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Clinical Trial Results:
A Phase 2 Open-Label Study to Evaluate Safety and Clinical Activity of Etavopivat in Patients with Thalassemia or Sickle Cell Disease

Summary
EudraCT number	2021-005267-48
Trial protocol	IT
Global end of trial date	24 Sep 2025

Results information
Results version number	v1(current)
This version publication date	09 Apr 2026
First version publication date	09 Apr 2026
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

4202-HEM-201

ISRCTN number

US NCT number

NCT04987489

WHO universal trial number (UTN)

Sponsor organisation name

Novo Nordisk A/S

Sponsor organisation address

Novo Alle, Bagsvaerd, Denmark, 2880

Public contact

Clinical Reporting Office (2834), Novo Nordisk A/S, clinicaltrials@novonordisk.com

Scientific contact

Clinical Reporting Office (2834), Novo Nordisk A/S, clinicaltrials@novonordisk.com

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

Yes

EMA paediatric investigation plan number(s)

EMEA-002924-PIP03-24

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

Yes

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

Analysis stage

Final

Date of interim/final analysis

13 Nov 2025

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

24 Sep 2025

Was the trial ended prematurely?

Main objective of the trial

The main objective of the study was to assess the erythroid response of etavopivat in adolescents and adults with sickle cell disease (SCD) or thalassemia.

Protection of trial subjects

The trial was conducted in accordance with the Declaration of Helsinki (Oct 2013) and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice, including archiving of essential documents (May 1996) and EN ISO 14155 Part 1 and 2 and Food and Drug Administration (FDA) 21 Code of Federal Regulations (CFR) 312.120.

Background therapy

Not applicable

Evidence for comparator

Actual start date of recruitment

28 Mar 2022

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 9

Country: Number of subjects enrolled

Egypt: 5

Country: Number of subjects enrolled

United Kingdom: 5

Country: Number of subjects enrolled

Lebanon: 4

Country: Number of subjects enrolled

United States: 29

Worldwide total number of subjects

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

The study was conducted across 20 sites in 5 countries.

Screening details

A total of 53 subjects were enrolled, of whom 44 completed the study. Cohorts were based on haemoglobinopathy (SCD or thalassaemia) and transfusion requirements. Subjects entered a 48-week primary treatment period with an optional 60-week extension. One subject was excluded from the population description for receiving both transfusion types.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort A: Simple transfusion

Arm description

Subjects received etavopivat 400 mg (2 tablets of 200mg each) daily orally for 48-week primary treatment period followed by an optional 60-week extension treatment period. In this arm, subjects with sickle cell disease (SCD) underwent chronic red blood cells (RBC) transfusion therapy through simple (manual) process to prevent stroke or recurrence of stroke.

Arm type

Experimental

Investigational medicinal product name

Etavopivat

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Etavopivat 400 mg was administered orally daily in the form of two tablets of 200 mg each.

Cohort A: Exchange transfusion

Arm description

Subjects received etavopivat 400 mg (2 tablets of 200mg each) daily orally for 48-week primary treatment period followed by an optional 60-week extension treatment period. In this arm, subjects with SCD underwent chronic RBC transfusion therapy through exchange transfusion process to prevent stroke or recurrence of stroke. The exchange transfusion process involved simultaneous blood removal and RBC infusion, which impacted clinical parameters, such as haemoglobin (Hb) iron levels, and volume balance, differently than the simple transfusion process.

Arm type

Experimental

Investigational medicinal product name

Etavopivat

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Etavopivat 400 mg was administered orally daily in the form of two tablets of 200 mg each.

Cohort B

Arm description

Arm type

Experimental

Investigational medicinal product name

Etavopivat

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Etavopivat 400 mg was administered orally daily in the form of two tablets of 200 mg each.

Cohort C

Arm description

Arm type

Experimental

Investigational medicinal product name

Etavopivat

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Etavopivat 400 mg was administered orally daily in the form of two tablets of 200 mg each.

Number of subjects in period 1	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C
Started	5	7	20	20
Full analysis set (FAS)	5	7	20	20
Safety analysis set (SAS)	5	7	20	20
Efficacy evaluable set (EES)	4	7	19	20
Completed	4	5	18	16
Not completed	1	2	2	4
Adverse event, serious fatal	1	-	-	-
Adverse event, non-fatal	-	-	1	1
Unclassified	-	2	1	3

Baseline characteristics

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Reporting group title

Cohort A: Simple transfusion

Reporting group description

Subjects received etavopivat 400 mg (2 tablets of 200mg each) daily orally for 48-week primary treatment period followed by an optional 60-week extension treatment period. In this arm, subjects with sickle cell disease (SCD) underwent chronic red blood cells (RBC) transfusion therapy through simple (manual) process to prevent stroke or recurrence of stroke.

Reporting group title

Cohort A: Exchange transfusion

Reporting group description

Subjects received etavopivat 400 mg (2 tablets of 200mg each) daily orally for 48-week primary treatment period followed by an optional 60-week extension treatment period. In this arm, subjects with SCD underwent chronic RBC transfusion therapy through exchange transfusion process to prevent stroke or recurrence of stroke. The exchange transfusion process involved simultaneous blood removal and RBC infusion, which impacted clinical parameters, such as haemoglobin (Hb) iron levels, and volume balance, differently than the simple transfusion process.

Reporting group title

Cohort B

Reporting group description

Reporting group title

Cohort C

Reporting group description

Reporting group values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C	Total
Number of subjects	5	7	20	20	52
Age Categorical
Units: Subjects
In utero	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0
Adolescents (12-17 years)	2	4	10	4	20
Adults (18-64 years)	3	3	10	16	32
From 65-84 years	0	0	0	0	0
85 years and over	0	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	30.8 ( 19.25 )	18.0 ( 5.23 )	21.5 ( 9.57 )	31.4 ( 14.77 )	-
Gender Categorical
Units: Subjects
Female	5	1	8	15	29
Male	0	6	12	5	23

End points

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Reporting group title

Cohort A: Simple transfusion

Reporting group description

Subjects received etavopivat 400 mg (2 tablets of 200mg each) daily orally for 48-week primary treatment period followed by an optional 60-week extension treatment period. In this arm, subjects with sickle cell disease (SCD) underwent chronic red blood cells (RBC) transfusion therapy through simple (manual) process to prevent stroke or recurrence of stroke.

Reporting group title

Cohort A: Exchange transfusion

Reporting group description

Subjects received etavopivat 400 mg (2 tablets of 200mg each) daily orally for 48-week primary treatment period followed by an optional 60-week extension treatment period. In this arm, subjects with SCD underwent chronic RBC transfusion therapy through exchange transfusion process to prevent stroke or recurrence of stroke. The exchange transfusion process involved simultaneous blood removal and RBC infusion, which impacted clinical parameters, such as haemoglobin (Hb) iron levels, and volume balance, differently than the simple transfusion process.

