Population) for Acute Chest Syndrome (Mean \[SD\])

Time frame: 12 months prior to treatment and time averaged 12 months post-treatment; maximum 15 months on IMP

Population: Time-averaged hospitalizations after treatment was determined by dividing incidence of hospitalizations prior to treatment by 12 if study end date was more than a year after treatment start date, or by dividing by (End date - Treatment Start Date)/30.4375 otherwise. Hospitalizations did not include visits to ER/accident without hospitalization. Hospitalizations were sub-categorized by a medical monitor. Data were obtained through medical record review and study participant recall.

Incidence of Adverse events during the course of the trial from screening to final follow up phone call at Week 64. Relatedness refers to 'at least possibly related to the IMP', with severity/toxicity assessed using the CTCAE Toxicity Grade and seriousness based on the standard definition for SAE in accordance with GCP. With the exception of SCA related events, requiring \>7day hospitalisation, or extension of hospitalisation before being reported as an SAE due to their frequency within the disease population. All other non-SCA related SAEs were reportable.

Time frame: Screening Up to Week 64

Population: Safety population n=32. Overall 339 AEs in 31 participants recorded. 7 adverse events included in this list of 339 were defined as 'Serious' as per the protocol definition (i.e. SCA related and \>7days hospitalisation). A separate SAE report was made at that time with a clearly defined start and end date to be able to denote a resolution to the 'seriousness' criteria as this is an ongoing chronic condition.

Impact of Hydroxyurea on Safety, Hematology and Biochemistry

Time frame: Up to Week 60

Population: Safety population = 32 participants, who received at least one dose of oral hydroxyurea.~At screening, subjects' experiences of clinical SCA symptoms within the 12 months prior to the screening visit were recorded.~At subsequent visits, subjects' experiences of SCA symptoms since the previous visit were recorded, until end of study.~Each subject counted a maximum of once each per SCA symptom for before treatment and after treatment.

Impact of Hydroxyurea on Safety, Hematology and Biochemistry

Time frame: Up to Week 60

Population: Safety population = 32 participants, who received at least one dose of oral hydroxyurea.~Baseline value is the last non-missing assessment prior to first exposure of oral hydroxyurea.~Week 60 is the final study visit or withdrawal at which point oral hydroxyurea was halted.

Biomarker Endpoints

Time frame: PK1 (day 1), week 20-32 (6 months) and Week 60 (Final Visit)

Population: Baseline value is the last non-missing assessment prior to first exposure of oral HU.~Analysis was from initiation of study drug, again at \~6months (between 20-32 weeks) and at final study visit.~Week 28 (6 months - 1.99 years) no measures were analysed at this timepoint.

Summary of maximum tolerated dose achieved in mg/kg (Mean \[SD\])

Time frame: Screening Up to Final Visit (Week 60 or Withdrawal), maximum 15 months on IMP

Population: Clinical status endpoints; Safety population = 32 participants, who received at least one dose of IMP.~Week 60 is the final study visit, or withdrawal point at which point IMP was halted.~MTD only summarized for subjects who investigator denoted as achieving MTD during the study (n=20). If several doses were marked as MTD for the subject, the highest dose was used.

Impact of Hydroxyurea on Safety, Hematology and Biochemistry, including Liver Function Tests (LFTs): Alkaline Phosphatase (ALP), Gamma Glutamyl Transferase (GGT), Aspartate Amino Transferase (AST), Alanine Aminotransferase (ALT)

Time frame: Up to Week 60

Population: Safety population = 32 participants, who received at least one dose of oral hydroxyurea.~Baseline value is the last non-missing assessment prior to first exposure of oral hydroxyurea.~Week 60 is the final study visit or withdrawal at which point oral hydroxyurea was halted.

