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Clinical Trial Results:
A Multi-Center, Open Label Study to Assess the Safety, Steady-State Pharmacokinetics and Pharmacodynamics of IMG-7289 in Patients With Myelofibrosis

Summary
EudraCT number	2018-003811-23
Trial protocol	DE IT GB
Global end of trial date	08 Mar 2022

Results information
Results version number	v1(current)
This version publication date	02 Dec 2023
First version publication date	02 Dec 2023
Other versions
Summary report(s)	Delayed Results Posting Memo

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

IMG-7289-CTP-102

ISRCTN number

US NCT number

NCT03136185

WHO universal trial number (UTN)

Other trial identifiers

Merck Protocol Number: MK-3543-002

Sponsor organisation name

Merck Sharp & Dohme LLC

Sponsor organisation address

126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065

Public contact

Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com

Scientific contact

Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

08 Mar 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

08 Mar 2022

Global end of trial reached?

Yes

Global end of trial date

08 Mar 2022

Was the trial ended prematurely?

Main objective of the trial

This is a Phase 1/2 open-label study to evaluate the safety, tolerability, steady-state pharmacokinetic (PK) and pharmacodynamics (PD) of a lysine-specific demethylase 1 (LSD1) inhibitor, bomedemstat (IMG-7289/MK-3543), administered orally once daily in participants with myelofibrosis. The primary hypothesis is that bomedemstat is a safe and tolerable orally available agent when administered to participants with myelofibrosis including primary myelofibrosis (PMF), post-polycythaemia vera-myelofibrosis (PPVMF), and post-essential thrombocythaemia-myelofibrosis (PET-MF) (collectively referred to as ‘MF’); inhibition of LSD1 by bomedemstat will reduce spleen size in those with splenomegaly, improve haematopoiesis and reduce constitutional symptoms associated with these disorders.

Protection of trial subjects

This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.

Background therapy

Evidence for comparator

Actual start date of recruitment

18 Jul 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 7

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

Hong Kong: 20

Country: Number of subjects enrolled

Italy: 13

Country: Number of subjects enrolled

United States: 37

Country: Number of subjects enrolled

United Kingdom: 9

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

Participants with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), and post-essential thrombocythemia myelofibrosis (PET-MF) were recruited for this study.

Screening details

Eighteen participants were enrolled in the Phase 1/2a portion of this study and 72 participants were enrolled in the Phase 2b portion of this study.

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

Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d

Arm description

In the Phase 1/2a portion of the study, PMF participants received 0.25 mg/kg/d bomedemstat orally every day (qd) for 85 days during the Initial Treatment Period (ITP). Qualifying participants could continue to receive treatment for an additional 169 days during the Additional Treatment Period (ATP) as determined by the investigator.

Arm type

Experimental

Investigational medicinal product name

Bomedemstat

Investigational medicinal product code

Other name

IMG-7289 MK-3543 LSD1 inhibitor

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Oral (capsule) administration according to dose allocation.

Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d

Arm description

In the Phase 1/2a portion of the study, PPV-MF participants received 0.25 mg/kg/d bomedemstat orally qd for 85 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator.

Arm type

Experimental

Investigational medicinal product name

Bomedemstat

Investigational medicinal product code

Other name

IMG-7289 MK-3543 LSD1 inhibitor

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Oral (capsule) administration according to dose allocation.

Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d

Arm description

In the Phase 1/2a portion of the study, PET-MF participants received 0.25 mg/kg/d bomedemstat orally qd for 85 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator.

Arm type

Experimental

Investigational medicinal product name

Bomedemstat

Investigational medicinal product code

Other name

IMG-7289 MK-3543 LSD1 inhibitor

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Oral (capsule) administration according to dose allocation.

Ph 2b PMF: Bomedemstat 0.5 mg/kg/d

Arm description

In the Phase 2b portion of the study, PMF participants received 0.5 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator.

Arm type

Experimental

Investigational medicinal product name

Bomedemstat

Investigational medicinal product code

Other name

IMG-7289 MK-3543 LSD1 inhibitor

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Oral (capsule) administration according to dose allocation.

Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d

Arm description

In the Phase 2b portion of the study, PPV-MF participants received 0.5 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator.

Arm type

Experimental

Investigational medicinal product name

Bomedemstat

Investigational medicinal product code

Other name

IMG-7289 MK-3543 LSD1 inhibitor

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Oral (capsule) administration according to dose allocation.

Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d

Arm description

In the Phase 2b portion of the study, PET-MF participants received 0.5 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator.

Arm type

Experimental

Investigational medicinal product name

Bomedemstat

Investigational medicinal product code

Other name

IMG-7289 MK-3543 LSD1 inhibitor

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Oral (capsule) administration according to dose allocation.

Ph 2b PMF: Bomedemstat 0.6 mg/kg/d

Arm description

In the Phase 2b portion of the study, PMF participants received 0.6 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator.

Arm type

Experimental

Investigational medicinal product name

Bomedemstat

Investigational medicinal product code

Other name

IMG-7289 MK-3543 LSD1 inhibitor

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Oral (capsule) administration according to dose allocation.

Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d

Arm description

In the Phase 2b portion of the study, PPV-MF participants received 0.6 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator.

Arm type

Experimental

Investigational medicinal product name

Bomedemstat

Investigational medicinal product code

Other name

IMG-7289 MK-3543 LSD1 inhibitor

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Oral (capsule) administration according to dose allocation.

Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d

Arm description

In the Phase 2b portion of the study, PET-MF participants received 0.6 mg/kg/d bomedemstat orally qd for 169 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator.

Arm type

Experimental

Investigational medicinal product name

Bomedemstat

Investigational medicinal product code

Other name

IMG-7289 MK-3543 LSD1 inhibitor

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Oral (capsule) administration according to dose allocation.

Number of subjects in period 1	Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d	Ph 2b PMF: Bomedemstat 0.5 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PMF: Bomedemstat 0.6 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d
Started	9	3	6	8	5	11	24	11	13
Completed Initial Treatment Period	7	3	4	4	1	4	18	8	10
Entered Additional Treatment Period	6	2	3	3	1	4	17	5	9
Completed	1	0	0	2	0	3	14	5	7
Not completed	8	3	6	6	5	8	10	6	6
Physician decision	3	1	1	2	1	2	1	-	1
Consent withdrawn by subject	1	-	1	1	1	1	2	3	3
Protocol Defined Disease Progression	-	-	1	-	-	1	-	1	1
Not Reported	4	1	-	1	-	2	1	1	-
Adverse event, non-fatal	-	1	3	1	2	2	5	1	1
Death	-	-	-	1	1	-	1	-	-

Baseline characteristics

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Reporting group title

Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d

Reporting group description

Reporting group title

Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d

Reporting group description

Reporting group title

Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PMF: Bomedemstat 0.5 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PMF: Bomedemstat 0.6 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d