Reporting group title

Cohort B

Reporting group description

Reporting group title

Cohort C

Reporting group description

Subject analysis set title

Total: Cohort A

Subject analysis set type

Safety analysis

Subject analysis set description

The total arm for Cohort A includes the Cohort A – simple transfusion arm, the Cohort A – exchange transfusion arm, and one subject who received both simple and exchange transfusions during the study.

Primary: Cohort C: Percentage of subjects achieving a haemoglobin (Hb) response (increase of >=1.0 grams per deciliter [g/dL] from baseline)

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End point title

Cohort C: Percentage of subjects achieving a haemoglobin (Hb) response (increase of >=1.0 grams per deciliter [g/dL] from baseline) ^[1] ^[2]

End point description

Percentage of subjects achieving a Hb response in cohort C is presented. Hb response at a given timepoint is defined as a change of >=1 g/dL from the baseline Hb with no RBC transfusions received in the prior 8 weeks. Hb response rate at a given timepoint is calculated as: number of Hb responders at a given timepoint/number of subjects who have completed assessment at the given timepoint. Efficacy evaluable set included subjects in the safety set who had completed the week 12 response visit and who had a baseline record of the primary endpoint.

End point type

Primary

End point timeframe

From baseline up to week 12

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: For Cohort C: One‑sided exact binomial statistical test versus a 10% null response rate (H0: P1 ≤ 0.10 vs H1: P1 > 0.10) at significance level α = 0.025 was performed. Exact two‑sided 95% confidence intervals for the response proportion were calculated using the Clopper–Pearson method.
[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 endpoint is reporting data for applicable arms only.

End point values	Cohort C
Number of subjects analysed	20
Units: Percentage of subjects
number (confidence interval 95%)	50.0 (27.2 to 72.8)

No statistical analyses for this end point

Primary: Cohorts A (Simple transfusion) and B: Percentage of subjects achieving greater than or equal to (>=) 20% reduction in RBC transfusion units over a continuous 12-week treatment period versus baseline RBC transfusion history

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End point title

Cohorts A (Simple transfusion) and B: Percentage of subjects achieving greater than or equal to (>=) 20% reduction in RBC transfusion units over a continuous 12-week treatment period versus baseline RBC transfusion history ^[3] ^[4]

End point description

Percentage of subjects achieving >= 20% reduction in red blood cell (RBC) transfusion units over a continuous 12-week treatment period versus baseline RBC transfusion history in cohort A (simple transfusion) group and cohort B is presented. Responders were defined as any subject with a >=20% reduction from baseline in RBC units transfused during at least one qualifying 12-week (84 day) interval in the primary treatment period (i.e. Days 2 to 85, 3 to 86, ..., 253 to end of primary treatment period), where baseline is defined as the total number of RBC units transfused from study day -83 to study day 1. Chronically transfused was defined as >=6 RBC units in the previous 24 weeks before the first dose of study treatment and no transfusion-free period for >35 days during that period. Efficacy evaluable set included subjects in the safety set who had completed the week 12 response visit and who had a baseline record of the primary endpoint.

End point type

Primary

End point timeframe

From baseline up to week 48 (any 12 weeks)

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: Cohort A: Prespecified one-sided exact binomial test vs 20% null response rate and corresponding Clopper–Pearson exact 95% confidence interval (CI) were performed; however, only 4 subjects were evaluable, hence formal inference was not performed. Cohort B: One-sided exact binomial statistical test vs 20% null response rate (H0: P1 ≤ 0.20 vs H1: P1 > 0.20) at significance level α = 0.025 was performed. Exact two sided 95% CIs for response proportion were calculated using Clopper–Pearson method.
[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 endpoint is reporting data for applicable arms only.

End point values	Cohort A: Simple transfusion	Cohort B
Number of subjects analysed	4	19
Units: Percentage of subjects
number (confidence interval 95%)	75.0 (19.4 to 99.4)	89.5 (66.9 to 98.7)

No statistical analyses for this end point

Secondary: Number of subjects with treatment emergent serious adverse events (TESAEs)

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End point title

Number of subjects with treatment emergent serious adverse events (TESAEs)

End point description

Number of subjects with TESAEs is presented. A treatment emergent adverse event (TEAE) was defined as any adverse event (AE) that emerged or worsened in the period from the first dose of study drug to 28 days after the last dose of study drug. An SAE is any untoward medical occurrence that occurs at any dose that: results in death, is life-threatening, requires in-patient hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect. Chronically transfused was defined as >=6 RBC units in the previous 24 weeks before the first dose of study treatment and no transfusion-free period for >35 days during that period. Safety set consisted of all subjects who received at least one dose of etavopivat.

End point type

Secondary

End point timeframe

From baseline up to week 152

End point values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C	Total: Cohort A
Number of subjects analysed	5	7	20	20	13
Units: Subjects	1	1	2	3	2

No statistical analyses for this end point

Secondary: Number of subjects with TEAEs leading to discontinuation

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End point title

Number of subjects with TEAEs leading to discontinuation

End point description

Number of subjects with TEAEs leading to discontinuation is presented. A TEAE was defined as any AE that emerged or worsened in the period from the first dose of study drug to 28 days after the last dose of study drug. Safety set consisted of all subjects who received at least one dose of etavopivat. Chronically transfused was defined as >=6 RBC units in the previous 24 weeks before the first dose of study treatment and no transfusion-free period for >35 days during that period.

End point type

Secondary

End point timeframe

From baseline up to week 152

End point values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C	Total: Cohort A
Number of subjects analysed	5	7	20	20	13
Units: Subjects	0	0	1	1	0

No statistical analyses for this end point

Secondary: Number of subjects with clinically significant laboratory parameters: Haematolysis

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End point title

Number of subjects with clinically significant laboratory parameters: Haematolysis

End point description

Number of subjects with clinically significant laboratory parameters: Haematolysis is presented. Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. Severity of the parameters are graded based on Common Terminology Criteria for Adverse Events (CTCAE) Version 5 grading scale which was used to determine grades based on the corresponding laboratory values. The 4 grades were defined as follows: Grade 1 (Mild): event is usually transient and does not interfere with subject’s daily activities, Grade 2 (Moderate): event introduces low level of inconvenience to the subject and may interfere with daily activities, Grade 3 (Severe): event interrupts subject’s daily activities and hospitalization may be required, Grade 4 (Life threatening): event requires urgent intervention to prevent death. Safety set consisted of all subjects who received at least one dose of etavopivat.

End point type

Secondary

End point timeframe

From baseline up to week 152

End point values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C	Total: Cohort A
Number of subjects analysed	5	7	20	20	13
Units: Subjects
Hemoglobin decreased: Grade 2	4	3	12	9	7
Hemoglobin decreased: Grade 3	1	2	8	11	3
Lymphocyte count increased: Grade 2	5	5	5	9	10
Lymphocyte count decreased: Grade 2	0	0	2	0	0
Neutrophil count decreased: Grade 2	0	0	1	0	0
Neutrophil count decreased: Grade 3	0	0	1	0	0
White blood cell decreased: Grade 2	0	0	1	0	0

No statistical analyses for this end point

Secondary: Number of subjects with clinically significant laboratory parameters: Biochemistry

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End point title

Number of subjects with clinically significant laboratory parameters: Biochemistry

End point description

Number of subjects with clinically significant laboratory parameters: biochemistry is presented. Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. Severity of parameters were graded based on CTCAE v 5 grading scale which was used to determine grades based on corresponding laboratory values. The 4 grades are defined as follows: Grade 1 - (Mild): event usually transient and does not interfere with subject’s daily activities, Grade 2 (Moderate): event introduces low level of inconvenience and may interfere with subject’s daily activities, Grade 3 (Severe): event interrupts subject’s daily activities and hospitalization may be required, Grade 4 (Life-threatening): event requires urgent intervention to prevent death. Safety set consisted of all subjects who received at least one dose of etavopivat.