Biomarker endpoints of Hydroxyurea efficacy

Time frame: Baseline to Week 60 (or Final Visit); max 15 months on treatment

Population: Safety population = 32 participants, who received at least one dose of oral hydroxyurea.~Baseline value is the last non-missing assessment prior to first exposure of oral hydroxyurea.~Week 60 is the final study visit or withdrawal at which point oral hydroxyurea was halted.

Impact of Hydroxyurea on Safety, Hematology and Biochemistry

Time frame: Up to Week 60

Population: At screening, subjects' experiences of clinical SCA symptoms within the 12 months prior to the screening visit were recorded.~At subsequent visits, subjects' experiences of SCA symptoms since the previous visit were recorded, until end of study.~Each subject counted a maximum of once each per SCA symptom for before treatment and after treatment.

Impact of Hydroxyurea on Safety, Hematology and Biochemistry

Time frame: Up to Week 60

Population: Safety population = 32 participants, who received at least one dose of oral hydroxyurea.~Baseline value is the last non-missing assessment prior to first exposure of oral hydroxyurea.~Week 60 is the final study visit or withdrawal at which point oral hydroxyurea was halted.

Safety and efficacy of hydroxyurea therapy

Time frame: Baseline to Week 60 (or Final Visit); max 15 months on treatment

Population: Safety population = 32 participants, who received at least one dose of oral hydroxyurea.~Baseline value is the last non-missing assessment prior to first exposure of oral hydroxyurea.~Week 60 is the final study visit or withdrawal at which point oral hydroxyurea was halted.

Clinical Status endpoints, all hospitalisations (not ER/Accident without hospitalization) (Mean \[SD\])

Time frame: 12 months prior to treatment and time-averaged 12 months post-treatment; maximum 15 months on IMP

Population: Time-averaged hospitalizations after treatment was determined by dividing incidence of hospitalizations prior to treatment by 12 if study end date was more than a year after treatment start date, or by dividing by (End date - Treatment Start Date)/30.4375 otherwise. Hospitalizations did not include visits to ER/accident without hospitalization. Hospitalizations were sub-categorized by a medical monitor. Data were obtained through medical record review and study participant recall.

Hospitalization Incidence for 12 Months Prior to and After First Dose of IMP (Safety Population) for vaso-occlusive crisis (Mean \[SD\])

Time frame: 12 months prior to treatment and time-averaged 12 months post-treatment; maximum 15 months on IMP

Population: Time-averaged hospitalizations after treatment was determined by dividing incidence of hospitalizations prior to treatment by 12 if study end date was more than a year after treatment start date, or by dividing by (End date - Treatment Start Date)/30.4375 otherwise. Hospitalizations did not include visits to ER/accident without hospitalization. Hospitalizations were sub-categorized by a medical monitor. Data were obtained through medical record review and study participant recall.

Impact of Hydroxyurea on Safety, Hematology and Biochemistry

Time frame: Up to Week 60

Population: At screening, subjects' experiences of clinical SCA symptoms within the 12 months prior to the screening visit were recorded.~At subsequent visits, subjects' experiences of SCA symptoms since the previous visit were recorded, until end of study.~Each subject counted a maximum of once each per SCA symptom for before treatment and after treatment.

Impact of Hydroxyurea on Safety, Hematology and Biochemistry

Time frame: Baseline to Week 60 (or Final Visit), max 15 months on treatment

Population: Safety population = 32 participants, who received at least one dose of oral hydroxyurea.~Baseline value is the last non-missing assessment prior to first exposure of oral hydroxyurea.~Week 60 is the final study visit or withdrawal at which point oral hydroxyurea was halted.

Biomarker endpoints of Hydroxyurea efficacy

Time frame: Baseline to Week 60 (or Final Visit); max 15 months on treatment

Population: Safety population = 32 participants, who received at least one dose of oral hydroxyurea.~Baseline value is the last non-missing assessment prior to first exposure of oral hydroxyurea.~Week 60 is the final study visit or withdrawal at which point oral hydroxyurea was halted.