Reporting group description

Reporting group values	Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d	Ph 2b PMF: Bomedemstat 0.5 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PMF: Bomedemstat 0.6 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d	Total
Number of subjects	9	3	6	8	5	11	24	11	13	90
Age categorical
Units: Subjects
Adults (18-64 years)	6	0	2	2	2	3	11	4	7	37
From 65-84 years	2	3	4	6	3	8	13	7	6	52
85 years and over	1	0	0	0	0	0	0	0	0	1
Age Continuous
Units: Years
arithmetic mean (standard deviation)	62.6 ± 12.43	74.7 ± 5.51	64.7 ± 6.59	69.6 ± 8.38	64.8 ± 7.46	69.4 ± 14.40	65.2 ± 9.42	66.7 ± 9.27	61.3 ± 12.07	-
Sex: Female, Male
Units: Participants
Female	1	0	4	4	4	6	12	8	4	43
Male	8	3	2	4	1	5	12	3	9	47
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	1	0	0	1	1	0	0	3
Not Hispanic or Latino	8	3	5	8	4	10	22	11	9	80
Unknown or Not Reported	1	0	0	0	1	0	1	0	4	7
Race/Ethnicity, Customized
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0	0	0
Asian	0	0	0	0	1	0	10	5	5	21
Black or African American	0	0	0	0	0	1	0	0	1	2
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	1	0	0	1
White	7	2	6	7	4	9	12	6	6	59
Other	1	1	0	0	0	0	0	0	0	2
Multiple	0	0	0	0	0	0	0	0	1	1
Not Reported	1	0	0	1	0	1	1	0	0	4

End points

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Reporting group title

Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d

Reporting group description

Reporting group title

Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d

Reporting group description

Reporting group title

Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PMF: Bomedemstat 0.5 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PMF: Bomedemstat 0.6 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d

Reporting group description

Subject analysis set title

Ph 1/2a Portion: Bomedemstat 0.25 mg/kg/d

Subject analysis set type

Safety analysis

Subject analysis set description

In the Phase 1/2a portion of the study, participants received 0.25 mg/kg/d bomedemstat orally qd for 85 days during the ITP. Qualifying participants could continue to receive treatment for an additional 169 days during the ATP as determined by the investigator.

Primary: Number of Participants with Dose Limiting Toxicities (DLTs)

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End point title

Number of Participants with Dose Limiting Toxicities (DLTs) ^[1]

End point description

DLT was defined as any one of the following adverse events (AEs) occurring through Day 7 of the ITP and considered by the Investigator to be possibly, probably or definitely related to bomedemstat: thrombocytopenia leading to clinically significant sequelae; a clinically significant bleeding event in a participant with a platelet count >50 x 10^9/L (50 k/μL); any Grade 4 or 5 non-haematologic adverse event; any Grade 3 non-haematologic adverse event with failure to recover to Grade 2 within 7 days of drug cessation, with the following exceptions: ≥ Grade 3 nausea, vomiting or diarrhea that responds to standard medical care; ≥ Grade 3 aesthenia lasting less than 14 days; any Grade 3 electrolyte abnormality unrelated to the underlying malignancy and persisting greater than 24 hours. The number of participants with a DLT were reported. All allocated participants receiving ≥1 dose of bomedemstat were included in the DLT analysis.

End point type

Primary

End point timeframe

Up to Day 7 of the ITP

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: No statistical analyses were planned for this endpoint.

End point values	Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d	Ph 2b PMF: Bomedemstat 0.5 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PMF: Bomedemstat 0.6 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d
Number of subjects analysed	9	3	6	8	5	11	24	11	13
Units: Participants	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Primary: Number of Participants with Serious Adverse Events

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End point title

Number of Participants with Serious Adverse Events ^[2]

End point description

An AE was any undesirable physical, psychological or behavioral effect experienced by a participant, in conjunction with the use of the drug or biologic, whether or not product-related. This included any untoward signs or symptoms experienced by the participant from the time of first dose with bomedemstat until completion of the study. Serious AEs (SAEs) were any AE that resulted in death, life-threatening experience, required or prolonged inpatient hospitalization, persistent or significant disability/incapacity, congenital anomaly, or important medical events. The number of participants with at least one treatment-emergent (TE) SAE was reported for each arm. All allocated participants receiving at least one dose of bomedemstat were included in the safety analysis.

End point type

Primary

End point timeframe

Up to approximately 30 months

Notes
[2] - 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: No statistical analyses were planned for this endpoint.

End point values	Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d	Ph 2b PMF: Bomedemstat 0.5 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PMF: Bomedemstat 0.6 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d
Number of subjects analysed	9	3	6	8	5	11	24	11	13
Units: Participants	4	2	5	4	4	7	12	3	3

No statistical analyses for this end point

Primary: Number of Participants with Adverse Events

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End point title

Number of Participants with Adverse Events ^[3]

End point description

End point type

Primary

End point timeframe

Up to approximately 30 months

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: No statistical analyses were planned for this endpoint.

End point values	Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d	Ph 2b PMF: Bomedemstat 0.5 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PMF: Bomedemstat 0.6 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d
Number of subjects analysed	9	3	6	8	5	11	24	11	13
Units: Participants	9	3	6	8	5	11	23	10	12

No statistical analyses for this end point

Primary: Number of Participants that Discontinued Study Treatment Due To AEs

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End point title

Number of Participants that Discontinued Study Treatment Due To AEs ^[4]

End point description

An AE was any undesirable physical, psychological or behavioral effect experienced by a participant, in conjunction with the use of the drug or biologic, whether or not product-related. This included any untoward signs or symptoms experienced by the participant from the time of first dose with bomedemstat until completion of the study. The number of participants that discontinued study treatment with bomedemstat due to a TE AE was reported for each arm. All allocated participants receiving at least one dose of bomedemstat were included in the safety analysis.

End point type

Primary

End point timeframe

Up to approximately 29 months

Notes
[4] - 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: No statistical analyses were planned for this endpoint.

End point values	Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d	Ph 2b PMF: Bomedemstat 0.5 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PMF: Bomedemstat 0.6 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d
Number of subjects analysed	9	3	6	8	5	11	24	11	13
Units: Participants	0	1	5	1	2	4	5	2	3

No statistical analyses for this end point

Primary: Phase 1/2a Portion: Observed Maximum Concentration (Cmax) of Bomedemstat

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End point title

Phase 1/2a Portion: Observed Maximum Concentration (Cmax) of Bomedemstat ^[5] ^[6]

End point description

Cmax was defined as the maximum observed concentration after administration obtained directly from the concentration time profile. Blood and plasma samples were collected at pre-specified timepoints to calculate Cmax in participants of the Phase 1/2a portion of the study. As pre-specified by the Pharmacokinetic Analysis Plan (PAP), all participants in the Phase 1/2a portion of the study who received bomedemstat and completed a sufficient portion of the study with enough data for the determination of pharmacokinetic parameters were analyzed. For the purposes of the analysis, Phase 1/2a participants were analyzed irrespective of myelofibrosis disorder (PMF, PPV-MF, or PET-MF). As pre-specified by the protocol and PAP, Phase 2b participants were excluded from this analysis.

