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Clinical Trial Results:
A Phase 2a, Open-label, Single and Multiple Dose Study to Evaluate the Pharmacokinetics, Safety, Tolerability and Treatment Effect of GBT440 in Pediatric Participants with Sickle Cell Disease

Summary
EudraCT number	2016-004209-15
Trial protocol	GB
Global end of trial date	02 Oct 2023

Results information
Results version number	v1(current)
This version publication date	13 Jun 2025
First version publication date	13 Jun 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

C5341020

ISRCTN number

US NCT number

NCT02850406

WHO universal trial number (UTN)

Other trial identifiers

GBT440-007: Pfizer Protocol Number

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

66 Hudson Boulevard East, New York, United States, NY 10001-2192

Public contact

Pfizer Inc., Pfizer ClinicalTrials.gov Call Center, 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer Inc., Pfizer ClinicalTrials.gov Call Center, 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-002356-PIP02-20

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

12 Dec 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

02 Oct 2023

Was the trial ended prematurely?

Yes

Main objective of the trial

Part A: To characterize the pharmacokinetic (PK) of voxelotor in plasma and whole blood following a single dose in pediatric participants with sickle cell disease (SCD). Part B: To assess the efficacy of voxelotor in pediatric participants with SCD as measured by improvement in anemia. Part C: To evaluate the effect of voxelotor on cerebral hemodynamics in pediatric participants with SCD with elevated or conditional transcranial Doppler (TCD) flow velocity as assessed by TCD ultrasonography. Part D: To evaluate the safety and tolerability of voxelotor in pediatric participants with SCD aged 6 months to < 4 years.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

21 Jul 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Lebanon: 38

Country: Number of subjects enrolled

United States: 95

Country: Number of subjects enrolled

United Kingdom: 14

Worldwide total number of subjects

147

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study consisted of four parts-Part A, B, C and D. The study was terminated as the emerging clinical data indicated that the risk profile of voxelotor in people with sickle cell disease (SCD) exceeded the benefits observed in previously generated global research and required further assessment.

Screening details

A total of 147 pediatric participants with SCD (13 in Part A, 40 in Part B, 62 in Part C and 32 in Part D) were enrolled in the study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Blinding implementation details

Are arms mutually exclusive

Yes

Part A: Participants aged 12 to 17 years: Voxelotor 600 mg

Arm description

Participants aged 12 to 17 years received a single oral dose of voxelotor 600 milligrams (mg) on Day 1.

Arm type

Experimental

Investigational medicinal product name

Voxelotor

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Single oral dose of voxelotor capsules or tablets were administered.

Part A: Participants aged 6 to 11 years: Voxelotor 600 mg

Arm description

Participants aged 6 to 11 years received a single oral dose of voxelotor 600 mg on Day 1.

Arm type

Experimental

Investigational medicinal product name

Voxelotor

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Single oral dose of granulation from voxelotor capsules were mixed with food and administered.

Part B: Voxelotor 900 mg QD

Arm description

Participants aged 12 to 17 years received once daily (QD) oral dose of voxelotor 900 mg for 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Voxelotor

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Capsule

Routes of administration

Oral use

Dosage and administration details

Single oral dose of voxelotor capsules or tablets were administered.

Part B: Voxelotor 1500 mg QD

Arm description

Participants aged 12 to 17 years received once daily oral dose of voxelotor 1500 mg for 24 weeks.

Arm type

Experimental

Investigational medicinal product name

Voxelotor

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet, Capsule

Routes of administration

Oral use

Dosage and administration details

Single oral dose of voxelotor capsules or tablets were administered.

Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD

Arm description

Participants aged 4 to 11 years received once daily oral dose of voxelotor 1500 mg for 48 weeks.

Arm type

Experimental

Investigational medicinal product name

Voxelotor

Investigational medicinal product code

Other name

Pharmaceutical forms

Dispersible tablet, Powder for oral suspension

Routes of administration

Oral use

Dosage and administration details

Voxelotor 1500 mg/day equivalent based on body weight administered for 48 weeks.

Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD

Arm description

Participants aged 12 to 17 years received once daily oral dose of voxelotor 1500 mg for 48 weeks.

Arm type

Experimental

Investigational medicinal product name

Voxelotor

Investigational medicinal product code

Other name

Pharmaceutical forms

Dispersible tablet, Powder for oral suspension

Routes of administration

Oral use

Dosage and administration details

Voxelotor 1500 mg/day administered for 48 weeks.

Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD

Arm description

Participants aged 6 months (M) to <2 years received once daily oral dose of voxelotor 1500 mg for 48 weeks.

Arm type

Experimental

Investigational medicinal product name

Voxelotor

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral suspension

Routes of administration

Oral use

Dosage and administration details

Voxelotor 1500 mg/day equivalent based on body weight administered for 48 weeks.

Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD

Arm description

Participants aged 2 to <4 years received once daily oral dose of voxelotor 1500 mg for 48 weeks.

Arm type

Experimental

Investigational medicinal product name

Voxelotor

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for oral suspension

Routes of administration

Oral use

Dosage and administration details

Voxelotor 1500 mg/day equivalent based on body weight administered for 48 weeks.

Number of subjects in period 1	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg	Part B: Voxelotor 900 mg QD	Part B: Voxelotor 1500 mg QD	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD	Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD	Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD
Started	7	6	25	15	51	11	9	23
Completed	7	6	22	12	39	3	7	20
Not completed	0	0	3	3	12	8	2	3
Consent withdrawn by subject	-	-	1	2	6	3	-	1
Physician decision	-	-	-	-	1	-	1	1
Adverse event, non-fatal	-	-	-	1	4	2	1	-
Non-compliance	-	-	1	-	-	-	-	-
Unspecified	-	-	-	-	1	3	-	1
Lost to follow-up	-	-	1	-	-	-	-	-

Baseline characteristics

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Reporting group title

Part A: Participants aged 12 to 17 years: Voxelotor 600 mg

Reporting group description

Participants aged 12 to 17 years received a single oral dose of voxelotor 600 milligrams (mg) on Day 1.

Reporting group title

Part A: Participants aged 6 to 11 years: Voxelotor 600 mg

Reporting group description

Participants aged 6 to 11 years received a single oral dose of voxelotor 600 mg on Day 1.

Reporting group title

Part B: Voxelotor 900 mg QD

Reporting group description

Participants aged 12 to 17 years received once daily (QD) oral dose of voxelotor 900 mg for 24 weeks.

Reporting group title

Part B: Voxelotor 1500 mg QD

Reporting group description

Participants aged 12 to 17 years received once daily oral dose of voxelotor 1500 mg for 24 weeks.

Reporting group title

Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD

Reporting group description

Participants aged 4 to 11 years received once daily oral dose of voxelotor 1500 mg for 48 weeks.

Reporting group title

Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD

Reporting group description

Participants aged 12 to 17 years received once daily oral dose of voxelotor 1500 mg for 48 weeks.

Reporting group title

Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD

Reporting group description

Participants aged 6 months (M) to <2 years received once daily oral dose of voxelotor 1500 mg for 48 weeks.

Reporting group title

Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD

Reporting group description

Participants aged 2 to <4 years received once daily oral dose of voxelotor 1500 mg for 48 weeks.

Reporting group values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg	Part B: Voxelotor 900 mg QD	Part B: Voxelotor 1500 mg QD	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD	Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD	Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD	Total
Number of subjects	7	6	25	15	51	11	9	23
Age Categorical
Units: Subjects
Age continuous
Units: Years
arithmetic mean (standard deviation)	15.4 ( 0.79 )	8.2 ( 1.72 )	14.0 ( 1.68 )	13.9 ( 1.58 )	7.3 ( 2.06 )	13.1 ( 1.04 )	1.4 ( 0.41 )	3.0 ( 0.51 )	-
Gender categorical
Units: Subjects
Male	4	3	11	10	27	4	3	9	71
Female	3	3	14	5	24	7	6	14	76
Race/Ethnicity, Customized
Units: Subjects
Arab/Middle Eastern	0	1	0	0	0	0	0	0	1
Black or African American	3	3	18	11	44	11	5	9	104
White	2	2	6	4	3	0	2	9	28
Multi-racial	2	0	1	0	0	0	2	0	5
Middle Eastern or North African	0	0	0	0	4	0	0	5	9
Ethnicity
Units: Subjects
Hispanic or Latino	0	0	1	1	3	0	1	1	7
Not Hispanic or Latino	7	6	24	14	48	11	8	22	140

End points

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Reporting group title

Part A: Participants aged 12 to 17 years: Voxelotor 600 mg

Reporting group description

Participants aged 12 to 17 years received a single oral dose of voxelotor 600 milligrams (mg) on Day 1.

Reporting group title

Part A: Participants aged 6 to 11 years: Voxelotor 600 mg

Reporting group description

Participants aged 6 to 11 years received a single oral dose of voxelotor 600 mg on Day 1.

Reporting group title

Part B: Voxelotor 900 mg QD

Reporting group description

Participants aged 12 to 17 years received once daily (QD) oral dose of voxelotor 900 mg for 24 weeks.

Reporting group title

Part B: Voxelotor 1500 mg QD

Reporting group description

Participants aged 12 to 17 years received once daily oral dose of voxelotor 1500 mg for 24 weeks.

Reporting group title

Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD

Reporting group description

Participants aged 4 to 11 years received once daily oral dose of voxelotor 1500 mg for 48 weeks.

Reporting group title

Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD

Reporting group description

Participants aged 12 to 17 years received once daily oral dose of voxelotor 1500 mg for 48 weeks.

Reporting group title

Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD

Reporting group description

Participants aged 6 months (M) to <2 years received once daily oral dose of voxelotor 1500 mg for 48 weeks.

Reporting group title

Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD

Reporting group description

Participants aged 2 to <4 years received once daily oral dose of voxelotor 1500 mg for 48 weeks.

