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Clinical Trial Results:
Prospective, randomised, controlled, double-blind, multi-centre, multinational study on the safety and efficacy of 6% Hydroxyethyl starch (HES) solution versus an electrolyte solution in patients undergoing elective abdominal surgery (PHOENICS)

Summary
EudraCT number	2016-002162-30
Trial protocol	BE CZ NL ES FR AT HR RO
Global end of trial date	06 Jul 2022

Results information
Results version number	v1(current)
This version publication date	04 Aug 2023
First version publication date	04 Aug 2023
Other versions

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

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Trial information

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Sponsor protocol code

HC-G-H-1504

ISRCTN number

US NCT number

NCT03278548

WHO universal trial number (UTN)

Other trial identifiers

Fresenius Kabi ID: VOLU-024-CP4

Sponsor organisation name

Fresenius Kabi Deutschland GmbH

Sponsor organisation address

Else-Kröner-Str. 1, Bad Homburg, Germany, 61352

Public contact

Medical Scientific Affairs Pharma and Nutrition, Fresenius Kabi Deutschland GmbH, Trial-Disclosure@Fresenius-Kabi.com

Scientific contact

Medical Scientific Affairs Pharma and Nutrition, Fresenius Kabi Deutschland GmbH, Trial-Disclosure@Fresenius-Kabi.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

16 Feb 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

06 Jul 2022

Was the trial ended prematurely?

Main objective of the trial

Primary objective was to investigate non-inferiority regarding the safety of a 6% HES solution for infusion (Volulyte 6%) compared to an electrolyte solution for infusion (Ionolyte) in patients with acute blood loss undergoing elective abdominal surgery

Protection of trial subjects

Subject protection was ensured by medical and ethical standards in accordance with Declaration of Helsinki, Good Clinical Practice and applicable national and local laws and regulation. The signed informed consent was obtained prior to inclusion in the study. The patients were informed in writing about their right to withdraw from the study at any time. Furthermore, a data safety monitoring board was established to protect the patients participating in the study

Background therapy

Evidence for comparator

Actual start date of recruitment

25 Sep 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

1 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 133

Country: Number of subjects enrolled

Poland: 83

Country: Number of subjects enrolled

Romania: 24

Country: Number of subjects enrolled

Spain: 896

Country: Number of subjects enrolled

Croatia: 17

Country: Number of subjects enrolled

Austria: 4

Country: Number of subjects enrolled

Belgium: 144

Country: Number of subjects enrolled

Czechia: 235

Country: Number of subjects enrolled

France: 320

Country: Number of subjects enrolled

Germany: 490

Worldwide total number of subjects

2346

EEA total number of subjects

2346

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)

1056

From 65 to 84 years

1279

85 years and over

Subject disposition

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Recruitment details

Screening details

Potential candidates for study participation were considered for the screening period. Before enrolling into screening informed consent had to be provided in writing. A patient was randomized only after eligibility was proven by checking the inclusion and exclusion criteria

Period 1 title

Overall trial without 1 year follow-up (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst

Are arms mutually exclusive

Yes

Volulyte

Arm description

Started = Number of patients randomised for this arm

Arm type

Experimental

Investigational medicinal product name

Volulyte 6% solution for infusion

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Dosing was individualised to the patient’s volume needs and guided by a volume algorithm based on either mean arterial pressure or other haemodynamic parameters. The daily dose of 30 ml/kg should not have been exceeded. If patients were still hypotensive during administration of the investigational test product, they could also receive vasoactive/inotropic drugs, if regarded necessary due to the patient’s clinical condition. Since HES preparations may rarely cause allergic reactions, the first 10-20 ml of the solution should have been infused slowly. In case of an allergic reaction, the infusion had to be stopped immediately, and appropriate treatment given.

Ionolyte

Arm description

Started = Number of patients randomised for this arm

Arm type

Active comparator

Investigational medicinal product name

Ionolyte solution for infusion

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Number of subjects in period 1 ^[1]	Volulyte	Ionolyte
Started	1147	1142
Completed	852	861
Not completed	295	281
Adverse event, serious fatal	32	31
Consent withdrawn by subject	57	42
Adverse event, non-fatal	2	-
Other	187	189
Lost to follow-up	15	18
Protocol deviation	2	1

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: In ‘period 1’ only the eligible and randomized subjects are mentioned whereas under ‘population of trial subjects’ and ‘subjects enrolled per age group’ all patients enrolled (including screen failures) are mentioned.