End point type

Primary

End point timeframe

Day 21: Pre-dose and 0.5, 1, 2, 3, 4, 8, and 24 hours (Day 22) after dosing.

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses were planned for this endpoint.
[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: For this analysis, Phase 1/2a participants were analyzed irrespective of myelofibrosis disorder. Phase 2b participants were excluded from this analysis.

End point values	Ph 2b PMF: Bomedemstat 0.5 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PMF: Bomedemstat 0.6 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d	Ph 1/2a Portion: Bomedemstat 0.25 mg/kg/d
Number of subjects analysed	0 ^[7]	0 ^[8]	0 ^[9]	0 ^[10]	0 ^[11]	0 ^[12]	12 ^[13]
Units: ng/mL
geometric mean (geometric coefficient of variation)
Plasma	±	±	±	±	±	±	12.63 ± 104.41
Blood	±	±	±	±	±	±	26.27 ± 66.76

Notes
[7] - Phase 2b participants were excluded from this analysis.
[8] - Phase 2b participants were excluded from this analysis.
[9] - Phase 2b participants were excluded from this analysis.
[10] - Phase 2b participants were excluded from this analysis.
[11] - Phase 2b participants were excluded from this analysis.
[12] - Phase 2b participants were excluded from this analysis.
[13] - For this analysis, Phase 1/2a participants were analyzed irrespective of myelofibrosis disorder.

No statistical analyses for this end point

Primary: Phase 1/2a Portion: Time to Maximum Concentration (Tmax) of Bomedemstat

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End point title

Phase 1/2a Portion: Time to Maximum Concentration (Tmax) of Bomedemstat ^[14] ^[15]

End point description

Tmax was defined as the time to maximum concentration after administration obtained by inspection. Blood and plasma samples were collected at pre-specified timepoints to calculate Tmax in participants of the Phase 1/2a portion of the study. As pre-specified by the PAP, all participants in the Phase 1/2a portion of the study who received bomedemstat and completed a sufficient portion of the study with enough data for the determination of pharmacokinetic parameters were analyzed. For the purposes of the analysis, Phase 1/2a participants were analyzed irrespective of myelofibrosis disorder (PMF, PPV-MF, or PET-MF). As pre-specified by the protocol and PAP, Phase 2b participants were excluded from this analysis.

End point type

Primary

End point timeframe

Day 21: Pre-dose and 0.5, 1, 2, 3, 4, 8, and 24 hours (Day 22) after dosing.

Notes
[14] - 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: No statistical analyses were planned for this endpoint.
[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: For this analysis, Phase 1/2a participants were analyzed irrespective of myelofibrosis disorder. Phase 2b participants were excluded from this analysis.

End point values	Ph 2b PMF: Bomedemstat 0.5 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PMF: Bomedemstat 0.6 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d	Ph 1/2a Portion: Bomedemstat 0.25 mg/kg/d
Number of subjects analysed	0 ^[16]	0 ^[17]	0 ^[18]	0 ^[19]	0 ^[20]	0 ^[21]	12 ^[22]
Units: hour
median (full range (min-max))
Plasma	( to )	( to )	( to )	( to )	( to )	( to )	1.00 (0.50 to 2.85)
Blood	( to )	( to )	( to )	( to )	( to )	( to )	1.05 (0.50 to 3.02)

Notes
[16] - Phase 2b participants were excluded from this analysis.
[17] - Phase 2b participants were excluded from this analysis.
[18] - Phase 2b participants were excluded from this analysis.
[19] - Phase 2b participants were excluded from this analysis.
[20] - Phase 2b participants were excluded from this analysis.
[21] - Phase 2b participants were excluded from this analysis.
[22] - For this analysis, Phase 1/2a participants were analyzed irrespective of myelofibrosis disorder.

No statistical analyses for this end point

Primary: Phase 1/2a Portion: Area Under the Concentration-time Curve of Bomedemstat from Time 0 to 24 hours post-dose (AUC0-24)

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End point title

Phase 1/2a Portion: Area Under the Concentration-time Curve of Bomedemstat from Time 0 to 24 hours post-dose (AUC0-24) ^[23] ^[24]

End point description

AUC0-24 was defined as the area under the concentration versus time curve calculated using the linear trapezoidal rule from the zero time-point to the 24-hour time-point concentration. Blood and plasma samples were collected at pre-specified timepoints to calculate AUC0-24 in participants of the Phase 1/2a portion of the study. As pre-specified by the PAP, all participants in the Phase 1/2a portion of the study who received bomedemstat and completed a sufficient portion of the study with enough data for the determination of pharmacokinetic parameters were analyzed. For the purposes of the analysis, Phase 1/2a participants were analyzed irrespective of myelofibrosis disorder (PMF, PPV-MF, or PET-MF). As pre-specified by the protocol and PAP, Phase 2b participants were excluded from this analysis.

End point type

Primary

End point timeframe

Day 21: Pre-dose and 0.5, 1, 2, 3, 4, 8, and 24 hours (Day 22) after dosing.

Notes
[23] - 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: No statistical analyses were planned for this endpoint.
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: For this analysis, Phase 1/2a participants were analyzed irrespective of myelofibrosis disorder. Phase 2b participants were excluded from this analysis.

End point values	Ph 2b PMF: Bomedemstat 0.5 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PMF: Bomedemstat 0.6 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d	Ph 1/2a Portion: Bomedemstat 0.25 mg/kg/d
Number of subjects analysed	0 ^[25]	0 ^[26]	0 ^[27]	0 ^[28]	0 ^[29]	0 ^[30]	12 ^[31]
Units: hour•ng/mL
geometric mean (geometric coefficient of variation)
Plasma	±	±	±	±	±	±	63.90 ± 68.56
Blood	±	±	±	±	±	±	265.92 ± 68.92

Notes
[25] - Phase 2b participants were excluded from this analysis.
[26] - Phase 2b participants were excluded from this analysis.
[27] - Phase 2b participants were excluded from this analysis.
[28] - Phase 2b participants were excluded from this analysis.
[29] - Phase 2b participants were excluded from this analysis.
[30] - Phase 2b participants were excluded from this analysis.
[31] - For this analysis, Phase 1/2a participants were analyzed irrespective of myelofibrosis disorder.

No statistical analyses for this end point

Primary: Phase 1/2a Portion: Apparent total clearance (CL/F) of Bomedemstat after oral administration

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End point title

Phase 1/2a Portion: Apparent total clearance (CL/F) of Bomedemstat after oral administration ^[32] ^[33]

End point description

CL/F was defined as the apparent total clearance of drug after oral administration. Blood and plasma samples were collected at pre-specified timepoints to calculate CL/F in participants of the Phase 1/2a portion of the study. As pre-specified by the PAP, all participants in the Phase 1/2a portion of the study who received bomedemstat and completed a sufficient portion of the study with enough data for the determination of pharmacokinetic parameters were analyzed. For the purposes of the analysis, Phase 1/2a participants were analyzed irrespective of myelofibrosis disorder (PMF, PPV-MF, or PET-MF). As pre-specified by the protocol and PAP, Phase 2b participants were excluded from this analysis.