Primary: Part A: Maximum Concentration (Cmax) of Voxelotor in Whole Blood

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End point title

Part A: Maximum Concentration (Cmax) of Voxelotor in Whole Blood ^[1] ^[2]

End point description

Pharmacokinetic (PK) population comprised of all participants who received any amount of study drug and who provided PK data from at least one post-dose sample in plasma.

End point type

Primary

End point timeframe

pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.

End point values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg
Number of subjects analysed	7	6
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)	24300 ( 36.39 )	47300 ( 43.62 )

No statistical analyses for this end point

Primary: Part B: Change From Baseline to Week 24 in Hemoglobin Level

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End point title

Part B: Change From Baseline to Week 24 in Hemoglobin Level ^[3] ^[4]

End point description

Efficacy-Evaluable Population comprised of all participants who received any amount of study drug. Here, ‘Overall Number of Participants Analyzed’ signifies number of participants evaluable for this outcome measure.

End point type

Primary

End point timeframe

Baseline, Week 24

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The end point is specific to Part B; hence, only Part B arms are reported.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part B; hence, only Part B arms are reported.

End point values	Part B: Voxelotor 900 mg QD	Part B: Voxelotor 1500 mg QD
Number of subjects analysed	22	12
Units: Gram per deciliter
arithmetic mean (standard deviation)	0.7 ( 0.86 )	0.2 ( 1.02 )

No statistical analyses for this end point

Primary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in Whole Blood

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End point title

Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in Whole Blood ^[5] ^[6]

End point description

AUC0-inf was calculated as AUCt + Ct/lambdaz, where AUCt=area under the concentration-time curve at designated time, Ct is the last quantifiable concentration for whole blood and lambdaz=elimination rate constant. PK population comprised of all participants who received any amount of study drug and who provided PK data from at least one post-dose sample in plasma.

End point type

Primary

End point timeframe

pre-dose, 2, 8, 24, 48, 96,168 and 336 hours post-dose

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.

End point values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg
Number of subjects analysed	6	6
Units: Hours*nanogram per milliliter
geometric mean (geometric coefficient of variation)	1520000 ( 40.98 )	2570000 ( 50.59 )

No statistical analyses for this end point

Primary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Voxelotor in Whole Blood

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End point title

Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Voxelotor in Whole Blood ^[7] ^[8]

End point description

End point type

Primary

End point timeframe

pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.

End point values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg
Number of subjects analysed	7	6
Units: Hours*nanogram per milliliter
geometric mean (geometric coefficient of variation)	1570000 ( 38.13 )	2540000 ( 50.25 )

No statistical analyses for this end point

Primary: Part C: Change From Baseline to Week 48 in Cerebral Blood Flow

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End point title

Part C: Change From Baseline to Week 48 in Cerebral Blood Flow ^[9] ^[10]

End point description

Cerebral blood flow was measured using transcranial Doppler (TCD) sonography. Change from baseline in cerebral blood flow as measured by the time-averaged mean of the maximum (TAMM) TCD velocity is reported. Efficacy-Evaluable Population comprised of all participants who received any amount of study drug. Here, ‘Overall Number of Participants Analyzed’ signifies number of participants evaluable for this outcome measure.

End point type

Primary

End point timeframe

Baseline, Week 48

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The end point is specific to Part C; hence, only Part C arms are reported.
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part C; hence, only Part C arms are reported.

End point values	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD
Number of subjects analysed	34	3
Units: Centimeter per second
arithmetic mean (standard deviation)	-0.4 ( 16.76 )	-26.3 ( 11.59 )

No statistical analyses for this end point

Primary: Part D: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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End point title

Part D: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) ^[11] ^[12]

End point description

An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. TEAE was defined as an AE that emerged on or after initiation of study drug (having been absent pre-treatment), or an AE that existed pre-treatment and worsened on treatment (relative to the pre-treatment state) through 28 days after study drug discontinuation. An SAE was any AE that resulted in any of the following outcomes: death, life threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, congenital anomaly or birth defect, other important medical events. AEs were classified as SCD-related and non-SCD related. Safety population comprised of all participants who received any amount of study drug.

End point type

Primary

End point timeframe

From start of study treatment up to 28 days after study treatment discontinuation (Up to 52 weeks)

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The end point is specific to Part D; hence, only Part D arms are reported.
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part D; hence, only Part D arms are reported.

End point values	Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD	Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD
Number of subjects analysed	9	23
Units: Participants
Non-SCD related TEAEs	9	20
Non-SCD related SAEs	6	12
SCD related TEAEs	6	14
SCD related SAEs	3	9

No statistical analyses for this end point

Secondary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Voxelotor in Plasma

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End point title

Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Voxelotor in Plasma ^[13]

End point description

AUC0-last was calculated using the linear/log trapezoid rule. PK population comprised of all participants who received any amount of study drug and who provided PK data from at least one post-dose sample in plasma. Here, 'Participants Analyzed’ signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.

End point values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg
Number of subjects analysed	7	5
Units: Hours*nanogram per milliliter
geometric mean (geometric coefficient of variation)	104000 ( 20.85 )	148000 ( 38.69 )

No statistical analyses for this end point

Secondary: Part A: Maximum Concentration (Cmax) of Voxelotor in Plasma

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End point title

Part A: Maximum Concentration (Cmax) of Voxelotor in Plasma ^[14]

End point description

PK population comprised of all participants who received any amount of study drug and who provided PK data from at least one post-dose sample in plasma. Here, ‘Participants Analyzed’ signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.

End point values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg
Number of subjects analysed	7	5
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)	1880 ( 32.49 )	3390 ( 37.82 )

No statistical analyses for this end point

Secondary: Part A: Maximum Concentration (Cmax) of Voxelotor in Red Blood Cells (RBC)

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End point title

Part A: Maximum Concentration (Cmax) of Voxelotor in Red Blood Cells (RBC) ^[15]

End point description

End point type

Secondary

End point timeframe

pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.

End point values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg
Number of subjects analysed	7	5
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)	91500 ( 33.17 )	168000 ( 35.56 )

No statistical analyses for this end point

Secondary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Voxelotor in RBC

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End point title

Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Voxelotor in RBC ^[16]

End point description

End point type

Secondary

End point timeframe

pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.

End point values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg
Number of subjects analysed	7	5
Units: Hours*nanogram per milliliter
geometric mean (geometric coefficient of variation)	6070000 ( 28.69 )	8950000 ( 47.05 )

No statistical analyses for this end point

Secondary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in Plasma

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End point title

Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in Plasma ^[17]

End point description

AUC0-inf was calculated as AUCt + Ct/lambdaz, where AUCt=area under the concentration-time curve at designated time, Ct is the last quantifiable concentration for plasma and lambdaz is the elimination rate constant. PK population comprised of all participants who received any amount of study drug and who provided PK data from at least one post-dose sample in plasma. Here, 'Participants Analyzed’ signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.

End point values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg
Number of subjects analysed	6	5
Units: Hours*nanogram per milliliter
geometric mean (geometric coefficient of variation)	101000 ( 20.51 )	150000 ( 38.01 )

No statistical analyses for this end point

Secondary: Part A: Time at Which Cmax Was Observed (Tmax) for Voxelotor in Whole Blood

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End point title

Part A: Time at Which Cmax Was Observed (Tmax) for Voxelotor in Whole Blood ^[18]

End point description

PK population comprised of all participants who received any amount of study drug and who provided PK data from at least one post-dose sample in plasma.

End point type

Secondary

End point timeframe

pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.

End point values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg
Number of subjects analysed	7	6
Units: Hours
median (full range (min-max))	24.2 (7.67 to 49.9)	8.73 (7.78 to 25.3)

No statistical analyses for this end point

Secondary: Part A: Time at Which Cmax Was Observed (Tmax) for Voxelotor in RBC

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End point title

Part A: Time at Which Cmax Was Observed (Tmax) for Voxelotor in RBC ^[19]

End point description

End point type

Secondary

End point timeframe

pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.

End point values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg
Number of subjects analysed	7	5
Units: Hours
median (full range (min-max))	9.00 (7.67 to 49.9)	8.75 (8.72 to 25.3)

No statistical analyses for this end point

Secondary: Part A: Time at Which Cmax Was Observed (Tmax) for Voxelotor in Plasma

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End point title

Part A: Time at Which Cmax Was Observed (Tmax) for Voxelotor in Plasma ^[20]

End point description

End point type

Secondary

End point timeframe

pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.

End point values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg
Number of subjects analysed	7	5
Units: Hours
median (full range (min-max))	2.83 (1.95 to 9.00)	2.83 (2.57 to 8.72)

No statistical analyses for this end point

Secondary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in RBC

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End point title

Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in RBC ^[21]

End point description

AUC0-inf was calculated as AUCt + Ct/lambdaz, where AUCt=area under the concentration-time curve at designated time, Ct is the last quantifiable concentration and lambdaz is the elimination rate constant. PK population comprised of all participants who received any amount of study drug and who provided PK data from at least one post-dose sample in plasma. Here, 'Participants Analyzed’ signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.

End point values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg
Number of subjects analysed	4	5
Units: Hours*nanogram per milliliter
geometric mean (geometric coefficient of variation)	5550000 ( 24.31 )	9070000 ( 47.47 )

No statistical analyses for this end point

Secondary: Part A: Terminal Elimination Half-Life (T1/2) for Voxelotor in Whole Blood

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End point title

Part A: Terminal Elimination Half-Life (T1/2) for Voxelotor in Whole Blood ^[22]

End point description

T1/2 was the time measured for the drug concentration to decrease by one half. PK population comprised of all participants who received any amount of study drug and who provided PK data from at least one post-dose sample in plasma. Here, ‘Participants Analyzed’ signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.