Baseline characteristics

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Reporting group title

Volulyte

Reporting group description

Started = Number of patients randomised for this arm

Reporting group title

Ionolyte

Reporting group description

Started = Number of patients randomised for this arm

Reporting group values	Volulyte	Ionolyte	Total
Number of subjects	1147	1142	2289
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
arithmetic mean (standard deviation)	64.9 ( 9.51 )	64.9 ( 9.92 )	-
Gender categorical
Units: Subjects
Female	414	446	860
Male	733	696	1429

Subject analysis set title

Safety analysis set (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

All patients with at least one administration of study medication were included in the SAF.

Subject analysis set title

Full analysis set for the primary endpoint (FAS‑pEP)

Subject analysis set type

Full analysis

Subject analysis set description

The FAS‑pEP comprised all patients from the SAF reaching the post-operative period and being monitored at least once with respect to the changes in cystatin C-based eGFR at POD1, POD2 or POD3.

Subject analysis set title

Full analysis set for efficacy analyses (FAS‑Eff)

Subject analysis set type

Full analysis

Subject analysis set description

The FAS‑Eff comprised all patients from the SAF providing any efficacy data after IP start.

Subject analysis set title

Per-protocol set for the primary endpoint (PPS‑pEP)

Subject analysis set type

Per protocol

Subject analysis set description

The PPS‑pEP comprised all subjects from the FAS‑pEP who did not have any major protocol deviations with regard to the primary endpoint.

Subject analysis set title

Per-protocol set for the key secondary endpoint (PPS‑KScEP)

Subject analysis set type

Per protocol

Subject analysis set description

The PPS‑KScEP comprised all subjects from the SAF who did not have any major protocol deviations with regard to the key secondary endpoint.

Subject analysis sets values	Safety analysis set (SAF)	Full analysis set for the primary endpoint (FAS‑pEP)	Full analysis set for efficacy analyses (FAS‑Eff)	Per-protocol set for the primary endpoint (PPS‑pEP)	Per-protocol set for the key secondary endpoint (PPS‑KScEP)
Number of subjects	1958	1946	1958	1857	1868
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Units: years
arithmetic mean (standard deviation)	64.9 ( 9.68 )	64.9 ( 9.67 )	64.9 ( 9.68 )	64.9 ( 9.59 )	64.9 ( 9.60 )
Gender categorical
Units: Subjects
Female	724	721	724	682	685
Male	1234	1225	1234	1175	1183

End points

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Reporting group title

Volulyte

Reporting group description

Started = Number of patients randomised for this arm

Reporting group title

Ionolyte

Reporting group description

Started = Number of patients randomised for this arm

Subject analysis set title

Safety analysis set (SAF)

Subject analysis set type

Safety analysis

Subject analysis set description

All patients with at least one administration of study medication were included in the SAF.

Subject analysis set title

Full analysis set for the primary endpoint (FAS‑pEP)

Subject analysis set type

Full analysis

Subject analysis set description

The FAS‑pEP comprised all patients from the SAF reaching the post-operative period and being monitored at least once with respect to the changes in cystatin C-based eGFR at POD1, POD2 or POD3.

Subject analysis set title

Full analysis set for efficacy analyses (FAS‑Eff)

Subject analysis set type

Full analysis

Subject analysis set description

The FAS‑Eff comprised all patients from the SAF providing any efficacy data after IP start.

Subject analysis set title

Per-protocol set for the primary endpoint (PPS‑pEP)

Subject analysis set type

Per protocol

Subject analysis set description

The PPS‑pEP comprised all subjects from the FAS‑pEP who did not have any major protocol deviations with regard to the primary endpoint.

Subject analysis set title

Per-protocol set for the key secondary endpoint (PPS‑KScEP)

Subject analysis set type

Per protocol

Subject analysis set description

The PPS‑KScEP comprised all subjects from the SAF who did not have any major protocol deviations with regard to the key secondary endpoint.