End point type

Secondary

End point timeframe

From baseline up to week 152

End point values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C	Total: Cohort A
Number of subjects analysed	5	7	20	20	13
Units: Subjects
eGFR decreased: Grade 2	1	0	0	1	1
Creatinine increased: Grade 2	1	1	1	0	2
Hypercalcemia (Calcium increased): Grade 2	1	0	0	0	1
Hyperkalemia (Potassium increased): Grade 2	0	1	0	1	1
Hypermagnesemia (Magnesium increased): Grade 3	0	0	2	1	0
Hypernatremia (Sodium increased): Grade 2	0	0	0	1	0
Hypocalcemia (Calcium decreased): Grade 4	0	0	3	1	0
Hypoglycemia (Glucose decreased): Grade 2	0	0	0	7	0
Hypoglycemia (Glucose decreased): Grade 3	0	0	0	2	0
Hypokalemia (Potassium decreased): Grade 2	1	0	10	3	1
Hypokalemia (Potassium decreased): Grade 3	0	0	1	0	0
Lipase increased: Grade 4	0	1	0	0	1
Lipase increased: Grade 2	0	0	1	3	0
Serum amylase increased: Grade 2	1	1	0	0	2
Serum amylase increased: Grade 3	0	0	1	0	0

No statistical analyses for this end point

Secondary: Number of subjects with clinically significant laboratory parameters: Coagulation

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End point title

Number of subjects with clinically significant laboratory parameters: Coagulation

End point description

Number of subjects with clinically significant laboratory parameters: coagulation is presented. Data is not reported for this endpoint as there are no clinically relevant findings. Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. Safety set consisted of all subjects who received at least one dose of etavopivat.

End point type

Secondary

End point timeframe

From baseline up to week 152

End point values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C	Total: Cohort A
Number of subjects analysed	5	7	20	20	13
Units: Subjects	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects with clinically significant laboratory parameters: Urinalysis

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End point title

Number of subjects with clinically significant laboratory parameters: Urinalysis

End point description

Number of subjects with clinically significant laboratory parameters: urinalysis is presented. Data is not reported for this endpoint as there are no clinically relevant findings. Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. Safety set consisted of all subjects who received at least one dose of etavopivat.

End point type

Secondary

End point timeframe

From baseline up to week 152

End point values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C	Total: Cohort A
Number of subjects analysed	5	7	20	20	13
Units: Subjects	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects with clinically significant laboratory parameters: Endocrinology

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End point title

Number of subjects with clinically significant laboratory parameters: Endocrinology

End point description

Number of subjects with clinically significant laboratory parameters: endocrinology is presented. Data is not reported for this endpoint as there are no clinically relevant findings. Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. Safety set consisted of all subjects who received at least one dose of etavopivat.

End point type

Secondary

End point timeframe

From baseline up to week 152

End point values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C	Total: Cohort A
Number of subjects analysed	5	7	20	20	13
Units: Subjects	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects with clinically significant laboratory parameters: Iron studies, folate and Vitamin B12

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End point title

Number of subjects with clinically significant laboratory parameters: Iron studies, folate and Vitamin B12

End point description

Number of subjects with clinically significant laboratory parameters: iron studies, folate and vitamin B12 is presented. Data is not reported for this endpoint as there are no clinically relevant findings. Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. Safety set consisted of all subjects who received at least one dose of etavopivat.

End point type

Secondary

End point timeframe

From baseline up to week 152

End point values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C	Total: Cohort A
Number of subjects analysed	5	7	20	20	13
Units: Subjects	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of participants with clinically significant laboratory parameters: Serolgy

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End point title

Number of participants with clinically significant laboratory parameters: Serolgy

End point description

Number of subjects with clinically significant laboratory parameters: serology is presented. Data is not reported for this endpoint as there are no clinically relevant findings. Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. Safety set consisted of all subjects who received at least one dose of etavopivat.

End point type

Secondary

End point timeframe

From baseline up to week 152

End point values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C	Total: Cohort A
Number of subjects analysed	5	7	20	20	13
Units: Subjects	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of subjects with clinically significant abnormal electrocardiograms (ECGs)

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End point title

Number of subjects with clinically significant abnormal electrocardiograms (ECGs)

End point description

Number of subjects with clinically significant abnormal ECGs is presented. Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. Safety set consisted of all subjects who received at least one dose of etavopivat.

End point type

Secondary

End point timeframe

From baseline up to week 152

End point values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C	Total: Cohort A
Number of subjects analysed	5	7	20	20	13
Units: Subjects	2	0	2	1	2

No statistical analyses for this end point

Secondary: Cohorts A (Simple transfusion) and B: Relative reduction from baseline in RBC transfusion burden from baseline to week 12

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End point title

Cohorts A (Simple transfusion) and B: Relative reduction from baseline in RBC transfusion burden from baseline to week 12 ^[5]

End point description

Relative reduction from baseline in RBC transfusion burden in cohorts A (simple transfusion) and cohort B is presented. Relative reduction from expected units transfused was derived as -100 x (actual RBC units transfused during interval-expected RBC units transfused)/expected RBC units transfused, where the expected RBC units transfused were defined as interval duration (Weeks)/12 x baseline RBC transfusion units. Baseline RBC transfusion units were defined as the summed RBC units transfused for 12 weeks prior to study start (Study Day -83 to 1). Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. Efficacy evaluable set included subjects in the safety set who had completed the week 12 response visit and who had a baseline record of the primary endpoint.

End point type

Secondary

End point timeframe

From baseline to week 12

Notes
[5] - 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 endpoint is reporting data for applicable arms only.

End point values	Cohort A: Simple transfusion	Cohort B
Number of subjects analysed	4	19
Units: Percentage of RBC transfusion units
arithmetic mean (standard deviation)	35.994 ( 38.2914 )	15.277 ( 20.9685 )

No statistical analyses for this end point

Secondary: Cohorts A (Simple transfusion) and B: Number of subjects achieving >= 33% reduction in RBC transfusion units over a continuous 12-week treatment period versus baseline RBC transfusion history

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End point title

Cohorts A (Simple transfusion) and B: Number of subjects achieving >= 33% reduction in RBC transfusion units over a continuous 12-week treatment period versus baseline RBC transfusion history ^[6]

End point description

Number of subjects achieving >= 33% reduction in RBC transfusion units over a continuous 12-week treatment period versus baseline RBC transfusion history in cohorts A (simple transfusion) and B is presented. Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. Efficacy evaluable set included subjects in the safety set who had completed the week 12 response visit and who had a baseline record of the primary endpoint.