End point values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg
Number of subjects analysed	6	6
Units: Hours
geometric mean (geometric coefficient of variation)	31.9 ( 18.76 )	28.5 ( 26.18 )

No statistical analyses for this end point

Secondary: Part A: Terminal Elimination Half-Life (T1/2) for Voxelotor in Plasma

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End point title

Part A: Terminal Elimination Half-Life (T1/2) for Voxelotor in Plasma ^[23]

End point description

End point type

Secondary

End point timeframe

pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.

End point values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg
Number of subjects analysed	6	5
Units: Hours
geometric mean (geometric coefficient of variation)	46.4 ( 6.40 )	40.7 ( 31.48 )

No statistical analyses for this end point

Secondary: Part A: Percentage Hemoglobin (Hb) Occupancy

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End point title

Part A: Percentage Hemoglobin (Hb) Occupancy ^[24]

End point description

Percentage hemoglobin occupancy (% Hb Occupancy) refers to the percentage of hemoglobin molecules within red blood cells that were bound to study drug. Concentration of voxelotor in whole blood and plasma was used to calculate %Hb occupancy. Percentage Hb occupancy within RBCs was estimated using the formula: ([Concentration of voxelotor in whole blood- {1-hematocrit}] *[Concentration of voxelotor in plasma/hematocrit])/5000*100. Data was not collected as the model for Hb occupancy within RBCs was not developed for single dose administration (Part A).

End point type

Secondary

End point timeframe

Day 28

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.

End point values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg
Number of subjects analysed	0 ^[25]	0 ^[26]
Units: Percentage of bound hemoglobin
geometric mean (geometric coefficient of variation)	( )	( )

Notes
[25] - Model for Hb occupancy within RBC not developed for single dose administration (Part A).
[26] - Model for Hb occupancy within RBC not developed for single dose administration (Part A).

No statistical analyses for this end point

Secondary: Part A: Terminal Elimination Half-Life (T1/2) for Voxelotor in RBC

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End point title

Part A: Terminal Elimination Half-Life (T1/2) for Voxelotor in RBC ^[27]

End point description

End point type

Secondary

End point timeframe

pre-dose, 2, 8, 24, 48, 96, 168 and 336 hours post-dose

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part A; hence, only Part A arms are reported.

End point values	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg
Number of subjects analysed	4	5
Units: Hours
geometric mean (geometric coefficient of variation)	28.8 ( 12.89 )	27.3 ( 30.95 )

No statistical analyses for this end point

Secondary: Part B: Change from Baseline to Week 21 to 24 in the Sickle Cell Disease Severity Measure (SCDSM) Total Symptom Score (TSS)

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End point title

Part B: Change from Baseline to Week 21 to 24 in the Sickle Cell Disease Severity Measure (SCDSM) Total Symptom Score (TSS) ^[28]

End point description

The SCDSM was a self-administered 9-item questionnaire of SCD core symptoms including pain severity, frequency, and type, as well as fatigue and mental acuity, on a 4-point response scale with a range of 0 (strongly disagree) to 4 (strongly agree) that was completed daily using a handheld electronic device by the participants. TSS was calculated as the sum of the 9-item questionnaire scores scaled to a 100-point scale with a range of 0 (no symptoms) to 100 (most severe symptoms). Baseline TSS was the average of the non-missing score during the Screening period. The average of change from baseline in SCDSM TSS score for the 4-week period (Week 21 to 24) is reported. Efficacy-Evaluable Population comprised of all participants who received any amount of study drug. Here, 'Participants Analyzed' signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Weeks 21 to 24

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part B; hence, only Part B arms are reported.

End point values	Part B: Voxelotor 900 mg QD	Part B: Voxelotor 1500 mg QD
Number of subjects analysed	14	8
Units: Units on a scale
arithmetic mean (standard deviation)	6.4 ( 17.98 )	-10.7 ( 18.70 )

No statistical analyses for this end point

Secondary: Part B: Percentage of Days With SCD Symptom Exacerbation During the First 24 Weeks of Treatment

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End point title

Part B: Percentage of Days With SCD Symptom Exacerbation During the First 24 Weeks of Treatment ^[29]

End point description

SCD symptoms were measured using the Sickle Cell Disease Severity Measure (SCDSM) which was a self-administered 9-item questionnaire of SCD core symptoms including pain severity, frequency, and type, as well as fatigue and mental acuity, on a 4-point response scale that was completed daily using a handheld electronic device by the participants. Data for this outcome measure was not collected as the definition for this variable was not available at the time of analysis.

End point type

Secondary

End point timeframe

From Day 1 up to 24 weeks

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part B; hence, only Part B arms are reported.

End point values	Part B: Voxelotor 900 mg QD	Part B: Voxelotor 1500 mg QD
Number of subjects analysed	0 ^[30]	0 ^[31]
Units: Percentage of days
number (not applicable)

Notes
[30] - Data not collected as variable was not defined at time of analysis.
[31] - Data not collected as variable was not defined at time of analysis.

No statistical analyses for this end point

Secondary: Part B: Percent Change From Baseline to Weeks 12 and 24 in Lactate Dehydrogenase (LDH)

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End point title

Part B: Percent Change From Baseline to Weeks 12 and 24 in Lactate Dehydrogenase (LDH) ^[32]

End point description

Efficacy-Evaluable Population comprised of all participants who received any amount of study drug. Here, ‘Participants Analyzed’ signifies number of participants evaluable for this endpoint and ‘n’ signifies number of participants evaluable for the specified rows.

End point type

Secondary

End point timeframe

Baseline, Weeks 12 and 24

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part B; hence, only Part B arms are reported.

End point values	Part B: Voxelotor 900 mg QD	Part B: Voxelotor 1500 mg QD
Number of subjects analysed	21	14
Units: Percent change
arithmetic mean (standard deviation)
Week 12	-6.3 ( 21.08 )	-1.7 ( 32.78 )
Week 24	-6.3 ( 22.47 )	-1.9 ( 14.59 )

No statistical analyses for this end point

Secondary: Part B: Percent Change From Baseline to Weeks 12 and 24 in Indirect Bilirubin

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End point title

Part B: Percent Change From Baseline to Weeks 12 and 24 in Indirect Bilirubin ^[33]

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 12 and 24

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part B; hence, only Part B arms are reported.

End point values	Part B: Voxelotor 900 mg QD	Part B: Voxelotor 1500 mg QD
Number of subjects analysed	22	13
Units: Percent change
arithmetic mean (standard deviation)
Week 12; n=22, 13	-32.1 ( 31.98 )	-29.9 ( 33.59 )
Week 24; n=22, 12	-37.5 ( 29.07 )	-32.1 ( 31.53 )

No statistical analyses for this end point

Secondary: Part B: Percent Change From Baseline to Week 12 and 24 in Percentage Reticulocytes

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End point title

Part B: Percent Change From Baseline to Week 12 and 24 in Percentage Reticulocytes ^[34]

End point description

Efficacy-Evaluable Population comprised of all participants who received any amount of study drug. Here, ‘Participants Analyzed’ signifies number of participants evaluable for this outcome measure and ‘n’ signifies number of participants evaluable for the specified rows.

End point type

Secondary

End point timeframe

Baseline, Weeks 12 and 24

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part B; hence, only Part B arms are reported.

End point values	Part B: Voxelotor 900 mg QD	Part B: Voxelotor 1500 mg QD
Number of subjects analysed	23	14
Units: Percent change
arithmetic mean (standard deviation)
Week 12; n=23, 14	-8.7 ( 36.46 )	-3.5 ( 42.96 )
Week 24; n=22, 12	-14.1 ( 34.06 )	1.5 ( 43.18 )

No statistical analyses for this end point

Secondary: Part B: Cmax of Voxelotor in Whole Blood and Plasma

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End point title

Part B: Cmax of Voxelotor in Whole Blood and Plasma ^[35]

End point description

PK population comprised of participants who received at least one dose of voxelotor and had at least 1 measurable voxelotor concentration observation in plasma or whole blood with associated sampling time and dosing information.

End point type

Secondary

End point timeframe

Day 1 (pre-dose, 2, 8, 24 hours post-dose), pre-dose on Weeks 2, 4, 8, 12, 16, 20 and 24

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part B; hence, only Part B arms are reported.

End point values	Part B: Voxelotor 900 mg QD	Part B: Voxelotor 1500 mg QD
Number of subjects analysed	25	15
Units: Microgram per milliliter
geometric mean (geometric coefficient of variation)
Cmax, plasma	5.64 ( 41 )	9.81 ( 37 )
Cmax, whole blood	102 ( 38 )	59 ( 32 )

No statistical analyses for this end point

Secondary: Part B: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor for Whole Blood and Plasma

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End point title

Part B: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor for Whole Blood and Plasma ^[36]

End point description

AUC0-inf was calculated as AUCt + Ct/lambdaz, where AUCt=area under the concentration-time curve at designated time, Ct is the last quantifiable concentration and lambdaz is the elimination rate constant. PK population comprised of participants who received at least one dose of voxelotor and had at least 1 measurable voxelotor concentration observation in plasma or whole blood with associated sampling time and dosing information.

End point type

Secondary

End point timeframe

Day 1 (pre-dose, 2, 8, 24 hours post-dose), pre-dose on Weeks 2, 4, 8, 12, 16, 20 and 24

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part B; hence, only Part B arms are reported.

End point values	Part B: Voxelotor 900 mg QD	Part B: Voxelotor 1500 mg QD
Number of subjects analysed	25	15
Units: Hours*microgram per milliliter
geometric mean (geometric coefficient of variation)
AUC0-inf, plasma	113 ( 46 )	195 ( 40 )
AUC0-inf, whole blood	2090 ( 43 )	3290 ( 36 )

No statistical analyses for this end point

Secondary: Part B: Accumulation Ratio (Rac) of Voxelotor for Plasma and Whole Blood

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End point title

Part B: Accumulation Ratio (Rac) of Voxelotor for Plasma and Whole Blood ^[37]

End point description

Accumulation ratio was calculated as ratio of area under the concentration-time curve from time zero (predose) to 24 hours (AUC0-24) at steady-state (Day 28) to AUC0-24 on Day 1. PK population comprised of participants who received at least one dose of voxelotor and had at least 1 measurable voxelotor concentration observation in plasma or whole blood with associated sampling time and dosing information.