End point type

Primary

End point timeframe

Day 21: Pre-dose and 0.5, 1, 2, 3, 4, 8, and 24 hours (Day 22) after dosing.

Notes
[32] - 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: No statistical analyses were planned for this endpoint.
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: For this analysis, Phase 1/2a participants were analyzed irrespective of myelofibrosis disorder. Phase 2b participants were excluded from this analysis.

End point values	Ph 2b PMF: Bomedemstat 0.5 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PMF: Bomedemstat 0.6 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d	Ph 1/2a Portion: Bomedemstat 0.25 mg/kg/d
Number of subjects analysed	0 ^[34]	0 ^[35]	0 ^[36]	0 ^[37]	0 ^[38]	0 ^[39]	12 ^[40]
Units: mL/min
geometric mean (geometric coefficient of variation)
Plasma	±	±	±	±	±	±	12787.43 ± 63.72
Blood	±	±	±	±	±	±	3067.57 ± 85.78

Notes
[34] - Phase 2b participants were excluded from this analysis.
[35] - Phase 2b participants were excluded from this analysis.
[36] - Phase 2b participants were excluded from this analysis.
[37] - Phase 2b participants were excluded from this analysis.
[38] - Phase 2b participants were excluded from this analysis.
[39] - Phase 2b participants were excluded from this analysis.
[40] - For this analysis, Phase 1/2a participants were analyzed irrespective of myelofibrosis disorder.

No statistical analyses for this end point

Primary: Percent Change from Baseline in Spleen Volume

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End point title

Percent Change from Baseline in Spleen Volume ^[41]

End point description

Change in spleen volume was to be assessed based on calculated spleen volume (ml) measured by magnetic resonance imaging (MRI), or computerized tomography (CT) scan (where locally permitted) if the participant was not a candidate for MRI from Day 0. Percent change from baseline in spleen volume was reported at Initial Treatment Period (ITP) Day 84, ITP Day 168, Additional Treatment Period 1 (ATP1) Day 84 (Study Day 253), and ATP1 Day 168 (Study Day 337). All allocated participants who received ≥1 dose of treatment and had available spleen volume data were analyzed. Due to differing dosing schedules, time points not applicable for certain arms or with no data collected are indicated by “0000” in the table (zero participants analyzed). 95% confidence intervals for arms with n>2 participants but where n<2 participants were evaluated at a time point are indicated as not evaluable with (-9999,9999) in the table.

End point type

Primary

End point timeframe

Baseline, ITP Day 84 (Study Day 84), ITP Day 168 (Study Day 168), ATP1 Day 84 (Study Day 253), and ATP1 Day 168 (Study Day 337)

Notes
[41] - 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: No between-group statistical analyses were performed for this endpoint.

End point values	Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d	Ph 2b PMF: Bomedemstat 0.5 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PMF: Bomedemstat 0.6 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d
Number of subjects analysed	3 ^[42]	3 ^[43]	2 ^[44]	5 ^[45]	3 ^[46]	6 ^[47]	17 ^[48]	8 ^[49]	8 ^[50]
Units: Percentage Change
arithmetic mean (confidence interval 95%)
ITP Day 84 (Study Day 84)	3.3 (-50.5 to 57.0)	-13.7 (-49.6 to 22.2)	2.2 (-110.3 to 114.8)	-9.1 (-27.9 to 9.6)	-7.2 (-80.2 to 65.8)	0.3 (-32.3 to 32.9)	10.0 (1.2 to 18.8)	-2.3 (-31.5 to 26.9)	1.2 (-10.9 to 13.2)
ITP Day 168 (Study Day 168)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)	-23.9 (-43.2 to -4.6)	-19.6 (-9999 to 9999)	-33.7 (-43.8 to -23.6)	12.3 (-4.1 to 28.6)	-15.4 (-56.7 to 25.8)	-4.4 (-20.6 to 11.8)
ATP1 Day 84 (Study Day 253)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)	-27.7 (-9999 to 9999)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)
ATP1 Day 168 (Study Day 337)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)	-36.5 (-9999 to 9999)	0000 (0000 to 0000)	-38.9 (-9999 to 9999)	37.4 (-55.6 to 130.5)	6.0 (-302.0 to 313.9)	-15.0 (-39.0 to 9.0)

Notes
[42] - 0000=no participants analyzed. -9999/9999= not evaluable
[43] - 0000=no participants analyzed. -9999/9999= not evaluable
[44] - 0000=no participants analyzed. -9999/9999= not evaluable
[45] - 0000=no participants analyzed. -9999/9999= not evaluable
[46] - 0000=no participants analyzed. -9999/9999= not evaluable
[47] - 0000=no participants analyzed. -9999/9999= not evaluable
[48] - 0000=no participants analyzed. -9999/9999= not evaluable
[49] - 0000=no participants analyzed. -9999/9999= not evaluable
[50] - 0000=no participants analyzed. -9999/9999= not evaluable

No statistical analyses for this end point

Primary: Percent Change from Baseline in Spleen Size

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End point title

Percent Change from Baseline in Spleen Size ^[51]

End point description

Change in spleen size assessed based on spleen palpation (in cm) at each visit. Percent change from baseline in spleen size was reported at ITP Day 84, ITP Day 168, ATP1 Day 84 (Study Day 253), ATP1 Day 168 (Study Day 337), ATP2 Day 84 (Study Day 422), ATP2 Day 168 (Study Day 506), and ATP3 Day 84 (Study Day 591). As prespecified by the Statistical Analysis Plan, assessments for Phase 1/2 groups summarized using visit windowing after the Day 84 visit of the ITP to allow for comparison with the Phase 2b groups at ITP Day 168. All allocated participants who received ≥1 dose of treatment and had available spleen size data were analyzed. Due to differing dosing schedules, time points not applicable for certain arms or with no data collected are indicated by “0000” in the table (zero participants analyzed). 95% confidence intervals for arms with n>2 participants but where n<2 participants were evaluated at a time point are indicated as not evaluable with (-9999,9999) in the table.

End point type

Primary

End point timeframe

Baseline, ITP Day 84 (Study Day 84), ITP Day 168 (Study Day 168), ATP1 Day 84 (Study Day 253), ATP1 Day 168 (Study Day 337), ATP2 Day 84 (Study Day 422), ATP2 Day 168 (Study Day 506), and ATP3 Day 84 (Study Day 591)

Notes
[51] - 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: No between-group statistical analyses were performed for this endpoint.