Primary: Change in cystatin C-based estimated glomerular filtration rate (eGFR) from pre-operative baseline to eGFR value calculated from the highest cystatin C level measured during post-operative days 1–3 (POD1–3) (i.e., minimal eGFR during POD1–3)

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End point title

Change in cystatin C-based estimated glomerular filtration rate (eGFR) from pre-operative baseline to eGFR value calculated from the highest cystatin C level measured during post-operative days 1–3 (POD1–3) (i.e., minimal eGFR during POD1–3)

End point description

The primary endpoint of this study was the change in cystatin C-based eGFR from pre-operative baseline to eGFR value calculated from the highest cystatin C level measured during post-operative days 1–3 (i.e., minimal eGFR during post-operative days 1–3). To calculate cystatin C-based eGFR the Chronic Kidney Disease Epidemiology Collaboration equation developed by Inker et al., 2012 was used.

End point type

Primary

End point timeframe

From pre-operative baseline to post-operative days 1-3

End point values	Volulyte	Ionolyte	Per-protocol set for the primary endpoint (PPS‑pEP)
Number of subjects analysed	922 ^[1]	935 ^[2]	1857 ^[3]
Units: ml/min/1.73m²
least squares mean (confidence interval 95%)	-1.713 (-3.274 to -0.153)	0.667 (-0.906 to 2.241)	-2.381 (-3.899 to -0.862)

Notes
[1] - PPS-pEP
[2] - PPS-pEP
[3] - 922 (Volulyte) + 935 (Ionolyte) LS mean value below is the difference in LS means between groups

Analysis of Primary Endpoint

Statistical analysis description

This study was intended to test confirmatively the primary hypothesis that treatment with Volulyte is non-inferior to treatment with Ionolyte regarding the primary endpoint change in cystatin C-based eGFR from pre-operative baseline to eGFR value calculated from the highest cystatin C level measured during POD 1–3 (i.e., minimal eGFR during POD1–3) considering a non-inferiority margin of Δ = 8.1 ml/min/1.73 m² and a type I error rate of α = 2.5% one-sided

Comparison groups

Volulyte v Ionolyte

Number of subjects included in analysis

1857

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

< 0.0001 ^[4]

Method

ANCOVA

Confidence interval

Notes
[4] - The treatment group difference was -2.381 ml/min/1.73m² (95% CI: -3.899 to -0.862 ml/min/1.73 m²). Since the lower limit of the 95% CI was greater than -Δ (i.e.,-8.1ml/min/1.73m²), non-inferiority to Ionolyte was demonstrated (p<0.0001)

Secondary: Key secondary endpoint: Mortality and major post-operative complications (including renal) until day 90

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End point title

Key secondary endpoint: Mortality and major post-operative complications (including renal) until day 90

End point description

This composite endpoint summarises the occurrence of death and major post-operative complications according to predefined criteria for the assessment of complications during the first 90 post-operative days.

End point type

Secondary

End point timeframe

End of surgery - 90 post-operative days

End point values	Volulyte	Ionolyte
Number of subjects analysed	887 ^[5]	907 ^[6]
Units: cases	324	322

Notes
[5] - SAF, N missing = 90
[6] - SAF, N missing = 74

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

The reporting period for adverse events (AEs) started at T0 i.e. baseline (after randomization and prior induction of anaesthesia) and ended after T8 (90 days after surgery)