End point type

Secondary

End point timeframe

Day 1 (0 to 24 hours post-dose) and Day 28 (0 to 24 hours post-dose)

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part B; hence, only Part B arms are reported.

End point values	Part B: Voxelotor 900 mg QD	Part B: Voxelotor 1500 mg QD
Number of subjects analysed	25	15
Units: Ratio
geometric mean (geometric coefficient of variation)
Rac, plasma	2.57 ( 29 )	2.62 ( 33 )
Rac, whole blood	2.46 ( 27 )	2.47 ( 30 )

No statistical analyses for this end point

Secondary: Part B: Terminal Elimination Half-life of Voxelotor for Plasma and Whole Blood

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End point title

Part B: Terminal Elimination Half-life of Voxelotor for Plasma and Whole Blood ^[38]

End point description

T1/2 was the time measured for the drug concentration to decrease by one half. PK population comprised of participants who received at least one dose of voxelotor and had at least 1 measurable voxelotor concentration observation in plasma or whole blood with associated sampling time and dosing information.

End point type

Secondary

End point timeframe

Day 1 (pre-dose, 2, 8, 24 hours post-dose), pre-dose on Weeks 2, 4, 8, 12, 16, 20 and 24

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part B; hence, only Part B arms are reported.

End point values	Part B: Voxelotor 900 mg QD	Part B: Voxelotor 1500 mg QD
Number of subjects analysed	25	15
Units: Hours
geometric mean (geometric coefficient of variation)
T1/2, plasma	33 ( 41 )	33.9 ( 44 )
T1/2, whole blood	31.1 ( 39 )	31.4 ( 41 )

No statistical analyses for this end point

Secondary: Part B: Change From Baseline to Week 12 and 24 in Cerebral Blood Flow as Measured by the TAMM TCD Velocity

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End point title

Part B: Change From Baseline to Week 12 and 24 in Cerebral Blood Flow as Measured by the TAMM TCD Velocity ^[39]

End point description

Cerebral blood flow velocity was measured using TCD sonography. Change from baseline in cerebral blood flow velocity as measured by TAMM TCD velocity is reported. Efficacy-Evaluable Population comprised of all participants who received any amount of study drug. Here, ‘Participants Analyzed’ signifies number of participants evaluable for this endpoint and 'n’ signifies number of participants evaluable for the specified rows.

End point type

Secondary

End point timeframe

Baseline, Weeks 12 and 24

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part B; hence, only Part B arms are reported.

End point values	Part B: Voxelotor 900 mg QD	Part B: Voxelotor 1500 mg QD
Number of subjects analysed	23	13
Units: Centimeter per second
geometric mean (geometric coefficient of variation)
Week 12; n=23, 13	0.9 ( 16.48 )	-0.1 ( 9.34 )
Week 24; n=20, 12	-2.1 ( 14.03 )	1.7 ( 14.26 )

No statistical analyses for this end point

Secondary: Part B: Percentage Hemoglobin Occupancy

Top of page

End point title

Part B: Percentage Hemoglobin Occupancy ^[40]

End point description

% Hb Occupancy refers to the percentage of hemoglobin molecules within red blood cells that were bound to study drug. Concentration of voxelotor in whole blood and plasma was used to calculate %Hb occupancy. Percentage Hb occupancy within RBCs was estimated using the formula: ([Concentration of voxelotor in whole blood- {1-hematocrit}]*[Concentration of voxelotor in plasma/ hematocrit])/5000*100. PK population comprised of participants who received at least one dose of voxelotor and had at least 1 measurable voxelotor concentration observation in plasma or whole blood with associated sampling time and dosing information.

End point type

Secondary

End point timeframe

Day 28

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part B; hence, only Part B arms are reported.

End point values	Part B: Voxelotor 900 mg QD	Part B: Voxelotor 1500 mg QD
Number of subjects analysed	25	15
Units: Percentage of bound hemoglobin
geometric mean (geometric coefficient of variation)	19.4 ( 34 )	29.5 ( 27 )

No statistical analyses for this end point

Secondary: Part C: Percent Change From Baseline to Weeks 24 and 48 in LDH

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End point title

Part C: Percent Change From Baseline to Weeks 24 and 48 in LDH ^[41]

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 24 and 48

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part C; hence, only Part C arms are reported.

End point values	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD
Number of subjects analysed	39	4
Units: Percent change
arithmetic mean (standard deviation)
Week 24; n=39, 4	-5.1 ( 21.95 )	-22.4 ( 22.08 )
Week 48; n=35, 2	-1.8 ( 23.80 )	3.9 ( 8.91 )

No statistical analyses for this end point

Secondary: Part C: Change From Baseline to Weeks 24 and 48 in Hemoglobin Level

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End point title

Part C: Change From Baseline to Weeks 24 and 48 in Hemoglobin Level ^[42]

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 24 and 48

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part C; hence, only Part C arms are reported.

End point values	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD
Number of subjects analysed	41	6
Units: Grams per deciliter
arithmetic mean (standard deviation)
Week 24; n=41, 6	1.0 ( 1.16 )	0.8 ( 1.14 )
Week 48; n=37, 3	0.7 ( 1.15 )	-0.1 ( 0.20 )

No statistical analyses for this end point

Secondary: Part C: Percent Change From Baseline to Weeks 24 and 48 in Indirect Bilirubin

Top of page

End point title

Part C: Percent Change From Baseline to Weeks 24 and 48 in Indirect Bilirubin ^[43]

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 24 and 48

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part C; hence, only Part C arms are reported.

End point values	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD
Number of subjects analysed	34	6
Units: Percent change
arithmetic mean (standard deviation)
Week 24; n=34, 6	-36.9 ( 26.55 )	-45.7 ( 24.93 )
Week 48; n=32, 3	-26.6 ( 37.05 )	-33.0 ( 36.76 )

No statistical analyses for this end point

Secondary: Part C: Percent Change From Baseline to Weeks 24 and 48 in Percentage Reticulocytes

Top of page

End point title

Part C: Percent Change From Baseline to Weeks 24 and 48 in Percentage Reticulocytes ^[44]

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 24 and 48

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part C; hence, only Part C arms are reported.

End point values	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD
Number of subjects analysed	37	5
Units: Percent change
arithmetic mean (standard deviation)
Week 24; n=37, 5	-4.76 ( 42.999 )	-1.17 ( 31.595 )
Week 48; n=34, 2	-0.33 ( 46.353 )	2.94 ( 38.295 )

No statistical analyses for this end point

Secondary: Part C: Change From Baseline to Week 24 in Cerebral Blood Flow as Measured by the TAMM TCD Velocity

Top of page

End point title

Part C: Change From Baseline to Week 24 in Cerebral Blood Flow as Measured by the TAMM TCD Velocity ^[45]

End point description

Efficacy-Evaluable Population comprised of all participants who received any amount of study drug. Here, 'Participants Analyzed’ signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 24

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part C; hence, only Part C arms are reported.

End point values	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD
Number of subjects analysed	40	6
Units: Centimeter per second
arithmetic mean (standard deviation)	-3.2 ( 15.69 )	-11.8 ( 18.82 )

No statistical analyses for this end point

Secondary: Part C: Time to Initial Hemoglobin Response

Top of page

End point title

Part C: Time to Initial Hemoglobin Response ^[46]

End point description

Time to initial Hb response was defined as the time from first dose of study treatment to the first occurrence of a change from baseline in Hb > 1 gram per deciliter (g/dL). Efficacy-Evaluable Population comprised of all participants who received any amount of study drug. Here, ‘Participants Analyzed’ signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

From first dose of study treatment (Day 1) up to Week 48

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part C; hence, only Part C arms are reported.

End point values	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD
Number of subjects analysed	36	8
Units: Weeks
arithmetic mean (standard deviation)	4.9 ( 5.51 )	5.6 ( 4.90 )

No statistical analyses for this end point

Secondary: Part C: Cmax of Voxelotor for Plasma and Whole Blood

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End point title

Part C: Cmax of Voxelotor for Plasma and Whole Blood ^[47]

End point description

End point type

Secondary

End point timeframe

Day 1 (15 minutes to 2 hours post-dose), pre-dose on Weeks 4, 8, 12, 16, 20, 24, 36 and 48

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part C; hence, only Part C arms are reported.

End point values	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD
Number of subjects analysed	49	11
Units: Microgram per milliliter
geometric mean (geometric coefficient of variation)
Cmax, plasma	7.83 ( 61 )	9.04 ( 43 )
Cmax, whole blood	127 ( 52 )	137 ( 38 )

No statistical analyses for this end point

Secondary: Part C: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor for Whole Blood and Plasma

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End point title

Part C: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor for Whole Blood and Plasma ^[48]

End point description

AUC0-inf was calculated as AUCt + Ct/lambdaz, where AUCt=area under the concentration-time curve at designated time, Ct is the last quantifiable concentration and lambdaz is the elimination rate constant. PK population comprised of participants who received at least one dose of voxelotor and had at least 1 measurable voxelotor concentration observation in plasma or whole blood with associated sampling time and dosing information. Here, ‘Participants Analyzed’ signifies participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Day 1 (15 minutes to 2 hours post-dose), pre-dose on Weeks 4, 8, 12, 16, 20, 24, 36 and 48

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part C; hence, only Part C arms are reported.