End point values	Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d	Ph 2b PMF: Bomedemstat 0.5 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PMF: Bomedemstat 0.6 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d
Number of subjects analysed	6 ^[52]	3 ^[53]	4 ^[54]	3 ^[55]	2 ^[56]	6 ^[57]	13 ^[58]	6 ^[59]	5 ^[60]
Units: Percentage Change
arithmetic mean (confidence interval 95%)
ITP Day 84 (Study Day 84)	-36.5 (-68.0 to -5.0)	9.6 (-95.1 to 114.2)	24.1 (-79.4 to 127.7)	20.7 (-132.2 to 173.7)	-28.1 (-257.8 to 201.6)	11.0 (-70.7 to 92.7)	-34.7 (-58.1 to -11.3)	-38.2 (-53.4 to -23.1)	-59.6 (-113.4 to -5.7)
ITP Day 168 (Study Day 168)	-20.7 (-48.3 to 6.9)	-39.6 (-9999 to 9999)	116.3 (-1794.8 to 2027.4)	-27.8 (-9999 to 9999)	0000 (0000 to 0000)	-36.1 (-212.6 to 140.4)	-24.8 (-74.2 to 24.5)	-28.5 (-60.1 to 3.0)	-41.2 (-102.9 to 20.6)
ATP1 Day 84 (Study Day 253)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)	-27.8 (-9999 to 9999)	0000 (0000 to 0000)	-36.1 (-212.6 to 140.4)	-27.9 (-84.8 to 29.0)	-50.4 (-101.7 to 0.9)	-28.4 (-97.7 to 40.9)
ATP1 Day 168 (Study Day 337)	-19.0 (-9999 to 9999)	0000 (0000 to 0000)	0000 (0000 to 0000)	-27.8 (-9999 to 9999)	0000 (0000 to 0000)	-38.9 (-180.1 to 102.3)	-1.9 (-151.0 to 147.3)	-38.9 (-9999 to 9999)	-82.4 (-117.4 to -47.4)
ATP2 Day 84 (Study Day 422)	-4.8 (-9999 to 9999)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)	-37.5 (-196.3 to 121.3)	0000 (0000 to 0000)	-44.4 (-9999 to 9999)	0000 (0000 to 0000)
ATP2 Day 168 (Study Day 506)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)	-22.0 (-9999 to 9999)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)
ATP3 Day 84 (Study Day 591)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)	-11.1 (-152.3 to 130.1)	0000 (0000 to 0000)	0000 (0000 to 0000)	0000 (0000 to 0000)

Notes
[52] - 0000=no participants analyzed. -9999/9999= not evaluable
[53] - 0000=no participants analyzed. -9999/9999= not evaluable
[54] - 0000=no participants analyzed. -9999/9999= not evaluable
[55] - 0000=no participants analyzed. -9999/9999= not evaluable
[56] - 0000=no participants analyzed. -9999/9999= not evaluable
[57] - 0000=no participants analyzed. -9999/9999= not evaluable
[58] - 0000=no participants analyzed. -9999/9999= not evaluable
[59] - 0000=no participants analyzed. -9999/9999= not evaluable
[60] - 0000=no participants analyzed. -9999/9999= not evaluable

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to approximately 30 months

Adverse event reporting additional description

All-Cause Mortality table includes all allocated participants. Serious and Non-serious adverse events (AEs) tables include all allocated participants who received at least 1 dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d

Reporting group description

Reporting group title

Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d

Reporting group description

Reporting group title

Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PMF: Bomedemstat 0.5 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PMF: Bomedemstat 0.6 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d