Adverse event reporting additional description

Only treatment-emergent adverse events included

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Volulyte

Reporting group description

Reporting group title

Ionolyte

Reporting group description

Serious adverse events	Volulyte	Ionolyte
Total subjects affected by serious adverse events
subjects affected / exposed	296 / 977 (30.30%)	291 / 981 (29.66%)
number of deaths (all causes)	32	31
number of deaths resulting from adverse events	0	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon neoplasm
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to peritoneum
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Neoplasm progression
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Ovarian neoplasm
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder cancer
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangiocarcinoma
Additional description: Cholangiocarcinoma
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Malignant neoplasm progression
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	3 / 981 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 2
Oesophageal carcinoma
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Ureteral neoplasm
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Arterial haemorrhage
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemodynamic instability
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage
Additional description: Treatment-emergent
subjects affected / exposed	4 / 977 (0.41%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Hypotension
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemic shock
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Lymphocele
Additional description: Treatment-emergent
subjects affected / exposed	7 / 977 (0.72%)	9 / 981 (0.92%)
occurrences causally related to treatment / all	0 / 7	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphorrhoea
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral ischaemia
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Shock haemorrhagic
Additional description: Treatment-emergent
subjects affected / exposed	9 / 977 (0.92%)	5 / 981 (0.51%)
occurrences causally related to treatment / all	0 / 9	0 / 5
deaths causally related to treatment / all	0 / 1	0 / 2
Peripheral arterial occlusive disease
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral artery occlusion
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Venous thrombosis limb
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Surgical and medical procedures
Therapy cessation
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Thyroid operation
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Death
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
General physical health deterioration
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Multiple organ dysfunction syndrome
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	5 / 981 (0.51%)
occurrences causally related to treatment / all	0 / 2	1 / 5
deaths causally related to treatment / all	0 / 2	1 / 5
Pyrexia
Additional description: Treatment-emergent
subjects affected / exposed	4 / 977 (0.41%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic inflammatory response syndrome
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Impaired healing
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	3 / 981 (0.31%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Inflammation
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Localised oedema
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Immune system disorders
Contrast media allergy
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Vaginal fistula
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic haematoma
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory distress syndrome
Additional description: Treatment-emergent
subjects affected / exposed	6 / 977 (0.61%)	3 / 981 (0.31%)
occurrences causally related to treatment / all	0 / 7	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0
Acute respiratory failure
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
Chronic obstructive pulmonary disease
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chylothorax
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemothorax
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung disorder
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
Additional description: Treatment-emergent
subjects affected / exposed	8 / 977 (0.82%)	9 / 981 (0.92%)
occurrences causally related to treatment / all	1 / 9	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
Additional description: Treatment-emergent
subjects affected / exposed	9 / 977 (0.92%)	7 / 981 (0.71%)
occurrences causally related to treatment / all	0 / 9	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 2
Pulmonary oedema
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
Additional description: Treatment-emergent
subjects affected / exposed	7 / 977 (0.72%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 8	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atelectasis
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleurisy
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Delirium
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Device dislocation
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device occlusion
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Blood creatine increased
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
International normalised ratio increased
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oxygen saturation decreased
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SARS-CoV-2 test positive
Additional description: Treatment-emergent
subjects affected / exposed	3 / 977 (0.31%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0
Transaminases increased
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Anastomotic fistula
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Anastomotic haemorrhage
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anastomotic leak
Additional description: Treatment-emergent
subjects affected / exposed	26 / 977 (2.66%)	15 / 981 (1.53%)
occurrences causally related to treatment / all	1 / 26	0 / 15
deaths causally related to treatment / all	0 / 1	0 / 0
Femoral nerve injury
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Flap necrosis
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	3 / 981 (0.31%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal anastomotic complication
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal anastomotic leak
Additional description: Treatment-emergent
subjects affected / exposed	7 / 977 (0.72%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 8	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal stoma complication
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Incisional hernia
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal anastomosis complication
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic leak
Additional description: Treatment-emergent
subjects affected / exposed	4 / 977 (0.41%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripancreatic fluid collection
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural bile leak
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	4 / 981 (0.41%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural complication
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural fever
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	3 / 981 (0.31%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haemorrhage
Additional description: Treatment-emergent
subjects affected / exposed	9 / 977 (0.92%)	8 / 981 (0.82%)
occurrences causally related to treatment / all	0 / 9	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural pulmonary embolism
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural urine leak
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural haemorrhage
Additional description: Treatment-emergent
subjects affected / exposed	4 / 977 (0.41%)	3 / 981 (0.31%)
occurrences causally related to treatment / all	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural intestinal perforation
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural pain
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural shock
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Stoma complication
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Suture related complication
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ureteric injury
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vaginal cuff dehiscence