End point values	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD
Number of subjects analysed	49	11
Units: Hours*microgram per milliliter
geometric mean (geometric coefficient of variation)
AUC0-inf, plasma	160 ( 72 )	184 ( 44 )
AUC0-inf, whole blood	2660 ( 64 )	2880 ( 41 )

No statistical analyses for this end point

Secondary: Part C: Terminal Elimination Half-life (T1/2) of Voxelotor for Whole Blood and Plasma

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End point title

Part C: Terminal Elimination Half-life (T1/2) of Voxelotor for Whole Blood and Plasma ^[49]

End point description

T1/2 was the time measured for the drug concentration to decrease by one half in whole blood and plasma, respectively. PK population comprised of participants who received at least one dose of voxelotor and had at least 1 measurable voxelotor concentration observation in plasma or whole blood with associated sampling time and dosing information. Here, ‘Participants Analyzed’ signifies participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Day 1 (15 minutes to 2 hours post-dose), pre-dose on Weeks 4, 8, 12, 16, 20, 24, 36 and 48

Notes
[49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part C; hence, only Part C arms are reported.

End point values	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD
Number of subjects analysed	49	11
Units: Hours
geometric mean (geometric coefficient of variation)
T1/2, plasma	41.6 ( 50 )	35.6 ( 28 )
T1/2, whole blood	37.4 ( 48 )	32.7 ( 25 )

No statistical analyses for this end point

Secondary: Part C: Percentage of Participants With Normal Transcranial Doppler (TCD) Flow Velocity at Week 48

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End point title

Part C: Percentage of Participants With Normal Transcranial Doppler (TCD) Flow Velocity at Week 48 ^[50]

End point description

Normal TCD flow velocity was considered as < 170 centimeter per second (cm/sec) by non-imagining TCD or < 155 cm/sec by imaging transcranial Doppler (TCDi). Percentage of participants with normal TCD flow velocity at Week 48 by Baseline TCD group (i.e. Baseline normal TCD [<170 cm/sec] and Baseline conditional TCD [>=170 cm/sec] is reported. Efficacy-Evaluable Population comprised of all participants who received any amount of study drug. All participants reported, ‘Participants Analyzed’ contributed data to the table; however, may not have evaluable data for each row. Here, ‘n ‘signifies number of participants evaluable for each row.

End point type

Secondary

End point timeframe

Week 48

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part C; hence, only Part C arms are reported.

End point values	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD
Number of subjects analysed	34	3
Units: Percentage of participants
number (not applicable)
Baseline normal; n=27, 1	96.3	100
Baseline conditional; n=7, 2	42.9	100

No statistical analyses for this end point

Secondary: Part C: Annualized Incidence Rate of Vaso-occlusive Crisis (VOC) Events

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End point title

Part C: Annualized Incidence Rate of Vaso-occlusive Crisis (VOC) Events ^[51]

End point description

VOC events included preferred terms of sickle cell anaemia with crisis, acute chest syndrome, pneumonia necrotising and pneumonia. Annualized incidence rate was calculated as total number of events divided by total person years. Total person years=sum of participants treatment period in years, which covered the time from first dose to last dose. Efficacy-Evaluable Population comprised of all participants who received any amount of study drug.

End point type

Secondary

End point timeframe

Up to Week 48

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part C; hence, only Part C arms are reported.

End point values	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD
Number of subjects analysed	51	11
Units: VOC events per person year
number (confidence interval 95%)	1.246 (0.912 to 1.662)	2.250 (1.123 to 4.025)

No statistical analyses for this end point

Secondary: Part C: Percentage Hemoglobin Occupancy of Voxelotor

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End point title

Part C: Percentage Hemoglobin Occupancy of Voxelotor ^[52]

End point description

End point type

Secondary

End point timeframe

Day 28

Notes
[52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part C; hence, only Part C arms are reported.

End point values	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD
Number of subjects analysed	49	11
Units: Percentage of bound hemoglobin
geometric mean (geometric coefficient of variation)	24.7 ( 47 )	27.7 ( 30 )

No statistical analyses for this end point

Secondary: Part D: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor for Plasma and Whole Blood

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End point title

Part D: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor for Plasma and Whole Blood ^[53]

End point description

AUC0-inf was calculated as AUCt + Ct/lambdaz, where AUCt=area under the concentration-time curve at designated time, Ct is the last quantifiable concentration and lambdaz is the elimination rate constant. PK population comprised of participants who received at least one dose of voxelotor and had at least 1 measurable voxelotor concentration observation in plasma or whole blood with associated sampling time and dosing information. Here, ‘Participants Analyzed’ signifies number of participants evaluable for this endpoint

End point type

Secondary

End point timeframe

Day 1 (anytime between 15 minutes to 2 hours post-dose), pre-dose on Weeks 2, 8, 12, 16, 24, 36 and 48

Notes
[53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part D; hence, only Part D arms are reported.

End point values	Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD	Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD
Number of subjects analysed	8	21
Units: Hours*microgram per milliliter
geometric mean (geometric coefficient of variation)
AUC0-inf, plasma	89.9 ( 110 )	186 ( 38 )
AUC0-inf, whole blood	1600 ( 120 )	3040 ( 36 )

No statistical analyses for this end point

Secondary: Part D: Cmax of Voxelotor for Plasma and Whole Blood

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End point title

Part D: Cmax of Voxelotor for Plasma and Whole Blood ^[54]

End point description

End point type

Secondary

End point timeframe

Day 1 (anytime between 15 minutes to 2 hours post-dose), pre-dose on Weeks 2, 8, 12, 16, 24, 36 and 48

Notes
[54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part D; hence, only Part D arms are reported.

End point values	Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD	Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD
Number of subjects analysed	8	21
Units: Microgram per milliliter
geometric mean (geometric coefficient of variation)
Cmax, plasma	5.01 ( 73 )	9.45 ( 34 )
Cmax, whole blood	87.2 ( 74 )	149 ( 30 )

No statistical analyses for this end point

Secondary: Part C: Annualized Incidence Rate of Stroke Events

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End point title

Part C: Annualized Incidence Rate of Stroke Events ^[55]

End point description

Annualized incidence rate was calculated as total number of events divided by total person years. Total person years=sum of participants treatment period in years, which covered the time from first dose to last dose. Efficacy-Evaluable Population comprised of all participants who received any amount of study drug.

End point type

Secondary

End point timeframe

Up to Week 48

Notes
[55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part C; hence, only Part C arms are reported.

End point values	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD
Number of subjects analysed	51	11
Units: Stroke events per person year
number (confidence interval 95%)	0.000 (0.000 to 0.100)	0.000 (0.000 to 0.754)

No statistical analyses for this end point

Secondary: Part D: Change From Baseline to Weeks 24 and 48 in Hemoglobin Level

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End point title

Part D: Change From Baseline to Weeks 24 and 48 in Hemoglobin Level ^[56]

End point description

Efficacy-Evaluable Population comprised of all participants who received any amount of study drug. Here, ‘Participants Analyzed’ signifies number of participants evaluable for this endpoint

End point type

Secondary

End point timeframe

Baseline, Weeks 24 and 48

Notes
[56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part D; hence, only Part D arms are reported.

End point values	Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD	Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD
Number of subjects analysed	7	20
Units: Grams per deciliter
arithmetic mean (standard deviation)
Week 24	0.4 ( 2.03 )	0.6 ( 1.02 )
Week 48	0.5 ( 1.53 )	0.7 ( 1.45 )

No statistical analyses for this end point

Secondary: Part D: Percentage Hemoglobin Occupancy

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End point title

Part D: Percentage Hemoglobin Occupancy ^[57]

End point description

End point type

Secondary

End point timeframe

Day 28

Notes
[57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part D; hence, only Part D arms are reported.

End point values	Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD	Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD
Number of subjects analysed	8	21
Units: Percentage of bound hemoglobin
geometric mean (geometric coefficient of variation)	17.5 ( 60 )	28.9 ( 26 )

No statistical analyses for this end point

Secondary: Part D: T1/2 of Voxelotor for Plasma and Whole Blood

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End point title

Part D: T1/2 of Voxelotor for Plasma and Whole Blood ^[58]

End point description

End point type

Secondary

End point timeframe

Day 1 (anytime between 15 minutes to 2 hours post-dose), pre-dose on Weeks 2, 8, 12, 16, 24, 36 and 48

Notes
[58] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part D; hence, only Part D arms are reported.

End point values	Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD	Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD
Number of subjects analysed	8	21
Units: Hours
geometric mean (geometric coefficient of variation)
T1/2, plasma	24.1 ( 70 )	36.1 ( 40 )
T1/2, whole blood	21.7 ( 82 )	32.7 ( 38 )

No statistical analyses for this end point

Secondary: Part D: Percent Change From Baseline to Weeks 24 and 48 in Indirect Bilirubin

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End point title

Part D: Percent Change From Baseline to Weeks 24 and 48 in Indirect Bilirubin ^[59]

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 24 and 48

Notes
[59] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part D; hence, only Part D arms are reported.

End point values	Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD	Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD
Number of subjects analysed	7	18
Units: Percent change
arithmetic mean (standard deviation)
Week 24; n=7, 18	-14.4 ( 28.11 )	-24.5 ( 24.50 )
Week 48; n=7, 17	4.4 ( 42.05 )	-24.5 ( 21.97 )

No statistical analyses for this end point

Secondary: Part D: Percent Change From Baseline to Weeks 24 and 48 in LDH

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End point title

Part D: Percent Change From Baseline to Weeks 24 and 48 in LDH ^[60]

End point description

End point type

Secondary

End point timeframe

Baseline, Weeks 24 and 48

Notes
[60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part D; hence, only Part D arms are reported.