Reporting group description

Reporting group title

Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d

Reporting group description

Serious adverse events	Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d	Ph 2b PMF: Bomedemstat 0.5 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PMF: Bomedemstat 0.6 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 9 (44.44%)	2 / 3 (66.67%)	5 / 6 (83.33%)	4 / 8 (50.00%)	4 / 5 (80.00%)	12 / 23 (52.17%)	7 / 11 (63.64%)	3 / 10 (30.00%)	3 / 12 (25.00%)
number of deaths (all causes)	0	0	0	1	1	1	0	0	0
number of deaths resulting from adverse events	0	0	0	1	1	1	0	0	0
General disorders and administration site conditions
Oedema peripheral
subjects affected / exposed	2 / 9 (22.22%)	0 / 3 (0.00%)	1 / 6 (16.67%)	4 / 8 (50.00%)	2 / 5 (40.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	1 / 10 (10.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 1	0 / 10	0 / 2	0 / 1	0 / 1	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 8 (25.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	3 / 11 (27.27%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 6	0 / 6	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	2 / 6 (33.33%)	1 / 8 (12.50%)	1 / 5 (20.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 3	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Hip fracture
subjects affected / exposed	0 / 9 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural complication
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post-traumatic pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac failure congestive
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	2 / 5 (40.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 1	1 / 2	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Toxic encephalopathy
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	2 / 9 (22.22%)	1 / 3 (33.33%)	3 / 6 (50.00%)	4 / 8 (50.00%)	2 / 5 (40.00%)	1 / 23 (4.35%)	7 / 11 (63.64%)	3 / 10 (30.00%)	3 / 12 (25.00%)
occurrences causally related to treatment / all	0 / 6	0 / 2	0 / 17	0 / 26	0 / 5	0 / 2	0 / 25	0 / 13	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Splenomegaly
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	2 / 9 (22.22%)	0 / 3 (0.00%)	3 / 6 (50.00%)	2 / 8 (25.00%)	2 / 5 (40.00%)	2 / 23 (8.70%)	5 / 11 (45.45%)	2 / 10 (20.00%)	2 / 12 (16.67%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 8	0 / 20	0 / 2	0 / 2	0 / 26	0 / 3	1 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 9 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	2 / 23 (8.70%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	1 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal wall haematoma
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 9 (0.00%)	2 / 3 (66.67%)	2 / 6 (33.33%)	0 / 8 (0.00%)	1 / 5 (20.00%)	1 / 23 (4.35%)	2 / 11 (18.18%)	1 / 10 (10.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 0	0 / 1	0 / 2	0 / 3	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Faecaloma
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 9 (0.00%)	2 / 3 (66.67%)	3 / 6 (50.00%)	2 / 8 (25.00%)	1 / 5 (20.00%)	4 / 23 (17.39%)	2 / 11 (18.18%)	1 / 10 (10.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 5	0 / 2	0 / 1	2 / 7	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	1 / 5 (20.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retroperitoneal haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Pyoderma gangrenosum
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	1 / 5 (20.00%)	1 / 23 (4.35%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 23 (0.00%)	2 / 11 (18.18%)	1 / 10 (10.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 6	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	2 / 9 (22.22%)	1 / 3 (33.33%)	3 / 6 (50.00%)	0 / 8 (0.00%)	2 / 5 (40.00%)	3 / 23 (13.04%)	2 / 11 (18.18%)	1 / 10 (10.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 1	0 / 5	0 / 0	0 / 4	0 / 3	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Clostridium difficile colitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 8 (0.00%)	1 / 5 (20.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 2	0 / 0	0 / 1	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis perforated
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 9 (11.11%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	2 / 9 (22.22%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritonsillar abscess
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 8 (37.50%)	0 / 5 (0.00%)	1 / 23 (4.35%)	2 / 11 (18.18%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4	0 / 0	0 / 1	0 / 5	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural cellulitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal abscess
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	1 / 5 (20.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spontaneous bacterial peritonitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 12 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Gout
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	3 / 6 (50.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 6	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypervolaemia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 12 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Ph 1/2a PMF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PPV-MF: Bomedemstat 0.25 mg/kg/d	Ph 1/2a PET-MF: Bomedemstat 0.25 mg/kg/d	Ph 2b PMF: Bomedemstat 0.5 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PMF: Bomedemstat 0.6 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.5 mg/kg/d	Ph 2b PPV-MF: Bomedemstat 0.6 mg/kg/d	Ph 2b PET-MF: Bomedemstat 0.6 mg/kg/d
Total subjects affected by non serious adverse events
subjects affected / exposed	9 / 9 (100.00%)	0 / 3 (0.00%)	6 / 6 (100.00%)	8 / 8 (100.00%)	0 / 5 (0.00%)	23 / 23 (100.00%)	11 / 11 (100.00%)	0 / 10 (0.00%)	12 / 12 (100.00%)
Vascular disorders
Hypertension
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0
Hot flush
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0
Haematoma
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	3 / 11 (27.27%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	0	0	5	0	0
Orthostatic hypotension
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0
Hypotension
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	2	0	0	2	0	0
Pallor
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	1	0	0	1
Generalised oedema
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	0	0	0	0	0	1
Chills
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Early satiety
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Fatigue
subjects affected / exposed	5 / 9 (55.56%)	0 / 3 (0.00%)	3 / 6 (50.00%)	2 / 8 (25.00%)	0 / 5 (0.00%)	2 / 23 (8.70%)	3 / 11 (27.27%)	0 / 10 (0.00%)	3 / 12 (25.00%)
occurrences all number	6	0	4	4	0	2	3	0	3
Chest discomfort
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	1	1	0	1
Hypothermia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Influenza like illness
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	2	0	0	0	0	0	1
Non-cardiac chest pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Temperature intolerance
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Pain
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	1	0	0	0	2	0	1
Peripheral swelling
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	0	0	0	1	0	1
Pyrexia
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	2 / 6 (33.33%)	2 / 8 (25.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	4 / 11 (36.36%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	2	2	0	6	7	0	2
Oedema peripheral
subjects affected / exposed	2 / 9 (22.22%)	0 / 3 (0.00%)	1 / 6 (16.67%)	4 / 8 (50.00%)	0 / 5 (0.00%)	4 / 23 (17.39%)	1 / 11 (9.09%)	0 / 10 (0.00%)	3 / 12 (25.00%)
occurrences all number	4	0	1	10	0	6	1	0	5
Thirst
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0
Reproductive system and breast disorders
Genital rash
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Vaginal haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Diaphragmalgia
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Cough
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	1	2	0	0	2	0	0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	2	0	1	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
Nasal congestion
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Hypoxia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Haemoptysis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0
Pleural effusion
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Dyspnoea exertional
subjects affected / exposed	2 / 9 (22.22%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0
Dyspnoea
subjects affected / exposed	2 / 9 (22.22%)	0 / 3 (0.00%)	3 / 6 (50.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	2	0	3	3	0	1	2	0	2
Dysphonia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Epistaxis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	2 / 8 (25.00%)	0 / 5 (0.00%)	2 / 23 (8.70%)	1 / 11 (9.09%)	0 / 10 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	4	3	0	2	1	0	2
Sleep apnoea syndrome
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Rhinorrhoea
subjects affected / exposed	2 / 9 (22.22%)	0 / 3 (0.00%)	2 / 6 (33.33%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	2	1	0	0	0	0	0
Respiratory failure
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Rales
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Pulmonary oedema
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Productive cough
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0
Sneezing
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Confusional state
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Dysphoria
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Delirium
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Flat affect
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Insomnia
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	0	0	1	1	0	1
Phonophobia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Sleep disorder
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Sleep terror
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Suicidal ideation
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	1	1	0	0
Alanine aminotransferase increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	2	0	1
Aspartate aminotransferase increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	2	0	0
Blast cell count increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	3 / 11 (27.27%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	3	0	0	5	0	0
Blood calcium decreased
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0
Blood creatinine increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	4	0	0	0
Blood glucose increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Blood phosphorus decreased
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Blood potassium decreased
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0
Blood sodium decreased
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Prothrombin time prolonged
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Body temperature increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Cardiac murmur
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0	0
Blood uric acid increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Weight decreased
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 8 (25.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	2 / 11 (18.18%)	0 / 10 (0.00%)	2 / 12 (16.67%)
occurrences all number	1	0	1	2	0	2	2	0	2
Troponin T increased
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 5 (0.00%)	3 / 23 (13.04%)	2 / 11 (18.18%)	0 / 10 (0.00%)	3 / 12 (25.00%)
occurrences all number	2	0	2	1	0	4	7	0	6
Cataract operation complication
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Eye contusion
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Fall
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 5 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	1	0	1	1	0	0
Humerus fracture
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Ligament sprain
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Post procedural swelling
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Periorbital haemorrhage
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Post procedural complication
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Post procedural haemorrhage
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Muscle strain
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Skin abrasion
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Soft tissue injury
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Cardiac disorders
Aortic valve incompetence
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Atrial fibrillation
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	3	0	0	0	0	0	1	0	0
Cardiomegaly
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Cardiac failure
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Cardiac failure congestive
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0
Cardiac valve disease
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Bradycardia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Cardiopulmonary failure
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Palpitations
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0
Ventricular extrasystoles
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Tachycardia
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	3	0	1	0	0	0
Pericardial effusion
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Nervous system disorders
Hypersomnia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Headache
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 12 (16.67%)
occurrences all number	1	0	2	1	0	1	0	0	3
Dysgeusia
subjects affected / exposed	6 / 9 (66.67%)	0 / 3 (0.00%)	3 / 6 (50.00%)	3 / 8 (37.50%)	0 / 5 (0.00%)	6 / 23 (26.09%)	4 / 11 (36.36%)	0 / 10 (0.00%)	5 / 12 (41.67%)
occurrences all number	7	0	6	3	0	8	5	0	6
Dizziness
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	1	0	0	1	1	0	0
Amnesia
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Peroneal nerve palsy
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Parosmia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Parkinson's disease