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Wound dehiscence
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound evisceration
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	3 / 981 (0.31%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Wound haematoma
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal wound dehiscence
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Craniocerebral injury
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Drain site complication
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural fistula
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural stroke
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative ileus
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative renal failure
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative respiratory failure
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural pneumothorax
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Seroma
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Suture rupture
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Toxicity to various agents
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vena cava injury
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound necrosis
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Arrhythmia
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
Additional description: Treatment-emergent
subjects affected / exposed	7 / 977 (0.72%)	3 / 981 (0.31%)
occurrences causally related to treatment / all	0 / 8	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
Additional description: Treatment-emergent
subjects affected / exposed	3 / 977 (0.31%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Bradyarrhythmia
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac arrest
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardio-respiratory arrest
Additional description: Treatment-emergent
subjects affected / exposed	4 / 977 (0.41%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 4	0 / 0
Cardiovascular disorder
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pericardial effusion
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Supraventricular tachycardia
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Torsade de pointes
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Cardiac failure
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac failure congestive
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial ischaemia
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pulseless electrical activity
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebral infarction
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Embolic stroke
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Hemiparesis
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hemiplegia
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic encephalopathy
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Brain stem syndrome
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Splenic haemorrhage
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal hernia
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anal haemorrhage
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocutaneous fistula
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterovesical fistula
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Functional gastrointestinal disorder
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric perforation
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Gastric ulcer
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
Additional description: Treatment-emergent
subjects affected / exposed	6 / 977 (0.61%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 6	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Haemoperitoneum
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus paralytic
Additional description: Treatment-emergent
subjects affected / exposed	20 / 977 (2.05%)	21 / 981 (2.14%)
occurrences causally related to treatment / all	0 / 21	0 / 21
deaths causally related to treatment / all	0 / 0	0 / 0
Impaired gastric emptying
Additional description: Treatment-emergent
subjects affected / exposed	6 / 977 (0.61%)	5 / 981 (0.51%)
occurrences causally related to treatment / all	0 / 6	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal haemorrhage
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal ischaemia
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	5 / 981 (0.51%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 1	0 / 2
Intestinal obstruction
Additional description: Treatment-emergent
subjects affected / exposed	9 / 977 (0.92%)	3 / 981 (0.31%)
occurrences causally related to treatment / all	0 / 9	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal perforation
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intra-abdominal fluid collection
Additional description: Treatment-emergent
subjects affected / exposed	14 / 977 (1.43%)	15 / 981 (1.53%)
occurrences causally related to treatment / all	0 / 14	0 / 15
deaths causally related to treatment / all	0 / 0	0 / 0
Intra-abdominal haemorrhage
Additional description: Treatment-emergent
subjects affected / exposed	3 / 977 (0.31%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Jejunal perforation
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine perforation
Additional description: Treatment-emergent
subjects affected / exposed	3 / 977 (0.31%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mechanical ileus
Additional description: Treatment-emergent
subjects affected / exposed	3 / 977 (0.31%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Melaena
Additional description: Treatment-emergent
subjects affected / exposed	3 / 977 (0.31%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mesenteric haemorrhage
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagopleural fistula
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic fistula
Additional description: Treatment-emergent
subjects affected / exposed	4 / 977 (0.41%)	5 / 981 (0.51%)
occurrences causally related to treatment / all	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic pseudocyst
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peptic ulcer haemorrhage
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal wall haematoma
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diaphragmatic hernia
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal obstruction
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal perforation
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroduodenal haemorrhage
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal necrosis
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematemesis
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal hernia
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal fistula
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Intra-abdominal haematoma
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic failure
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis necrotising
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumatosis intestinalis
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth disorder
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Retroperitoneal haematoma
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Acute hepatic failure
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2
Cholangitis
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholestasis
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic artery aneurysm
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic function abnormal
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic vascular thrombosis
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Hepatorenal failure
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Ischaemic hepatitis
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Portal vein thrombosis
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemobilia
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hepatic artery occlusion
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic haemorrhage
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Renal and urinary disorders
Acute kidney injury
Additional description: Treatment-emergent
subjects affected / exposed	21 / 977 (2.15%)	38 / 981 (3.87%)
occurrences causally related to treatment / all	1 / 21	1 / 42
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder tamponade
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic kidney disease
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