End point values	Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD	Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD
Number of subjects analysed	6	20
Units: Percent change
arithmetic mean (standard deviation)
Week 24; n=6, 20	27.6 ( 56.46 )	-0.4 ( 31.53 )
Week 48; n=6, 18	26.3 ( 43.98 )	7.4 ( 45.94 )

No statistical analyses for this end point

Secondary: Part D: Percent Change From Baseline to Weeks 24 and 48 in Reticulocytes Count

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End point title

Part D: Percent Change From Baseline to Weeks 24 and 48 in Reticulocytes Count ^[61]

End point description

Efficacy-Evaluable Population comprised of all participants who received any amount of study drug. Here, Participants Analyzed’ signifies number of participants evaluable for this endpoint and ‘n’ signifies participants evaluable for the specified rows

End point type

Secondary

End point timeframe

Baseline, Weeks 24 and 48

Notes
[61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part D; hence, only Part D arms are reported.

End point values	Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD	Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD
Number of subjects analysed	6	14
Units: Percent change
arithmetic mean (standard deviation)
Week 24; n=6, 14	-3.6 ( 28.64 )	3.8 ( 31.88 )
Week 48; n=6, 13	-11.5 ( 31.19 )	-0.7 ( 29.70 )

No statistical analyses for this end point

Secondary: Part D: Time to Initial Hemoglobin Response

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End point title

Part D: Time to Initial Hemoglobin Response ^[62]

End point description

Time to initial Hb response, defined as the time from first dose of study treatment to the first occurrence of a change from baseline in Hb > 1 g/dL. Efficacy-Evaluable Population comprised of all participants who received any amount of study drug. Here, 'Participants Analyzed’ signifies number of participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

From first dose of study treatment (Day 1) up to Week 48

Notes
[62] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part D; hence, only Part D arms are reported.

End point values	Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD	Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD
Number of subjects analysed	6	18
Units: Weeks
arithmetic mean (standard deviation)	8.0 ( 7.60 )	4.7 ( 8.80 )

No statistical analyses for this end point

Secondary: Part D: Annualized Incidence Rate of VOC Events

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End point title

Part D: Annualized Incidence Rate of VOC Events ^[63]

End point description

VOC events included preferred terms of 'Sickle cell anemia with crisis', 'Acute chest syndrome', 'Pneumonia necrotising,' and 'Pneumonia. Annualized incidence rate was calculated as total number of events divided by total person years. Total person years=sum of participants treatment period in years, which covered the time from first dose to last dose. Efficacy-Evaluable Population comprised of all participants who received any amount of study drug.

End point type

Secondary

End point timeframe

Up to Week 48

Notes
[63] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part D; hence, only Part D arms are reported.

End point values	Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD	Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD
Number of subjects analysed	9	23
Units: VOC events per person year
number (confidence interval 95%)	1.473 (0.706 to 2.708)	1.399 (0.914 to 2.050)

No statistical analyses for this end point

Secondary: Part D: Annualized Incidence Rate of Stroke Events

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End point title

Part D: Annualized Incidence Rate of Stroke Events ^[64]

End point description

End point type

Secondary

End point timeframe

Up to Week 48

Notes
[64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is specific to Part D; hence, only Part D arms are reported.

End point values	Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD	Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg QD
Number of subjects analysed	9	23
Units: Stroke events per person year
number (confidence interval 95%)	0.000 (0.000 to 2.708)	0.000 (0.000 to 0.198)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Part A: From start of treatment on Day 1 up to 2 weeks after last dose (up to Day 15); Part B, C and D: From start of treatment on Day 1 up to 4 weeks after last dose (up to Week 28 for Part B and up to Week 52 for Parts C and D).

Adverse event reporting additional description

An AE term may be reported as both serious and non-serious AE but are distinct events. An AE may be serious for 1 participant and non-serious for another participant, or a participant may have experienced both a serious and non-serious episode of the same event. Safety population comprised of all participants who received any amount of study drug.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

Part A: Participants aged 12 to 17 years: Voxelotor 600 mg

Reporting group description

Participants aged 12 to 17 years received a single oral dose of voxelotor 600 milligrams (mg) on Day 1.

Reporting group title

Part B: Voxelotor 900 mg QD

Reporting group description

Participants aged 12 to 17 years received once daily (QD) oral dose of voxelotor 900 mg for 24 weeks.

Reporting group title

Part A: Participants aged 6 to 11 years: Voxelotor 600 mg

Reporting group description

Participants aged 6 to 11 years received a single oral dose of voxelotor 600 mg on Day 1.

Reporting group title

Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD

Reporting group description

Participants aged 6 months (M) to <2 years received once daily oral dose of voxelotor 1500 mg for 48 weeks.

Reporting group title

Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD

Reporting group description

Participants aged 12 to 17 years received once daily oral dose of voxelotor 1500 mg for 48 weeks.

Reporting group title

Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD

Reporting group description

Participants aged 4 to 11 years received once daily oral dose of voxelotor 1500 mg for 48 weeks.

Reporting group title

Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg

Reporting group description

Participants aged 2 to <4 years received once daily oral dose of voxelotor 1500 mg for 48 weeks.

Reporting group title

Part B: Voxelotor 1500 mg QD

Reporting group description

Participants aged 12 to 17 years received once daily oral dose of voxelotor 1500 mg for 24 weeks.