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Paraesthesia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1	0	0	0	0	1
Lethargy
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Neuralgia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Nerve compression
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Migraine
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Neuropathy peripheral
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0
Presyncope
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Restless legs syndrome
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	2	0	0	0	0	0	1
Sciatica
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Sinus headache
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Syncope
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Toxic encephalopathy
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	5 / 9 (55.56%)	0 / 3 (0.00%)	4 / 6 (66.67%)	2 / 8 (25.00%)	0 / 5 (0.00%)	5 / 23 (21.74%)	5 / 11 (45.45%)	0 / 10 (0.00%)	3 / 12 (25.00%)
occurrences all number	7	0	10	20	0	5	26	0	8
Leukocytosis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	1	0	0	1
Leukopenia
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	3	0	0	1	0	0	0
Splenomegaly
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0
Lymphopenia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	2	0	0	5	0	0
Neutropenia
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	2 / 6 (33.33%)	1 / 8 (12.50%)	0 / 5 (0.00%)	3 / 23 (13.04%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	4	0	2	1	0	3	0	0	0
Lymphadenopathy
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	0	0	0	1	0	1
Thrombocytopenia
subjects affected / exposed	5 / 9 (55.56%)	0 / 3 (0.00%)	4 / 6 (66.67%)	7 / 8 (87.50%)	0 / 5 (0.00%)	4 / 23 (17.39%)	8 / 11 (72.73%)	0 / 10 (0.00%)	4 / 12 (33.33%)
occurrences all number	9	0	19	29	0	11	29	0	8
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Tinnitus
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	1	0	0	0	0	0	1
Vertigo
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Eye disorders
Photophobia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Conjunctival haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0
Eye oedema
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Ocular hyperaemia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	1	0	0	0	0	1
Blepharitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0
Photopsia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Vision blurred
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	3 / 23 (13.04%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	3	1	0	0
Abdominal distension
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	3 / 6 (50.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	4	1	0	0	0	0	1
Diarrhoea
subjects affected / exposed	4 / 9 (44.44%)	0 / 3 (0.00%)	5 / 6 (83.33%)	3 / 8 (37.50%)	0 / 5 (0.00%)	9 / 23 (39.13%)	4 / 11 (36.36%)	0 / 10 (0.00%)	2 / 12 (16.67%)
occurrences all number	5	0	6	3	0	12	6	0	2
Abdominal pain
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	2 / 6 (33.33%)	1 / 8 (12.50%)	0 / 5 (0.00%)	3 / 23 (13.04%)	2 / 11 (18.18%)	0 / 10 (0.00%)	2 / 12 (16.67%)
occurrences all number	1	0	2	1	0	4	3	0	2
Abdominal pain lower
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	1	0	0	0	0	0	0
Constipation
subjects affected / exposed	3 / 9 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)	0 / 5 (0.00%)	4 / 23 (17.39%)	6 / 11 (54.55%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	4	0	0	3	0	5	8	0	1
Abdominal mass
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Dry mouth
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Dyspepsia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	1	0	0	0	0	0	1
Dysphagia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	1	0	1
Haematochezia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Flatulence
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	1	0	0	0	0	0	1
Gingival bleeding
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0
Eructation
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0
Hiatus hernia
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Inguinal hernia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Lip haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0
Oral mucosal blistering
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Mouth ulceration
subjects affected / exposed	2 / 9 (22.22%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	0	0	1	0	0	0
Nausea
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	3 / 6 (50.00%)	5 / 8 (62.50%)	0 / 5 (0.00%)	7 / 23 (30.43%)	3 / 11 (27.27%)	0 / 10 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	5	5	0	11	3	0	2
Odynophagia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Lip ulceration
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Oral pain
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Rectal haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Retroperitoneal haematoma
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Tongue discolouration
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Small intestinal haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Stomatitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Retroperitoneal haemorrhage
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Toothache
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Vomiting
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 8 (25.00%)	0 / 5 (0.00%)	2 / 23 (8.70%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	1	4	0	2	3	0	1
Hepatobiliary disorders
Biliary colic
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	2 / 9 (22.22%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	1	0	0	1	1	0	0
Decubitus ulcer
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Alopecia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	2 / 23 (8.70%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	2	2	0	0
Ecchymosis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Granulomatous dermatitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Hyperkeratosis
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Koilonychia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0
Pyoderma gangrenosum
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Night sweats
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	2 / 23 (8.70%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	2	0	0	0	0	2	1	0	1
Onychalgia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Petechiae
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	1	0	0	0	1	0	1
Pruritus
subjects affected / exposed	2 / 9 (22.22%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 5 (0.00%)	2 / 23 (8.70%)	2 / 11 (18.18%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	4	0	1	1	0	3	3	0	2
Nail dystrophy
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Rash
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	1	2	0	0	2	0	1
Rash erythematous
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Rash macular
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Rash maculo-papular
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	2	1	0	0	3	0	0
Rash pruritic
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	0	0	0	0	0
Skin mass
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Renal and urinary disorders
Chronic kidney disease
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Haematuria
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Acute kidney injury
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	1	0	1
Renal failure
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Nephrolithiasis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Nocturia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Pollakiuria
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0
Proteinuria
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Musculoskeletal and connective tissue disorders
Bone pain
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	2 / 23 (8.70%)	2 / 11 (18.18%)	0 / 10 (0.00%)	2 / 12 (16.67%)
occurrences all number	1	0	1	0	0	2	2	0	2
Back pain
subjects affected / exposed	2 / 9 (22.22%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	4 / 11 (36.36%)	0 / 10 (0.00%)	2 / 12 (16.67%)
occurrences all number	2	0	0	0	0	0	8	0	3
Arthralgia
subjects affected / exposed	4 / 9 (44.44%)	0 / 3 (0.00%)	3 / 6 (50.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	5 / 23 (21.74%)	2 / 11 (18.18%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	9	0	5	0	0	5	2	0	1
Bursitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Intervertebral disc protrusion
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Joint swelling
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	2	0	0	1	2	0	0
Myalgia
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 8 (25.00%)	0 / 5 (0.00%)	2 / 23 (8.70%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	1	2	0	2	4	0	0
Neck pain
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	3 / 23 (13.04%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	0	0	3	0	0	1
Musculoskeletal chest pain
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	0	0	1	0	0	1
Muscular weakness
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	2	0	0	1	0	0
Muscle spasms
subjects affected / exposed	2 / 9 (22.22%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	1 / 23 (4.35%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	1	0	1	0	0	0
Musculoskeletal pain
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	1	0	0	0	0	1
Osteitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Vertebral osteophyte
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Spinal stenosis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Spinal osteoarthritis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Pain in extremity
subjects affected / exposed	2 / 9 (22.22%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 8 (25.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	2 / 11 (18.18%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	5	0	2	2	0	1	5	0	1
Infections and infestations
Appendicitis perforated
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Conjunctivitis
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	0	1	0	0	0	0	1
COVID-19
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	2	0	1	1	0	0
Cellulitis
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 8 (0.00%)	0 / 5 (0.00%)	3 / 23 (13.04%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	4	0	2	0	0	3	0	0	0
Clostridium difficile colitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	1	2	0	0
Atypical pneumonia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Cystitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Diverticulitis
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	1	0	0	0	1	0	0
Erysipelas
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	4	0	0
Furuncle
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Influenza
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0
Gastroenteritis viral
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Gingivitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Herpes zoster
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	1	0	1	0	0	0	0	0	1
Gastroenteritis
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Lower respiratory tract infection
subjects affected / exposed	2 / 9 (22.22%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0
Nasal herpes
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Onychomycosis
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Sepsis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Pneumonia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 8 (37.50%)	0 / 5 (0.00%)	1 / 23 (4.35%)	2 / 11 (18.18%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	4	0	1	5	0	1
Rash pustular
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	3	0	0
Respiratory tract infection
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Oral herpes
subjects affected / exposed	2 / 9 (22.22%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0
Septic shock
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Skin infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	1 / 23 (4.35%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	2	1	0	0
Spontaneous bacterial peritonitis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	0	0	0	0	0	1
Subcutaneous abscess
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	2 / 23 (8.70%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 12 (16.67%)
occurrences all number	0	0	0	0	0	3	0	0	3
Viral pericarditis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	2	1	0	0	0	0	0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Decreased appetite
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	2 / 6 (33.33%)	2 / 8 (25.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	4 / 11 (36.36%)	0 / 10 (0.00%)	2 / 12 (16.67%)
occurrences all number	3	0	2	2	0	0	5	0	4
Hypernatraemia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Hyperglycaemia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0
Hyperkalaemia
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	2	0	0	0	1	0	0
Hypermagnesaemia
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0
Gout
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	3 / 6 (50.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	2 / 23 (8.70%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	2	0	6	0	0	3	1	0	0
Hyponatraemia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Hypokalaemia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 8 (25.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 12 (8.33%)
occurrences all number	0	0	0	2	0	0	0	0	4
Hyperuricaemia
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 8 (12.50%)	0 / 5 (0.00%)	3 / 23 (13.04%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	3	1	0	3	1	0	0
Hypophosphataemia
subjects affected / exposed	1 / 9 (11.11%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	1	0	0	2	0	0	0	0	0
Lactic acidosis
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 8 (0.00%)	0 / 5 (0.00%)	0 / 23 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0
Increased appetite
subjects affected / exposed	0 / 9 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 8 (12.50%)	0 / 5 (0.00%)	0 / 23 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 12 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