Additional description: Treatment-emergent
subjects affected / exposed	3 / 977 (0.31%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nephropathy toxic
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Postrenal failure
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prerenal failure
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal impairment
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ureteric perforation
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	3 / 981 (0.31%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract obstruction
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinoma
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder perforation
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hydronephrosis
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urogenital fistula
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Hyperthyroidism
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Compartment syndrome
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
Additional description: Treatment-emergent
subjects affected / exposed	5 / 977 (0.51%)	6 / 981 (0.61%)
occurrences causally related to treatment / all	0 / 6	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal infection
Additional description: Treatment-emergent
subjects affected / exposed	4 / 977 (0.41%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Abdominal sepsis
Additional description: Treatment-emergent
subjects affected / exposed	3 / 977 (0.31%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal wall abscess
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial sepsis
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary sepsis
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Catheter site infection
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholangitis infective
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
Additional description: Treatment-emergent
subjects affected / exposed	3 / 977 (0.31%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Device related sepsis
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Incision site abscess
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
Additional description: Treatment-emergent
subjects affected / exposed	6 / 977 (0.61%)	4 / 981 (0.41%)
occurrences causally related to treatment / all	0 / 6	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral discitis
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver abscess
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nosocomial infection
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Paraspinal abscess
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic abscess
Additional description: Treatment-emergent
subjects affected / exposed	4 / 977 (0.41%)	4 / 981 (0.41%)
occurrences causally related to treatment / all	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic infection
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Perihepatic abscess
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Perineal abscess
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Perinephric abscess
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
Additional description: Treatment-emergent
subjects affected / exposed	7 / 977 (0.72%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 8	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
Additional description: Treatment-emergent
subjects affected / exposed	8 / 977 (0.82%)	9 / 981 (0.92%)
occurrences causally related to treatment / all	0 / 8	0 / 9
deaths causally related to treatment / all	0 / 1	0 / 0
Pneumonia aspiration
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Post procedural infection
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperative abscess
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Postoperativ wound infection
Additional description: Treatment-emergent
subjects affected / exposed	17 / 977 (1.74%)	19 / 981 (1.94%)
occurrences causally related to treatment / all	0 / 17	0 / 19
deaths causally related to treatment / all	0 / 1	0 / 2
Pyelonephritis
Additional description: Treatment-emergent
subjects affected / exposed	4 / 977 (0.41%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis acute
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
Additional description: Treatment-emergent
subjects affected / exposed	8 / 977 (0.82%)	6 / 981 (0.61%)
occurrences causally related to treatment / all	0 / 8	0 / 6
deaths causally related to treatment / all	0 / 2	0 / 0
Septic shock
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	7 / 981 (0.71%)
occurrences causally related to treatment / all	0 / 3	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 1
Skin infection
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subdiaphragmatic abscess
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic candida
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
Additional description: Treatment-emergent
subjects affected / exposed	14 / 977 (1.43%)	11 / 981 (1.12%)
occurrences causally related to treatment / all	0 / 14	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	3 / 981 (0.31%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Anal abscess
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19 pneumonia
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Empyema
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epididymitis
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gallbladder abscess
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Large intestine infection
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatic abscess
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	2 / 981 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Perirectal abscess
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia pseudomonal
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural sepsis
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal bacteraemia
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypokalaemia
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemia
Additional description: Treatment-emergent
subjects affected / exposed	1 / 977 (0.10%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lactic acidosis
Additional description: Treatment-emergent
subjects affected / exposed	2 / 977 (0.20%)	0 / 981 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Dehydration
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fluid retention
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Malnutrition
Additional description: Treatment-emergent
subjects affected / exposed	0 / 977 (0.00%)	1 / 981 (0.10%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Volulyte	Ionolyte
Total subjects affected by non serious adverse events
subjects affected / exposed	617 / 977 (63.15%)	630 / 981 (64.22%)
Injury, poisoning and procedural complications
Procedural pain
Additional description: Treatment-emergent
subjects affected / exposed	76 / 977 (7.78%)	79 / 981 (8.05%)
occurrences all number	78	83
Vascular disorders
Hypotension
Additional description: Treatment-emergent
subjects affected / exposed	46 / 977 (4.71%)	55 / 981 (5.61%)
occurrences all number	46	56
Blood and lymphatic system disorders
Anaemia
Additional description: Treatment-emergent
subjects affected / exposed	138 / 977 (14.12%)	136 / 981 (13.86%)
occurrences all number	178	168
General disorders and administration site conditions
Pain
Additional description: Treatment-emergent
subjects affected / exposed	77 / 977 (7.88%)	73 / 981 (7.44%)
occurrences all number	79	81
Gastrointestinal disorders
Constipation
Additional description: Treatment-emergent
subjects affected / exposed	53 / 977 (5.42%)	50 / 981 (5.10%)
occurrences all number	55	53
Diarrhoea
Additional description: Treatment-emergent
subjects affected / exposed	51 / 977 (5.22%)	53 / 981 (5.40%)
occurrences all number	53	57
Nausea
Additional description: Treatment-emergent
subjects affected / exposed	95 / 977 (9.72%)	95 / 981 (9.68%)
occurrences all number	102	101
Vomiting
Additional description: Treatment-emergent
subjects affected / exposed	58 / 977 (5.94%)	75 / 981 (7.65%)
occurrences all number	62	75
Renal and urinary disorders
Acute kidney injury
Additional description: Treatment-emergent
subjects affected / exposed	91 / 977 (9.31%)	82 / 981 (8.36%)
occurrences all number	101	91
Metabolism and nutrition disorders
Hypocalcaemia
Additional description: Treatment-emergent
subjects affected / exposed	91 / 977 (9.31%)	80 / 981 (8.15%)
occurrences all number	97	91
Hypokalaemia
Additional description: Treatment-emergent
subjects affected / exposed	91 / 977 (9.31%)	79 / 981 (8.05%)
occurrences all number	101	85