Clinical status endpoints, related to blood transfusions for treatment of SCA, this may be hospitalization, A&E, or in-clinic treatment from safety population (n=32)

Time frame: Up to Week 60

Population: Safety population = 32 participants, who received at least one dose of oral hydroxyurea.~Baseline value is the last non-missing assessment prior to first exposure of oral hydroxyurea.~Week 60 is the final study visit or withdrawal at which point oral hydroxyurea was halted.~Age group (6 months to 1.99 years) did not report any blood transfusions.

Clinical parameters (symptoms), secondary clinical status endpoints (not including ACS, VOC, Other SCA-related)

Time frame: 12 months prior to treatment and 12 months post-treatment; maximum 15 months on IMP

Population: Hospitalizations 'Prior to Treatment' having a start date within 1 year prior to initial treatment. Hospitalizations 'After Treatment' defined as all hospitalizations (not ER/Accident without hospitalization) within 1 year after treatment start date.

Clinical parameters (symptoms), secondary clinical status endpoints (not including ACS, VOC, Other Non-SCA related) (mean \[SD\])

Time frame: 12 months prior to treatment and time averaged 12 months post-treatment; maximum 15 months on IMP

Population: Time-averaged hospitalizations after treatment was determined by dividing incidence of hospitalizations prior to treatment by 12 if study end date was more than a year after treatment start date, or by dividing by (End date - Treatment Start Date)/30.4375 otherwise. Hospitalizations did not include visits to ER/accident without hospitalization. Hospitalizations were sub-categorized by a medical monitor. Data were obtained through medical record review and study participant recall.

Clinical status endpoints. Visual Analogue scale used to determine, taste, smell, aftertaste, acceptability and ease of dosing (1-100mm scale) with 1 being worst possible and 100 being best possible. Assessed for \<6 years of age by parents/guardians. Assessed for \>6 years of age, combination of parent/guardian and participant responses.

Time frame: Taken once at any point after 8 weeks on study medication (or at early Withdrawal)

Population: Results are presented for all 32 safety participants.

Impact of Hydroxyurea on Safety, Hematology and Biochemistry

Time frame: Baseline to Week 60 (or Final Visit), max 15 months on treatment

Population: Safety population = 32 participants, who received at least one dose of oral hydroxyurea.~Baseline value is the last non-missing assessment prior to first exposure of oral hydroxyurea.~Week 60 is the final study visit or withdrawal at which point oral hydroxyurea was halted.

Impact of Hydroxyurea on Safety, Hematology and Biochemistry

Time frame: Up to Week 60

Population: At screening, subjects' experiences of clinical SCA symptoms within the 12 months prior to the screening visit were recorded.~At subsequent visits, subjects' experiences of SCA symptoms since the previous visit were recorded, until end of study.~Each subject counted a maximum of once each per SCA symptom for before treatment and after treatment.

Biochemistry

Time frame: From Screening Up to Final Visit (Week 60 or WD)

Population: Safety population = 32 participants, who received at least one dose of oral hydroxyurea.~Baseline value is the last non-missing assessment prior to first exposure of oral hydroxyurea.~Week 60 is the final study visit or withdrawal at which point oral hydroxyurea was halted.

Impact of Hydroxyurea on Safety, Hematology and Biochemistry

Time frame: Baseline to Week 60 or Final Visit; max 15 months on treatment

Population: Leukocytes Safety population = 32 participants, who received at least one dose of oral hydroxyurea.~Baseline value is the last non-missing assessment prior to first exposure of oral hydroxyurea.~Week 60 is the final study visit or withdrawal at which point oral hydroxyurea was halted.

Exploratory Endpoint; clinical output of hydroxyurea treatment

Time frame: Baseline to Week 40-56 (Follow up scan).

Population: Time Averaged Mean Maximum Velocity (TAMV) in cm/sec at Baseline and Week 40-56 Visit (Safety Population).~max 15 months on treatment at Week 60.~Only participants with non-missing values at screening and end of study are included in the Baseline shift summary (change from baseline).