Serious adverse events	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part B: Voxelotor 900 mg QD	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg	Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg	Part B: Voxelotor 1500 mg QD
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 7 (14.29%)	12 / 25 (48.00%)	0 / 6 (0.00%)	7 / 9 (77.78%)	8 / 11 (72.73%)	23 / 51 (45.10%)	14 / 23 (60.87%)	7 / 15 (46.67%)
number of deaths (all causes)	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0
Vascular disorders
Pallor
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Splenectomy
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	2 / 9 (22.22%)	1 / 11 (9.09%)	5 / 51 (9.80%)	3 / 23 (13.04%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 1	1 / 7	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Priapism
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	2 / 15 (13.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Hypoxia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute chest syndrome
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	8 / 51 (15.69%)	2 / 23 (8.70%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1	0 / 0	0 / 11	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Haemoglobin decreased
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Electrocardiogram T wave inversion
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ultrasound head abnormal
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Sickle cell anaemia with crisis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	1 / 7 (14.29%)	9 / 25 (36.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	7 / 11 (63.64%)	18 / 51 (35.29%)	7 / 23 (30.43%)	4 / 15 (26.67%)
occurrences causally related to treatment / all	0 / 2	0 / 16	0 / 0	0 / 1	0 / 10	1 / 42	0 / 13	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemolytic anaemia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypersplenism
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	4 / 51 (7.84%)	3 / 23 (13.04%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 4	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Platelet disorder
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	2 / 9 (22.22%)	0 / 11 (0.00%)	0 / 51 (0.00%)	4 / 23 (17.39%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4	0 / 0	0 / 0	0 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Periorbital swelling
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Constipation
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Pain in extremity
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Influenza
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	3 / 23 (13.04%)	1 / 15 (6.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	3 / 51 (5.88%)	3 / 23 (13.04%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0	0 / 4	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Salmonellosis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchiolitis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malaria
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rotavirus infection
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia necrotising
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Part A: Participants aged 12 to 17 years: Voxelotor 600 mg	Part B: Voxelotor 900 mg QD	Part A: Participants aged 6 to 11 years: Voxelotor 600 mg	Part D: Participants aged 6M to <2 years: Voxelotor 1500 mg QD	Part C: Participants aged 12 to 17 years: Voxelotor 1500 mg QD	Part C: Participants aged 4 to 11 years: Voxelotor 1500 mg QD	Part D: Participants aged 2 to <4 years: Voxelotor 1500 mg	Part B: Voxelotor 1500 mg QD
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 7 (85.71%)	22 / 25 (88.00%)	3 / 6 (50.00%)	9 / 9 (100.00%)	11 / 11 (100.00%)	46 / 51 (90.20%)	21 / 23 (91.30%)	15 / 15 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign lymph node neoplasm
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
General disorders and administration site conditions
Non-cardiac chest pain
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	1 / 7 (14.29%)	2 / 25 (8.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	1 / 51 (1.96%)	0 / 23 (0.00%)	2 / 15 (13.33%)
occurrences all number	1	2	0	0	1	1	0	3
Pyrexia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	2 / 25 (8.00%)	0 / 6 (0.00%)	4 / 9 (44.44%)	2 / 11 (18.18%)	15 / 51 (29.41%)	8 / 23 (34.78%)	2 / 15 (13.33%)
occurrences all number	0	4	0	6	2	27	12	4
Pain
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	2 / 25 (8.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	4 / 51 (7.84%)	1 / 23 (4.35%)	1 / 15 (6.67%)
occurrences all number	0	2	0	0	0	5	1	2
Fatigue
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	2 / 51 (3.92%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	1	0	0	0	2	0	1
Chest discomfort
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Peripheral swelling
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	1 / 11 (9.09%)	1 / 51 (1.96%)	2 / 23 (8.70%)	1 / 15 (6.67%)
occurrences all number	0	0	0	1	1	1	2	1
Chest pain
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1	0	1
Gait disturbance
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Immune system disorders
Seasonal allergy
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1	0	1
Allergic oedema
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0
Reproductive system and breast disorders
Priapism
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0
Respiratory, thoracic and mediastinal disorders
Acute chest syndrome
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	2 / 25 (8.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Cough
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	2 / 11 (18.18%)	2 / 51 (3.92%)	1 / 23 (4.35%)	1 / 15 (6.67%)
occurrences all number	0	2	0	1	2	3	1	1
Oropharyngeal pain
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	3 / 15 (20.00%)
occurrences all number	0	1	0	0	0	0	0	3
Nasal congestion
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	2 / 15 (13.33%)
occurrences all number	0	1	0	0	0	0	1	2
Epistaxis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	2 / 25 (8.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	3 / 51 (5.88%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	3	0	1	0	3	0	0
Dyspnoea
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Rhinorrhoea
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1	0	1
Upper-airway cough syndrome
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Hypoxia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Sinus congestion
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Paranasal sinus hypersecretion
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Obstructive sleep apnoea syndrome
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Tonsillar erythema
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Tonsillar hypertrophy
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Allergic respiratory symptom
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0
Psychiatric disorders
Stress
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Anxiety
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	1	0	0	0	1
Insomnia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Mental status changes
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Post-traumatic stress disorder
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Enuresis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0
Encopresis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Investigations
Transaminases increased
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	1	0	0	0	1	0	1
Bacterial test positive
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Alanine aminotransferase increased
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	2 / 51 (3.92%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	2	1	0
Neutrophil count decreased
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Influenza A virus test positive
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Haemoglobin decreased
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	1 / 11 (9.09%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0
Electrocardiogram QT prolonged
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Breath sounds abnormal
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Blood bilirubin increased
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Aspartate aminotransferase increased
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	2 / 51 (3.92%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	2	0	0
Blood alkaline phosphatase increased
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Ultrasound head abnormal
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Injury, poisoning and procedural complications
Fall
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0
Arthropod bite
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Joint injury
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Laceration
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Foot fracture
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Epiphyseal fracture
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Sports injury
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	2 / 51 (3.92%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0
Muscle strain
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Foreign body ingestion
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Cardiac disorders
Tachycardia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	2 / 51 (3.92%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	2	0	1
Ventricular hypertrophy
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Left atrial dilatation
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Diastolic dysfunction
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Cardiomegaly
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Nervous system disorders
Headache
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	1 / 7 (14.29%)	7 / 25 (28.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	9 / 51 (17.65%)	0 / 23 (0.00%)	4 / 15 (26.67%)
occurrences all number	1	10	0	0	1	11	0	10
Lethargy
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	1	0	0	1
Migraine
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Syncope
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Dizziness
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	3 / 25 (12.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	3	0	0	0	0	0	0
Depressed level of consciousness
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Hypersomnia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Blood and lymphatic system disorders
Sickle cell anaemia with crisis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	1 / 7 (14.29%)	5 / 25 (20.00%)	1 / 6 (16.67%)	5 / 9 (55.56%)	2 / 11 (18.18%)	10 / 51 (19.61%)	10 / 23 (43.48%)	3 / 15 (20.00%)
occurrences all number	1	13	1	9	6	19	14	6
Anaemia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	2 / 51 (3.92%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences all number	0	1	0	1	0	2	2	0
Neutropenia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	1	1
Thrombocytopenia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	1 / 6 (16.67%)	0 / 9 (0.00%)	0 / 11 (0.00%)	4 / 51 (7.84%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	1	1	0	0	4	1	0
Thrombocytosis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	4 / 51 (7.84%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	4	1	0
Reticulocytopenia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Splenomegaly
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Hypersplenism
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Hypercoagulation
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Ear and labyrinth disorders
Hypoacusis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Tinnitus
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Eye disorders
Retinopathy sickle cell
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	2
Visual impairment
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Eye pain
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0
Gastrointestinal disorders
Vomiting
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	5 / 25 (20.00%)	0 / 6 (0.00%)	5 / 9 (55.56%)	1 / 11 (9.09%)	15 / 51 (29.41%)	2 / 23 (8.70%)	2 / 15 (13.33%)
occurrences all number	0	10	0	6	1	17	2	2
Abdominal pain
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	4 / 25 (16.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	1 / 11 (9.09%)	5 / 51 (9.80%)	1 / 23 (4.35%)	3 / 15 (20.00%)
occurrences all number	0	6	0	1	1	5	1	3
Nausea
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	2 / 7 (28.57%)	9 / 25 (36.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	4 / 51 (7.84%)	1 / 23 (4.35%)	3 / 15 (20.00%)
occurrences all number	2	12	0	0	1	7	1	5
Diarrhoea
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	3 / 25 (12.00%)	0 / 6 (0.00%)	2 / 9 (22.22%)	1 / 11 (9.09%)	10 / 51 (19.61%)	3 / 23 (13.04%)	2 / 15 (13.33%)
occurrences all number	0	5	0	3	1	11	3	3
Constipation
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	3 / 25 (12.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	2 / 51 (3.92%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences all number	0	3	0	1	0	3	2	0
Abdominal pain upper
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	4 / 51 (7.84%)	2 / 23 (8.70%)	2 / 15 (13.33%)
occurrences all number	0	0	0	0	0	4	2	2
Dental caries
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0
Gastritis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Toothache
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Abdominal distension
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
gastrointestinal disorder
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Lip blister
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Flatulence
subjects affected / exposed	1 / 7 (14.29%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0
Hepatobiliary disorders
Cholelithiasis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Ocular icterus
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Hypertransaminasaemia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Jaundice
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Skin and subcutaneous tissue disorders
Rash papular
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0
Dermatitis contact
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0
Rash
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	6 / 51 (11.76%)	2 / 23 (8.70%)	1 / 15 (6.67%)
occurrences all number	0	0	0	1	0	6	2	1
Rash generalised
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Pruritus
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	1 / 7 (14.29%)	2 / 25 (8.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	2 / 51 (3.92%)	0 / 23 (0.00%)	2 / 15 (13.33%)
occurrences all number	1	2	0	0	0	3	0	4
Urticaria
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Rash maculo-papular
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0
Dry skin
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Dermatitis allergic
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Rash pruritic
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Renal and urinary disorders
Micturition urgency
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Proteinuria
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Dysuria
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Albuminuria
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Hypertonic bladder
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Musculoskeletal and connective tissue disorders
Osteonecrosis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Pain in extremity
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	1 / 7 (14.29%)	10 / 25 (40.00%)	1 / 6 (16.67%)	2 / 9 (22.22%)	0 / 11 (0.00%)	7 / 51 (13.73%)	4 / 23 (17.39%)	3 / 15 (20.00%)
occurrences all number	1	12	1	2	0	13	6	8
Back pain
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	1 / 7 (14.29%)	4 / 25 (16.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	2 / 11 (18.18%)	3 / 51 (5.88%)	1 / 23 (4.35%)	4 / 15 (26.67%)
occurrences all number	1	4	0	0	2	3	1	4
Musculoskeletal pain
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	2 / 25 (8.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0
Flank pain
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	1	0	0	0	1	0	1
Arthralgia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	3 / 25 (12.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	2 / 11 (18.18%)	1 / 51 (1.96%)	0 / 23 (0.00%)	4 / 15 (26.67%)
occurrences all number	0	3	0	1	2	1	0	9
Myalgia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	1	0	0	0	0	0	1
Bone pain
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Pain in jaw
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Musculoskeletal chest pain
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0
Muscular weakness
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Dactylitis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Joint swelling
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Infections and infestations
Viral infection
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	5 / 25 (20.00%)	0 / 6 (0.00%)	2 / 9 (22.22%)	0 / 11 (0.00%)	7 / 51 (13.73%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	6	0	3	0	7	1	0
Upper respiratory tract infection
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	2 / 25 (8.00%)	0 / 6 (0.00%)	2 / 9 (22.22%)	2 / 11 (18.18%)	8 / 51 (15.69%)	7 / 23 (30.43%)	2 / 15 (13.33%)
occurrences all number	0	4	0	2	2	11	7	2
Gastroenteritis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	1 / 7 (14.29%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	1	2	0	0	1	0	1	0
Body tinea
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Cellulitis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	0	0	1
Conjunctivitis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	2 / 51 (3.92%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	2	0	1
Acute sinusitis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	1 / 11 (9.09%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0
Pharyngitis streptococcal
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0
Rhinitis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	1 / 15 (6.67%)
occurrences all number	0	0	0	0	0	1	0	1
Sinusitis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Influenza
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	3 / 51 (5.88%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	3	1	0
Lower respiratory tract infection
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	2 / 11 (18.18%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	2	0	0	0
Nasopharyngitis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	2 / 11 (18.18%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	2	0	1	0
Otitis media
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	2 / 51 (3.92%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	2	1	0
Urinary tract infection
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	2 / 51 (3.92%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	2	0	0
COVID-19
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	4 / 23 (17.39%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	4	0
Febrile infection
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Tooth abscess
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0
Viral upper respiratory tract infection
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0
Tinea faciei
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Sepsis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Impetigo
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Hepatitis A
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Pneumonia
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Respiratory syncytial virus infection
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Oral herpes
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0
Lip infection
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Gastroenteritis rotavirus
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0
Tonsillitis
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0
Respiratory tract infection viral
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	1 / 9 (11.11%)	0 / 11 (0.00%)	0 / 51 (0.00%)	2 / 23 (8.70%)	0 / 15 (0.00%)
occurrences all number	0	0	0	1	0	0	3	0
Rotavirus infection
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Viral rash
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0
Metabolism and nutrition disorders
Vitamin D deficiency
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	1 / 25 (4.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	0 / 51 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0
Decreased appetite
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0
Dehydration
Additional description: MedDRA v19.1 for Part A and Part B arms, MedDRA v25.1 for Part C arms and MedDRA v26.0 for Part D arms
subjects affected / exposed	0 / 7 (0.00%)	0 / 25 (0.00%)	0 / 6 (0.00%)	0 / 9 (0.00%)	0 / 11 (0.00%)	1 / 51 (1.96%)	0 / 23 (0.00%)	0 / 15 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

30 Aug 2016

Amendment 1: Modified restrictions regarding concomitant medications to reflect new data regarding the potential of voxelotor to interact with cytochrome P (CYP) substrates.

10 Nov 2016

Amendment 2: In Part B, increased duration of study drug dosing to 24 weeks. In Part B, revised voxelotor dose groups to 900 mg and 1500 mg. Updated objectives and endpoints of the study to reflect the revisions to Part B (eg, increased dosing period and changes in doses).