End point type

Secondary

End point timeframe

From baseline up to week 48 (any 12 weeks)

Notes
[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 endpoint is reporting data for applicable arms only.

End point values	Cohort A: Simple transfusion	Cohort B
Number of subjects analysed	4	19
Units: Subjects	3	15

No statistical analyses for this end point

Secondary: Cohorts A (Simple transfusion) and B: Relative reduction from baseline in RBC transfusion burden from baseline to week 24

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End point title

Cohorts A (Simple transfusion) and B: Relative reduction from baseline in RBC transfusion burden from baseline to week 24 ^[7]

End point description

End point type

Secondary

End point timeframe

From baseline to week 24

Notes
[7] - 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 endpoint is reporting data for applicable arms only.

End point values	Cohort A: Simple transfusion	Cohort B
Number of subjects analysed	4	18
Units: Percentage of RBC transfusion units
arithmetic mean (standard deviation)	23.494 ( 32.6929 )	11.874 ( 18.1068 )

No statistical analyses for this end point

Secondary: Cohorts A (Simple transfusion) and B: Relative reduction from baseline in RBC transfusion burden from baseline to week 48

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End point title

Cohorts A (Simple transfusion) and B: Relative reduction from baseline in RBC transfusion burden from baseline to week 48 ^[8]

End point description

Relative reduction from baseline in RBC transfusion burden from cohorts A (simple transfusion) and cohort B is presented. Relative reduction from expected units transfused was derived as -100 x (actual RBC units transfused during interval-expected RBC units transfused)/expected RBC units transfused, where the expected RBC units transfused were defined as interval duration (Weeks)/12 x baseline RBC transfusion units. Baseline RBC transfusion units were defined as the summed RBC units transfused for 12 weeks prior to study start (Study Day -83 to 1). Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. Efficacy evaluable set included subjects in the safety set who had completed the week 12 response visit and who had a baseline record of the primary endpoint. Number of subjects analysed = Subjects with available data for the endpoint.

End point type

Secondary

End point timeframe

From baseline to week 48

Notes
[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 endpoint is reporting data for applicable arms only.

End point values	Cohort A: Simple transfusion	Cohort B
Number of subjects analysed	4	18
Units: Percentage of RBC transfusion units
arithmetic mean (standard deviation)	22.315 ( 23.6839 )	10.855 ( 15.7686 )

No statistical analyses for this end point

Secondary: Cohorts A (Simple transfusion) and B: Relative reduction from baseline in RBC transfusion burden from baseline to end of extension treatment period (week 108)

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End point title

Cohorts A (Simple transfusion) and B: Relative reduction from baseline in RBC transfusion burden from baseline to end of extension treatment period (week 108) ^[9]

End point description

End point type

Secondary

End point timeframe

From baseline to end of extension treatment period (week 108)

Notes
[9] - 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 endpoint is reporting data for applicable arms only.

End point values	Cohort A: Simple transfusion	Cohort B
Number of subjects analysed	0 ^[10]	14
Units: Percentage of RBC transfusion units
arithmetic mean (standard deviation)	( )	4.573 ( 20.5664 )

Notes
[10] - No subjects were analysed for this arm in this particular timepoint.

No statistical analyses for this end point

Secondary: Cohort C: Number of subjects achieving a Hb response (increase of >=1.0 g/dL from baseline) at week 24

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End point title

Cohort C: Number of subjects achieving a Hb response (increase of >=1.0 g/dL from baseline) at week 24 ^[11]

End point description

Number of subjects achieving a Hb response in cohort C is presented. Hb response at a given timepoint is defined as a change of >=1 g/dL from the baseline Hb with no RBC transfusions received in the prior 8 weeks. Hb response rate at a given timepoint is calculated as: number of Hb responders at a given timepoint/number of subjects who have completed assessment at the given timepoint. Efficacy evaluable set included subjects in the safety set who had completed the week 12 response visit and who had a baseline record of the primary endpoint. Number of subjects analysed = Subjects with available data for the endpoint.

End point type

Secondary

End point timeframe

From baseline to week 24

Notes
[11] - 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 endpoint is reporting data for applicable arms only.

End point values	Cohort C
Number of subjects analysed	18
Units: Subjects	7

No statistical analyses for this end point

Secondary: Cohort C: Number of subjects achieving a Hb response (increase of >=1.0 g/dL from baseline) at week 48

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End point title

Cohort C: Number of subjects achieving a Hb response (increase of >=1.0 g/dL from baseline) at week 48 ^[12]

End point description

End point type

Secondary

End point timeframe

From baseline to week 48

Notes
[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 endpoint is reporting data for applicable arms only.

End point values	Cohort C
Number of subjects analysed	16
Units: Subjects	6

No statistical analyses for this end point

Secondary: Cohort C: Number of subjects achieving a Hb response (increase of >=1.0 g/dL from baseline) at end of extension treatment period (week 108)

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End point title

Cohort C: Number of subjects achieving a Hb response (increase of >=1.0 g/dL from baseline) at end of extension treatment period (week 108) ^[13]

End point description

Number of subjects achieving a Hb response in cohort C is presented. Hb response at a given timepoint is defined as a change of >=1 g/dL from the baseline Hb with no RBC transfusions received in the prior 8 weeks. Hb response rate at end of extension treatment (EOET) was defined as number of Hb responders at EOET/number of subjects continuing into the extension treatment period who have completed assessment or dropped out. Efficacy evaluable set included subjects in the safety set who had completed the week 12 response visit and who had a baseline record of the primary endpoint. Number of subjects analysed = Subjects with available data for the endpoint.

End point type

Secondary

End point timeframe

From baseline to end of extension treatment period (week 108)

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 endpoint is reporting data for applicable arms only.

End point values	Cohort C
Number of subjects analysed	13
Units: Subjects	8

No statistical analyses for this end point

Secondary: Cohort C: Mean change from baseline to week 12 in Hb

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End point title

Cohort C: Mean change from baseline to week 12 in Hb ^[14]

End point description

Mean change from baseline to week 12 in Hb in cohort C is presented. FAS was defined as all subjects who completed informed consent and received at least one dose of etavopivat (including partial dosing).

End point type

Secondary

End point timeframe

From baseline to week 12

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 endpoint is reporting data for applicable arms only.

End point values	Cohort C
Number of subjects analysed	20
Units: grams per deciliter (g/dL)
least squares mean (confidence interval 95%)	1.12 (0.81 to 1.43)

No statistical analyses for this end point

Secondary: Cohort C: Mean change from baseline to week 24 in Hb

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End point title

Cohort C: Mean change from baseline to week 24 in Hb ^[15]

End point description

Mean change from baseline to week 24 in Hb in cohort C is presented. FAS was defined as all subjects who completed informed consent and received at least one dose of etavopivat (including partial dosing). Number of subjects analysed = Subjects with available data for the endpoint.