06 Feb 2017

Major changes of Amendment (AM) 1 include editorial revisions and corrections to the Ph1/2a Initial Treatment Period transfusion language, restructuring/renumbering of the protocol document, and corrections to the Schedule of Assessments. These changes were instituted before the first participant was enrolled.

13 Sep 2017

Major changes of AM 2 include the reclassification of the “Reduction in spleen volume” from a secondary objective/endpoint to a primary objective/endpoint, as well as revisions to the eligibility criteria and revision of the DLT period to 7 days.

13 Sep 2017

Major changes of AM 3 include inclusion of a definition for clinical benefit and modifications to the titration and re-challenge rules.

21 May 2019

Major changes of AM 4 included the expansion of the study from a Phase 1/2a study to a Phase 2b study with addition of approximately 35 more participants, modification of the starting dose to 0.5 mg/kg/day, extension of the treatment period from 85 to 169 days with removal of the washout period, removal of pharmacokinetic and dose concentration sample collection requirements, and revision of some eligibility criteria.

22 Jan 2020

Major changes of AM 5 included modifications to the up-titration frequency, starting at ITP Day 14, addition of a Baseline run-in collection of Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score 24-HOUR recall, and addition of approximately 25 more participants.

15 Dec 2020

Major changes of AM 6 included modification of starting dose to 0.6 mg/kg/day, modification of some eligibility criteria, and prolongation of the time of first up-titration from ITP Day 14 to ITP Day 28.

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 Multi-Center, Open Label Study to Assess the Safety, Steady-State Pharmacokinetics and Pharmacodynamics of IMG-7289 in Patients With Myelofibrosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants with Dose Limiting Toxicities (DLTs)

Primary: Number of Participants with Dose Limiting Toxicities (DLTs)

Primary: Number of Participants with Serious Adverse Events

Primary: Number of Participants with Serious Adverse Events

Primary: Number of Participants with Adverse Events

Primary: Number of Participants with Adverse Events

Primary: Number of Participants that Discontinued Study Treatment Due To AEs

Primary: Number of Participants that Discontinued Study Treatment Due To AEs

Primary: Phase 1/2a Portion: Observed Maximum Concentration (Cmax) of Bomedemstat

Primary: Phase 1/2a Portion: Observed Maximum Concentration (Cmax) of Bomedemstat

Primary: Phase 1/2a Portion: Time to Maximum Concentration (Tmax) of Bomedemstat

Primary: Phase 1/2a Portion: Time to Maximum Concentration (Tmax) of Bomedemstat

Primary: Phase 1/2a Portion: Area Under the Concentration-time Curve of Bomedemstat from Time 0 to 24 hours post-dose (AUC0-24)

Primary: Phase 1/2a Portion: Area Under the Concentration-time Curve of Bomedemstat from Time 0 to 24 hours post-dose (AUC0-24)

Primary: Phase 1/2a Portion: Apparent total clearance (CL/F) of Bomedemstat after oral administration

Primary: Phase 1/2a Portion: Apparent total clearance (CL/F) of Bomedemstat after oral administration

Primary: Percent Change from Baseline in Spleen Volume

Primary: Percent Change from Baseline in Spleen Volume

Primary: Percent Change from Baseline in Spleen Size

Primary: Percent Change from Baseline in Spleen Size

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: A Multi-Center, Open Label Study to Assess the Safety, Steady-State Pharmacokinetics and Pharmacodynamics of IMG-7289 in Patients With Myelofibrosis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants with Dose Limiting Toxicities (DLTs)

Primary: Number of Participants with Dose Limiting Toxicities (DLTs)

Primary: Number of Participants with Serious Adverse Events

Primary: Number of Participants with Serious Adverse Events

Primary: Number of Participants with Adverse Events

Primary: Number of Participants with Adverse Events

Primary: Number of Participants that Discontinued Study Treatment Due To AEs

Primary: Number of Participants that Discontinued Study Treatment Due To AEs

Primary: Phase 1/2a Portion: Observed Maximum Concentration (Cmax) of Bomedemstat

Primary: Phase 1/2a Portion: Observed Maximum Concentration (Cmax) of Bomedemstat

Primary: Phase 1/2a Portion: Time to Maximum Concentration (Tmax) of Bomedemstat

Primary: Phase 1/2a Portion: Time to Maximum Concentration (Tmax) of Bomedemstat

Primary: Phase 1/2a Portion: Area Under the Concentration-time Curve of Bomedemstat from Time 0 to 24 hours post-dose (AUC0-24)

Primary: Phase 1/2a Portion: Area Under the Concentration-time Curve of Bomedemstat from Time 0 to 24 hours post-dose (AUC0-24)

Primary: Phase 1/2a Portion: Apparent total clearance (CL/F) of Bomedemstat after oral administration

Primary: Phase 1/2a Portion: Apparent total clearance (CL/F) of Bomedemstat after oral administration

Primary: Percent Change from Baseline in Spleen Volume

Primary: Percent Change from Baseline in Spleen Volume

Primary: Percent Change from Baseline in Spleen Size

Primary: Percent Change from Baseline in Spleen Size

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Multi-Center, Open Label Study to Assess the Safety, Steady-State Pharmacokinetics and Pharmacodynamics of IMG-7289 in Patients With Myelofibrosis