06 Mar 2017

Amendment 3: Added an independent Drug Safety Monitoring Board (DSMB) to monitor the safety and conduct of the study. Added a taste and palatability questionnaire to evaluate the pediatric participants taste and palatability experience after taking study drug. Added a study drug formulation that was the granulation from the voxelotor common blend capsules (to be mixed with food by the caregiver and administered to participants aged 6–11 years).

09 Jun 2017

Amendment 4: For Part B, revised the age distribution of the sample size (approximately, 36 pediatric participants). For Part B, increased the duration of the Screening Period from 28 days to 35 days to allow for greater visit scheduling flexibility for parents and children. For Part B, revised the dose-modification guidelines and additional actions for liver function test (LFT) elevations of alanine aminotransferase (ALT) >= 5* upper limit of normal (ULN) and < 10*ULN.

14 Jun 2018

Amendment 5: Added Part C to the study (including objectives, endpoints, additional participants, additional study entry criteria, Schedule of Assessments, analysis methods) to assess the safety, tolerability, PK, hematologic response, and effect on TCD flow velocity of voxelotor in participants with SCD aged 4 to 17 years. Added the dispersible tablet formulation (50, 100, and/or 300 mg) of voxelotor for oral administration to subjects in Part C. Increased the number of clinical sites participating in the study to approximately 25 to allow for enrollment of participants in Part C. Added Part C to the ongoing safety and data review performed by the DSMB. Updated the dose-modification guidelines for participants aged 12 to 17 years and added dose-modification tables for participants aged 4 to 11 years in Part C. Removed the requirement that participants avoid a high-fat meal within 4 hours of voxelotor administration to align with the ongoing Phase 3 study GBT440-031. Updated fertility/contraception requirements based on available nonclinical data indicating that voxelotor administration was associated with a low risk of genotoxic effects and had no effects on embryo-fetal development or fertility.

15 Nov 2019

Amendment 6: Added Part D to the study (including objectives, endpoints, additional subjects, additional study entry criteria, Schedule of Assessments, analysis methods) to assess the safety, tolerability, PK, and hematologic response of voxelotor 1500-mg equivalent in approximately 30 pediatric participants aged 9 months to < 4 years. Updated the summary of known and potential risks and benefits of voxelotor and also the risk assessment for voxelotor. Updated restrictions regarding concomitant medications to align with current clinical pharmacological data for voxelotor. For Part C, removed voxelotor 50 mg dispersible tablets and added voxelotor powder for oral suspension formulation. Updated PK-related secondary endpoint (Part C) and PK analysis, and included an additional Hb-related secondary endpoint.

28 Apr 2021

Amendment 7: For Part C, added 2 new secondary objectives evaluating the proportion of participants with normal TCD flow velocity and the effect of voxelotor on the incidence of stroke and VOC. For Part D, changed the range of pediatric participants being evaluated from 9 months to < 4 years of age to 6 months to < 4 years of age. For Part D, added a new secondary objective evaluating the effect of voxelotor on the incidence of stroke and VOC in pediatric participants with SCD. Added a new exclusion criterion for active symptomatic COVID-19 infection.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 2a, Open-label, Single and Multiple Dose Study to Evaluate the Pharmacokinetics, Safety, Tolerability and Treatment Effect of GBT440 in Pediatric Participants with Sickle Cell Disease

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part A: Maximum Concentration (Cmax) of Voxelotor in Whole Blood

Primary: Part A: Maximum Concentration (Cmax) of Voxelotor in Whole Blood

Primary: Part B: Change From Baseline to Week 24 in Hemoglobin Level

Primary: Part B: Change From Baseline to Week 24 in Hemoglobin Level

Primary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in Whole Blood

Primary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in Whole Blood

Primary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Voxelotor in Whole Blood

Primary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Voxelotor in Whole Blood

Primary: Part C: Change From Baseline to Week 48 in Cerebral Blood Flow

Primary: Part C: Change From Baseline to Week 48 in Cerebral Blood Flow

Primary: Part D: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Primary: Part D: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

Secondary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Voxelotor in Plasma

Secondary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Voxelotor in Plasma

Secondary: Part A: Maximum Concentration (Cmax) of Voxelotor in Plasma

Secondary: Part A: Maximum Concentration (Cmax) of Voxelotor in Plasma

Secondary: Part A: Maximum Concentration (Cmax) of Voxelotor in Red Blood Cells (RBC)

Secondary: Part A: Maximum Concentration (Cmax) of Voxelotor in Red Blood Cells (RBC)

Secondary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Voxelotor in RBC

Secondary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Voxelotor in RBC

Secondary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in Plasma

Secondary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in Plasma

Secondary: Part A: Time at Which Cmax Was Observed (Tmax) for Voxelotor in Whole Blood

Secondary: Part A: Time at Which Cmax Was Observed (Tmax) for Voxelotor in Whole Blood

Secondary: Part A: Time at Which Cmax Was Observed (Tmax) for Voxelotor in RBC

Secondary: Part A: Time at Which Cmax Was Observed (Tmax) for Voxelotor in RBC

Secondary: Part A: Time at Which Cmax Was Observed (Tmax) for Voxelotor in Plasma

Secondary: Part A: Time at Which Cmax Was Observed (Tmax) for Voxelotor in Plasma

Secondary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in RBC

Secondary: Part A: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor in RBC

Secondary: Part A: Terminal Elimination Half-Life (T1/2) for Voxelotor in Whole Blood

Secondary: Part A: Terminal Elimination Half-Life (T1/2) for Voxelotor in Whole Blood

Secondary: Part A: Terminal Elimination Half-Life (T1/2) for Voxelotor in Plasma

Secondary: Part A: Terminal Elimination Half-Life (T1/2) for Voxelotor in Plasma

Secondary: Part A: Percentage Hemoglobin (Hb) Occupancy

Secondary: Part A: Percentage Hemoglobin (Hb) Occupancy

Secondary: Part A: Terminal Elimination Half-Life (T1/2) for Voxelotor in RBC

Secondary: Part A: Terminal Elimination Half-Life (T1/2) for Voxelotor in RBC

Secondary: Part B: Change from Baseline to Week 21 to 24 in the Sickle Cell Disease Severity Measure (SCDSM) Total Symptom Score (TSS)

Secondary: Part B: Change from Baseline to Week 21 to 24 in the Sickle Cell Disease Severity Measure (SCDSM) Total Symptom Score (TSS)

Secondary: Part B: Percentage of Days With SCD Symptom Exacerbation During the First 24 Weeks of Treatment

Secondary: Part B: Percentage of Days With SCD Symptom Exacerbation During the First 24 Weeks of Treatment

Secondary: Part B: Percent Change From Baseline to Weeks 12 and 24 in Lactate Dehydrogenase (LDH)

Secondary: Part B: Percent Change From Baseline to Weeks 12 and 24 in Lactate Dehydrogenase (LDH)

Secondary: Part B: Percent Change From Baseline to Weeks 12 and 24 in Indirect Bilirubin

Secondary: Part B: Percent Change From Baseline to Weeks 12 and 24 in Indirect Bilirubin

Secondary: Part B: Percent Change From Baseline to Week 12 and 24 in Percentage Reticulocytes

Secondary: Part B: Percent Change From Baseline to Week 12 and 24 in Percentage Reticulocytes

Secondary: Part B: Cmax of Voxelotor in Whole Blood and Plasma

Secondary: Part B: Cmax of Voxelotor in Whole Blood and Plasma

Secondary: Part B: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor for Whole Blood and Plasma

Secondary: Part B: Area Under the Concentration-Time Curve (AUC) From Time 0 Extrapolated to Infinity (AUC0-inf) of Voxelotor for Whole Blood and Plasma

Secondary: Part B: Accumulation Ratio (Rac) of Voxelotor for Plasma and Whole Blood

Secondary: Part B: Accumulation Ratio (Rac) of Voxelotor for Plasma and Whole Blood

Secondary: Part B: Terminal Elimination Half-life of Voxelotor for Plasma and Whole Blood

Secondary: Part B: Terminal Elimination Half-life of Voxelotor for Plasma and Whole Blood

Secondary: Part B: Change From Baseline to Week 12 and 24 in Cerebral Blood Flow as Measured by the TAMM TCD Velocity

Secondary: Part B: Change From Baseline to Week 12 and 24 in Cerebral Blood Flow as Measured by the TAMM TCD Velocity

Secondary: Part B: Percentage Hemoglobin Occupancy

Secondary: Part B: Percentage Hemoglobin Occupancy

Secondary: Part C: Percent Change From Baseline to Weeks 24 and 48 in LDH

Secondary: Part C: Percent Change From Baseline to Weeks 24 and 48 in LDH

Secondary: Part C: Change From Baseline to Weeks 24 and 48 in Hemoglobin Level

Secondary: Part C: Change From Baseline to Weeks 24 and 48 in Hemoglobin Level

Secondary: Part C: Percent Change From Baseline to Weeks 24 and 48 in Indirect Bilirubin

Secondary: Part C: Percent Change From Baseline to Weeks 24 and 48 in Indirect Bilirubin

Secondary: Part C: Percent Change From Baseline to Weeks 24 and 48 in Percentage Reticulocytes

Secondary: Part C: Percent Change From Baseline to Weeks 24 and 48 in Percentage Reticulocytes

Secondary: Part C: Change From Baseline to Week 24 in Cerebral Blood Flow as Measured by the TAMM TCD Velocity

Secondary: Part C: Change From Baseline to Week 24 in Cerebral Blood Flow as Measured by the TAMM TCD Velocity

Clinical Trial Results:
A Phase 2a, Open-label, Single and Multiple Dose Study to Evaluate the Pharmacokinetics, Safety, Tolerability and Treatment Effect of GBT440 in Pediatric Participants with Sickle Cell Disease