End point type

Secondary

End point timeframe

From baseline to week 24

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 endpoint is reporting data for applicable arms only.

End point values	Cohort C
Number of subjects analysed	18
Units: g/dL
least squares mean (confidence interval 95%)	0.88 (0.56 to 1.21)

No statistical analyses for this end point

Secondary: Cohort C: Mean change from baseline to week 48 in Hb

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End point title

Cohort C: Mean change from baseline to week 48 in Hb ^[16]

End point description

Mean change from baseline to week 48 in Hb in cohort C is presented. FAS was defined as all subjects who completed informed consent and received at least one dose of etavopivat (including partial dosing). Number of subjects analysed = Subjects with available data for the endpoint.

End point type

Secondary

End point timeframe

From baseline to week 48

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 endpoint is reporting data for applicable arms only.

End point values	Cohort C
Number of subjects analysed	16
Units: g/dL
least squares mean (confidence interval 95%)	0.91 (0.56 to 1.26)

No statistical analyses for this end point

Secondary: Cohort A and B and C: Change from baseline to week 24 in serum ferritin levels

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End point title

Cohort A and B and C: Change from baseline to week 24 in serum ferritin levels

End point description

Change from baseline to week 24 in serum ferritin levels in cohort and B and C is presented. Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. FAS was defined as all subjects who completed informed consent and received at least one dose of etavopivat (including partial dosing). Number of subjects analysed = Subjects with available data for the endpoint.

End point type

Secondary

End point timeframe

From baseline to week 24

End point values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C
Number of subjects analysed	4	6	17	16
Units: pmol/L
least squares mean (confidence interval 95%)	832.8 (-835.8 to 2501.3)	-188.6 (-2393.2 to 2016.0)	-344.1 (-903.9 to 215.7)	18.6 (-136.0 to 173.3)

No statistical analyses for this end point

Secondary: Cohort A and B and C: Change from baseline to week 12 in serum ferritin levels

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End point title

Cohort A and B and C: Change from baseline to week 12 in serum ferritin levels

End point description

Change from baseline to week 12 in serum ferritin levels in cohort A, cohort B and cohort C is presented. Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. FAS was defined as all subjects who completed informed consent and received at least one dose of etavopivat (including partial dosing). Number of subjects analysed = Subjects with available data for the endpoint.

End point type

Secondary

End point timeframe

From baseline to week 12

End point values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C
Number of subjects analysed	4	7	18	18
Units: picomoles per liter (pmol/L)
least squares mean (confidence interval 95%)	952.0 (-716.5 to 2620.5)	1085.7 (-937.5 to 3108.9)	-101.8 (-652.6 to 448.9)	113.7 (-32.9 to 260.2)

No statistical analyses for this end point

Secondary: Cohort C: Mean change from baseline to end of extension treatment period (week 108) in Hb

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End point title

Cohort C: Mean change from baseline to end of extension treatment period (week 108) in Hb ^[17]

End point description

Mean change from baseline to end of extension treatment period (week 108) in Hb in cohort C is presented. FAS was defined as all subjects who completed informed consent and received at least one dose of etavopivat (including partial dosing).

End point type

Secondary

End point timeframe

From baseline to end of extension treatment period (week 108)

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 endpoint is reporting data for applicable arms only.

End point values	Cohort C
Number of subjects analysed	20
Units: g/dL
least squares mean (confidence interval 95%)	0.92 (0.33 to 1.51)

No statistical analyses for this end point

Secondary: Cohort A and B and C: Change from baseline to end of extension treatment period (week 108) in serum ferritin levels

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End point title

Cohort A and B and C: Change from baseline to end of extension treatment period (week 108) in serum ferritin levels

End point description

Change from baseline to end of extension treatment period (week 108) in serum ferritin levels in cohort A and B and C is presented. Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. FAS was defined as all subjects who completed informed consent and received at least one dose of etavopivat (including partial dosing). Number of subjects analysed = Subjects with available data for the endpoint.

End point type

Secondary

End point timeframe

From baseline to end of extension treatment period (week 108)

End point values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C
Number of subjects analysed	0 ^[18]	1	6	2
Units: pmol/L
least squares mean (confidence interval 95%)	( to )	6335.6 (723.9 to 11947.4)	-127.1 (-1015.2 to 761.1)	-129.4 (-562.0 to 303.1)

Notes
[18] - No subjects were analysed for this arm in this particular timepoint.

No statistical analyses for this end point

Secondary: Cohort A and B and C: Change from baseline to week 48 in serum ferritin levels

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End point title

Cohort A and B and C: Change from baseline to week 48 in serum ferritin levels

End point description

Change from baseline to week 48 in serum ferritin levels in cohort A and B and C is presented. Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. FAS was defined as all subjects who completed informed consent and received at least one dose of etavopivat (including partial dosing). Number of subjects analysed = Subjects with available data for the endpoint.

End point type

Secondary

End point timeframe

From baseline to week 48

End point values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C
Number of subjects analysed	4	5	17	16
Units: pmol/L
least squares mean (confidence interval 95%)	1249.5 (-419.0 to 2918.0)	585.2 (-1835.7 to 3006.1)	-359.0 (-922.0 to 204.0)	-56.4 (-213.0 to 100.3)

No statistical analyses for this end point

Secondary: Cohort A and B and C: Change from baseline to week 48 in liver iron concentration (LIC)

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End point title

Cohort A and B and C: Change from baseline to week 48 in liver iron concentration (LIC)

End point description

Change from baseline to week 48 in LIC is presented. Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. FAS was defined as all subjects who completed informed consent and received at least one dose of etavopivat (including partial dosing). Number of subjects analysed = Subjects with available data for the endpoint.

End point type

Secondary

End point timeframe

From baseline to week 48

End point values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C
Number of subjects analysed	3	4	17	13
Units: milligrams iron per gram (mgFe/g)
arithmetic mean (standard deviation)	1.553 ( 2.3951 )	-1.645 ( 2.5148 )	0.337 ( 2.4807 )	-1.588 ( 2.7642 )

No statistical analyses for this end point

Secondary: Cohort A and B and C: Change from baseline to week 96 in LIC

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End point title

Cohort A and B and C: Change from baseline to week 96 in LIC

End point description

Change from baseline to week 96 in LIC is presented. Chronically transfused was defined as >=6 RBC units in previous 24 weeks before first dose of study treatment and no transfusion-free period for >35 days during that period. FAS was defined as all subjects who completed informed consent and received at least one dose of etavopivat (including partial dosing). Number of subjects analysed = Subjects with available data for the endpoint.

End point type

Secondary

End point timeframe

From baseline to week 96

End point values	Cohort A: Simple transfusion	Cohort A: Exchange transfusion	Cohort B	Cohort C
Number of subjects analysed	0 ^[19]	1	12	6
Units: mgFe/g
arithmetic mean (standard deviation)	( )	-5.800 ( 0.0 )	0.525 ( 3.7794 )	-1.512 ( 2.0428 )

Notes
[19] - No subjects were analysed for this arm in this particular timepoint.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From baseline to week 152

Adverse event reporting additional description

All presented AEs are TEAEs. TEAE: an AE if they emerge or worsen in the period from first dose of study drug (Day 1) to 28 days after last dose of study drug. Safety set: all subjects who received at least one dose of etavopivat. Planned duration of study was up to 120 weeks. However, some subjects duration was longer due to operational reasons.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

Cohort A: Simple Transfusion

Reporting group description

Subjects received etavopivat 400 mg (2 tablets of 200mg each) daily orally for 48-week primary treatment period followed by an optional 60-week extension treatment period. In this arm, subjects with sickle cell disease (SCD) underwent chronic red blood cells (RBC) transfusion therapy through simple (manual) process to prevent stroke or recurrence of stroke.

Reporting group title

Cohort A: Exchange Transfusion

Reporting group description

Subjects received etavopivat 400 mg (2 tablets of 200mg each) daily orally for 48-week primary treatment period followed by an optional 60-week extension treatment period. In this arm, subjects with SCD underwent chronic RBC transfusion therapy through exchange transfusion process to prevent stroke or recurrence of stroke. The exchange transfusion process involved simultaneous blood removal and RBC infusion, which impacted clinical parameters, such as haemoglobin (Hb) iron levels, and volume balance, differently than the simple transfusion process.

Reporting group title

Cohort C

Reporting group description

Reporting group title

Cohort B

Reporting group description

Reporting group title

Total: Cohort A

Reporting group description

The total arm for cohort A includes subjects in the cohort A - simple transfusion arm and cohort A - exchange transfusion arm and one subject who underwent both simple and exchange transfusion procedures throughout the duration of the study. This subject was included in the Cohort A Total column in this and all other Cohort A summaries.

Serious adverse events	Cohort A: Simple Transfusion	Cohort A: Exchange Transfusion	Cohort C	Cohort B	Total: Cohort A
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	3 / 20 (15.00%)	2 / 20 (10.00%)	2 / 13 (15.38%)
number of deaths (all causes)	1	0	0	0	1
number of deaths resulting from adverse events	1	0	0	0	1
Investigations
Electrocardiogram T wave abnormal
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	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
Injury, poisoning and procedural complications
Allergic transfusion reaction
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	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
Vascular disorders
Portal vein thrombosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	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
Cardiac disorders
Cardiac arrest
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	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
Disseminated intravascular coagulation
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
Hypersplenism
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	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
Sickle cell anaemia with crisis
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	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
General disorders and administration site conditions
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	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
Vomiting
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	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
Reproductive system and breast disorders
Haemorrhagic ovarian cyst
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	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
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	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
Hepatic failure
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Tonsillitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences causally related to treatment / all	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

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Cohort A: Simple Transfusion	Cohort A: Exchange Transfusion	Cohort C	Cohort B	Total: Cohort A
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 5 (100.00%)	6 / 7 (85.71%)	20 / 20 (100.00%)	19 / 20 (95.00%)	12 / 13 (92.31%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign hepatic neoplasm
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	0	1
Hot flush
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Portal vein thrombosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
General disorders and administration site conditions
Discomfort
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Fatigue
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	4 / 20 (20.00%)	3 / 20 (15.00%)	1 / 13 (7.69%)
occurrences all number	1	0	4	5	1
Influenza like illness
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	5 / 20 (25.00%)	1 / 20 (5.00%)	1 / 13 (7.69%)
occurrences all number	0	1	13	1	1
Peripheral swelling
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Non-cardiac chest pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	3 / 20 (15.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	3	0	0
Pyrexia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	3 / 20 (15.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	3	1	0
Immune system disorders
Allergy to arthropod sting
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Hypersensitivity
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	2 / 20 (10.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	1	0	2	0	1
Reproductive system and breast disorders
Menorrhagia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 20 (10.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	2	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	4 / 20 (20.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	5	2	0
Dyspnoea exertional
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Dry throat
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Epistaxis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	1	0
Nasal congestion
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	2 / 20 (10.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	2	0
Oropharyngeal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	3 / 20 (15.00%)	3 / 20 (15.00%)	0 / 13 (0.00%)
occurrences all number	0	0	4	3	0
Throat irritation
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Depression
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	2 / 20 (10.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	3	0
Amylase increased
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	1 / 13 (7.69%)
occurrences all number	1	0	0	1	1
Alanine aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	2 / 20 (10.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	3	0
Blood uric acid increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Blood testosterone decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Blood phosphorus decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Blood creatinine increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Electrocardiogram abnormal
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Electrocardiogram T wave abnormal
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	1	0	0	0	1
Haemoglobin S increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	0	1
Lipase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Pancreatic enzymes increased
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	0	1
Prothrombin time prolonged
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Thyroxine increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Vitamin B12 decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Weight decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Foot fracture
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Ligament sprain
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	2	0	0	2
Limb injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Neck injury
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Thermal burn
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Road traffic accident
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Transfusion reaction
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Cardiac disorders
Arrhythmia supraventricular
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Extrasystoles
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Palpitations
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	1	0
Tachycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	1	0
Supraventricular extrasystoles
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Ventricular extrasystoles
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	1	0	0	0	1
Ventricular arrhythmia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	0	1
Headache
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	9 / 20 (45.00%)	5 / 20 (25.00%)	2 / 13 (15.38%)
occurrences all number	1	5	14	6	6
Migraine
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Parosmia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Paraesthesia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Hyperviscosity syndrome
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	0	1
Leukocytosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Lymphadenopathy
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 20 (10.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	2	0	0
Splenomegaly
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Sickle cell anaemia with crisis
subjects affected / exposed	1 / 5 (20.00%)	2 / 7 (28.57%)	0 / 20 (0.00%)	0 / 20 (0.00%)	4 / 13 (30.77%)
occurrences all number	1	4	0	0	6
Eye disorders
Dry eye
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	1	0	0	0	1
Eye disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Aphthous ulcer
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	2	0	0
Abdominal pain upper
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 20 (10.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	2	0	0
Abdominal pain
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	5 / 20 (25.00%)	0 / 20 (0.00%)	2 / 13 (15.38%)
occurrences all number	1	1	6	0	2
Constipation
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Diarrhoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 20 (10.00%)	2 / 20 (10.00%)	0 / 13 (0.00%)
occurrences all number	0	0	2	2	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 20 (0.00%)	1 / 20 (5.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	1	1
Gastritis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Food poisoning
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Nausea
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	4 / 20 (20.00%)	2 / 20 (10.00%)	1 / 13 (7.69%)
occurrences all number	0	2	5	3	2
Mouth cyst
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Vomiting
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 20 (10.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	3	1	0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Cholecystitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Gallbladder polyp
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Hepatic lesion
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Hyperbilirubinaemia
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	0	1
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Acne
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Eczema
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Rash papular
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 20 (10.00%)	2 / 20 (10.00%)	0 / 13 (0.00%)
occurrences all number	0	0	2	2	0
Rash maculo-papular
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	3	0	0
Pruritus
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 20 (10.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	2	0	0
Urticaria
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	2 / 20 (10.00%)	2 / 20 (10.00%)	1 / 13 (7.69%)
occurrences all number	1	0	3	5	1
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 20 (10.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	2	0	0
Haematuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Hypercalciuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Hypocitraturia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Pollakiuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Nephrolithiasis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Arthralgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 20 (10.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	2	3	0
Bone pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	1 / 13 (7.69%)
occurrences all number	0	0	0	3	2
Back pain
subjects affected / exposed	2 / 5 (40.00%)	1 / 7 (14.29%)	2 / 20 (10.00%)	2 / 20 (10.00%)	3 / 13 (23.08%)
occurrences all number	2	1	2	2	3
Fibromyalgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Myalgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	1	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 20 (5.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	1	0	1
Muscle spasms
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	2	0	0
Limb discomfort
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Pain in extremity
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 20 (10.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	3	0	0
Tendon pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Infections and infestations
COVID-19
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 20 (10.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	3	1	0
Bronchitis
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 20 (5.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	1	0	1
Beta haemolytic streptococcal infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Gastrointestinal viral infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Gastroenteritis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Hordeolum
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	1	0
Influenza
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	3 / 20 (15.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	4	0	0
Nasopharyngitis
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	1 / 20 (5.00%)	0 / 20 (0.00%)	2 / 13 (15.38%)
occurrences all number	1	3	1	0	4
Pneumonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Pharyngitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Otitis media
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Rhinitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Upper respiratory tract infection
subjects affected / exposed	1 / 5 (20.00%)	1 / 7 (14.29%)	11 / 20 (55.00%)	10 / 20 (50.00%)	2 / 13 (15.38%)
occurrences all number	1	1	18	14	2
Urinary tract infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	2 / 20 (10.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	3	0	0
Tonsillitis
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	0	1
Viral infection
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	1 / 20 (5.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	1	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	3 / 20 (15.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	1	0	3	0	1
Dehydration
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Gout
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	0 / 20 (0.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	0	0
Hypoglycaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	1 / 20 (5.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	1	2	0
Hypokalaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Iron deficiency
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	0	1
Iron overload
subjects affected / exposed	1 / 5 (20.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	1	0	0	0	1
Type 2 diabetes mellitus
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Vitamin D deficiency
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	0	1
Vitamin C deficiency
subjects affected / exposed	0 / 5 (0.00%)	0 / 7 (0.00%)	0 / 20 (0.00%)	1 / 20 (5.00%)	0 / 13 (0.00%)
occurrences all number	0	0	0	1	0
Vitamin B6 deficiency
subjects affected / exposed	0 / 5 (0.00%)	1 / 7 (14.29%)	0 / 20 (0.00%)	0 / 20 (0.00%)	1 / 13 (7.69%)
occurrences all number	0	1	0	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

08 Apr 2021

The changes included were as follows: i) Study visit nomenclature and visit windows were adjusted to clarify visit structure and better accommodate individual subject’s transfusion schedules. ii) The risk/benefit assessment language and dose justification text was updated to provide current supportive data from the ongoing first-in-human phase 1 study (4202-HVS-101). iii) Study assessments, exploratory objectives, and endpoints were modified to include the 36-Item Short Form Health Survey (SF-36) quality of life instrument. iv) Adverse event dose interruption/stopping criteria were updated and clarified to address regulatory authority feedback. v) Liver chemistry dose interruption/stopping criteria were updated and clarified to address regulatory authority feedback. vi) Text was added to provide guidelines for determination of whether a subject’s worsening alanine transaminase (ALT) is related or unrelated to the subject’s underlying disease. vii) Study assessment text was reorganized to improve presentation and consolidate text across the assessment and statistical consideration sections. viii) Text was added to describe the statistical analysis of change from baseline in serum ferritin and liver iron concentration. ix) The Appendices were updated as needed to reflect changes to the protocol.

10 Mar 2022

The changes included were as follows: i) Respective sections were updated to remove text regarding the replacement of subjects who drop out prior to week 12 for consistency with other sections of the protocol. ii) Respective sections were updated to reflect that subjects who discontinue the study prior to 24 weeks of treatment should complete the early discontinuation visit.

21 Nov 2022

The changes included were as follows: i) The study’s medical lead and associated contact infor-mation was updated. ii) Etavopivat, the international nonproprietary name for FT-4202, was in-corporated throughout the protocol iii) The screening period was extended to 8 weeks to better align with subject transfusion schedules which tend to occur every 4 weeks, thus allowing sites additional screening time iv) The allowed range for post-transfusion Hb values for patients with SCD (Cohort A) was expanded to allow for subjects with values of ~9 to 12 g/dL to align with cur-rent clinical practice. v) Risk/benefit text was updated to reflect currently available information based on Investigator’s Brochure (Version 4.0, dated 06 Jan 2022). vi) Dose justification text was updated to provide a more complete and current assessment of available information supporting the etavopivat dose of 400 mg once daily as the selected dose for the study. vii) Contraception language was updated throughout the protocol to align with guidelines provided in the current etavopivat Investigator’s Brochure (Version 4.0, dated 06 Jan 2022). viii) Cohort-specific inclusion and exclusion criteria were updated to clarify procedures and adjust requirements to improve enrollment. ix) Exclusion criteria were updated to remove restrictions on subjects receiving con-comitant medications that were moderate or strong inhibitors of CYP3A4/5 based on currently available drug-drug interaction data. x) A new section was added to provide guidelines for study drug administration that was inadvertently missed in the previous version of the protocol. x) The Schedule of Events and Appendices were updated as needed to reflect the above changes to the protocol. xi) The Schedule of Events was also updated to expand the safety visit windows and the time between safety visits to close potential gaps surrounding the safety visits which are situated between the response and EOT visits.

24 Aug 2023

The changes included were as follows: i) An optional 60-week extension treatment period was added to the study. Impacted sections included: study endpoints, study design, treatment/study duration, end of study and study/treatment discontinuation. ii) Study endpoints were clarified to align with the Statistical Analysis Plan (SAP) and current clinical guidance. iii) Study drug administration text was updated to clarify that actions taken in relation to study drug administration (dose hold, dose reduction, rechallenge) must be recorded on an ongoing basis during the entire duration of the study, including the time between study visits. iv) Statistical considerations text was clarified to align with the SAP and current clinical guidance, and to correct typographical errors. v) The Schedule of Events and Appendices were updated as needed to reflect the above changes to the protocol.

11 Dec 2023

The changes included were as follows: i) Update of the contraception guidance based on the safety profile agreed for etavopivat. ii) Update of the safety reporting information as Novo Nordisk Global Safety is now responsible for safety surveillance in the study. Safety text has been added throughout the document to reflect the Novo Nordisk Safety Surveillance practice. iii) Inclusion of an appendix for country specific considerations in alignment with Novo Nordisk protocol process and to prevent separate country specific amendments. iv) Update to ensure alignment with the Statistical Analysis Plan. v) Implementation of wording allowing transition into a future roll-over study after completion of the primary treatment period or while on the extension treatment period vi) The Schedule of Events table (Table 1 and Table 2) and associated footnotes have been updated to reflect the described changes.

28 Oct 2024

The changes included were as follows: i) New potential risk (Histiocytic sarcomas) added. Based on a signal from a non-clinical study. ii) Drug-drug interaction with CYP3A4 inducers. Based on a clinical evaluation. iii) An End of Study visit will not be performed in case subjects were enrolled in the roll-over study.

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 2 Open-Label Study to Evaluate Safety and Clinical Activity of Etavopivat in Patients with Thalassemia or Sickle Cell Disease

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Cohort C: Percentage of subjects achieving a haemoglobin (Hb) response (increase of >=1.0 grams per deciliter [g/dL] from baseline)

Primary: Cohort C: Percentage of subjects achieving a haemoglobin (Hb) response (increase of >=1.0 grams per deciliter [g/dL] from baseline)

Primary: Cohorts A (Simple transfusion) and B: Percentage of subjects achieving greater than or equal to (>=) 20% reduction in RBC transfusion units over a continuous 12-week treatment period versus baseline RBC transfusion history

Primary: Cohorts A (Simple transfusion) and B: Percentage of subjects achieving greater than or equal to (>=) 20% reduction in RBC transfusion units over a continuous 12-week treatment period versus baseline RBC transfusion history

Secondary: Number of subjects with treatment emergent serious adverse events (TESAEs)

Secondary: Number of subjects with treatment emergent serious adverse events (TESAEs)

Secondary: Number of subjects with TEAEs leading to discontinuation

Secondary: Number of subjects with TEAEs leading to discontinuation

Secondary: Number of subjects with clinically significant laboratory parameters: Haematolysis

Secondary: Number of subjects with clinically significant laboratory parameters: Haematolysis

Secondary: Number of subjects with clinically significant laboratory parameters: Biochemistry

Secondary: Number of subjects with clinically significant laboratory parameters: Biochemistry

Secondary: Number of subjects with clinically significant laboratory parameters: Coagulation

Secondary: Number of subjects with clinically significant laboratory parameters: Coagulation

Secondary: Number of subjects with clinically significant laboratory parameters: Urinalysis

Secondary: Number of subjects with clinically significant laboratory parameters: Urinalysis

Secondary: Number of subjects with clinically significant laboratory parameters: Endocrinology

Secondary: Number of subjects with clinically significant laboratory parameters: Endocrinology

Secondary: Number of subjects with clinically significant laboratory parameters: Iron studies, folate and Vitamin B12

Secondary: Number of subjects with clinically significant laboratory parameters: Iron studies, folate and Vitamin B12

Secondary: Number of participants with clinically significant laboratory parameters: Serolgy

Secondary: Number of participants with clinically significant laboratory parameters: Serolgy

Secondary: Number of subjects with clinically significant abnormal electrocardiograms (ECGs)

Secondary: Number of subjects with clinically significant abnormal electrocardiograms (ECGs)

Secondary: Cohorts A (Simple transfusion) and B: Relative reduction from baseline in RBC transfusion burden from baseline to week 12

Secondary: Cohorts A (Simple transfusion) and B: Relative reduction from baseline in RBC transfusion burden from baseline to week 12

Secondary: Cohorts A (Simple transfusion) and B: Number of subjects achieving >= 33% reduction in RBC transfusion units over a continuous 12-week treatment period versus baseline RBC transfusion history

Secondary: Cohorts A (Simple transfusion) and B: Number of subjects achieving >= 33% reduction in RBC transfusion units over a continuous 12-week treatment period versus baseline RBC transfusion history

Secondary: Cohorts A (Simple transfusion) and B: Relative reduction from baseline in RBC transfusion burden from baseline to week 24

Secondary: Cohorts A (Simple transfusion) and B: Relative reduction from baseline in RBC transfusion burden from baseline to week 24

Secondary: Cohorts A (Simple transfusion) and B: Relative reduction from baseline in RBC transfusion burden from baseline to week 48

Secondary: Cohorts A (Simple transfusion) and B: Relative reduction from baseline in RBC transfusion burden from baseline to week 48

Secondary: Cohorts A (Simple transfusion) and B: Relative reduction from baseline in RBC transfusion burden from baseline to end of extension treatment period (week 108)

Secondary: Cohorts A (Simple transfusion) and B: Relative reduction from baseline in RBC transfusion burden from baseline to end of extension treatment period (week 108)

Secondary: Cohort C: Number of subjects achieving a Hb response (increase of >=1.0 g/dL from baseline) at week 24

Secondary: Cohort C: Number of subjects achieving a Hb response (increase of >=1.0 g/dL from baseline) at week 24

Secondary: Cohort C: Number of subjects achieving a Hb response (increase of >=1.0 g/dL from baseline) at week 48

Secondary: Cohort C: Number of subjects achieving a Hb response (increase of >=1.0 g/dL from baseline) at week 48

Secondary: Cohort C: Number of subjects achieving a Hb response (increase of >=1.0 g/dL from baseline) at end of extension treatment period (week 108)

Secondary: Cohort C: Number of subjects achieving a Hb response (increase of >=1.0 g/dL from baseline) at end of extension treatment period (week 108)

Secondary: Cohort C: Mean change from baseline to week 12 in Hb

Secondary: Cohort C: Mean change from baseline to week 12 in Hb

Secondary: Cohort C: Mean change from baseline to week 24 in Hb

Secondary: Cohort C: Mean change from baseline to week 24 in Hb

Secondary: Cohort C: Mean change from baseline to week 48 in Hb

Secondary: Cohort C: Mean change from baseline to week 48 in Hb

Secondary: Cohort A and B and C: Change from baseline to week 24 in serum ferritin levels

Secondary: Cohort A and B and C: Change from baseline to week 24 in serum ferritin levels

Secondary: Cohort A and B and C: Change from baseline to week 12 in serum ferritin levels

Secondary: Cohort A and B and C: Change from baseline to week 12 in serum ferritin levels

Secondary: Cohort C: Mean change from baseline to end of extension treatment period (week 108) in Hb

Secondary: Cohort C: Mean change from baseline to end of extension treatment period (week 108) in Hb

Secondary: Cohort A and B and C: Change from baseline to end of extension treatment period (week 108) in serum ferritin levels

Secondary: Cohort A and B and C: Change from baseline to end of extension treatment period (week 108) in serum ferritin levels

Secondary: Cohort A and B and C: Change from baseline to week 48 in serum ferritin levels

Secondary: Cohort A and B and C: Change from baseline to week 48 in serum ferritin levels

Secondary: Cohort A and B and C: Change from baseline to week 48 in liver iron concentration (LIC)

Secondary: Cohort A and B and C: Change from baseline to week 48 in liver iron concentration (LIC)

Secondary: Cohort A and B and C: Change from baseline to week 96 in LIC

Secondary: Cohort A and B and C: Change from baseline to week 96 in LIC

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 2 Open-Label Study to Evaluate Safety and Clinical Activity of Etavopivat in Patients with Thalassemia or Sickle Cell Disease