More information

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Were there any global substantial amendments to the protocol? Yes

14 Dec 2016

The main reasons for this amendment* were the following: - Adjustment of “concomitant medication”, “duration per patient” and “duration of whole study” - Clarification that (serious) adverse events/ reactions are recorded and processed on timepoints T6-T8 - Addition of discontinuation criteria related to the study site and to the patient - Explanation of actions in case of a breach against the data protection. T6: post-operative day 8 until post-operative day 10 or hospital discharge, whatever occurs first T8: 90 days after surgery * Depending on the ethics committees' and national authorities’ feedback and on timepoint of initial submission the number of amendments, the amendment dates, as well as the changes to the protocol may differ between the participating countries. As representative information, the overview of amendments in Germany is given here.

20 Apr 2017

The main reason for this amendment* was the addition of subgroup analysis for gender. * Depending on the ethics committees' and national authorities’ feedback and on timepoint of initial submission the number of amendments, the amendment dates, as well as the changes to the protocol may differ between the participating countries. As representative information, the overview of amendments in Germany is given here.

27 Feb 2018

The main reason for this amendment* was to reflect the referral procedure in relation to risk-benefit-assessment. * Depending on the ethics committees' and national authorities’ feedback and on timepoint of initial submission the number of amendments, the amendment dates, as well as the changes to the protocol may differ between the participating countries. As representative information, the overview of amendments in Germany is given here.

01 Aug 2019

The main reason for this amendment* was to reflect sponsor transfer from B. Braun to Fresenius Kabi. * Depending on the ethics committees' and national authorities’ feedback and on timepoint of initial submission the number of amendments, the amendment dates, as well as the changes to the protocol may differ between the participating countries. As representative information, the overview of amendments in Germany is given here.

05 Nov 2019

The main reason for this amendment* was to adapt MAP-guided volume algorithm to increase patient recruitment. MAP=Mean arterial (blood) pressure. * Depending on the ethics committees' and national authorities’ feedback and on timepoint of initial submission the number of amendments, the amendment dates, as well as the changes to the protocol may differ between the participating countries. As representative information, the overview of amendments in Germany is given here.

30 Jul 2021

The main reason for this amendment* was to clarify some statistical aspects. * Depending on the ethics committees' and national authorities’ feedback and on timepoint of initial submission the number of amendments, the amendment dates, as well as the changes to the protocol may differ between the participating countries. As representative information, the overview of amendments in Germany is given here.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
12 Jan 2018	The study was set on temporary recruitment hold on 12.01.2018. The decision was taken after a meeting with the Pharmacovigilance Risk Assessment Committee (PRAC) and their recommendation to suspend the market authorisation of HES based on the off-label use in certain patient populations (e.g., critically ill or severe sepsis/septic shock patients). Although this did not directly affect the use of HES in the present study in abdominal surgery patients, where patient selection was controlled and in line with the SmPCs, the risk/benefit assessment of the study protocol and the ICF had to be adapted. Recruitment re-started in the respective countries after the approval of the updated protocol and ICF.	-

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

None reported

http://www.ncbi.nlm.nih.gov/pubmed/35193648

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Clinical trials

Clinical Trial Results:
Prospective, randomised, controlled, double-blind, multi-centre, multinational study on the safety and efficacy of 6% Hydroxyethyl starch (HES) solution versus an electrolyte solution in patients undergoing elective abdominal surgery (PHOENICS)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in cystatin C-based estimated glomerular filtration rate (eGFR) from pre-operative baseline to eGFR value calculated from the highest cystatin C level measured during post-operative days 1–3 (POD1–3) (i.e., minimal eGFR during POD1–3)

Primary: Change in cystatin C-based estimated glomerular filtration rate (eGFR) from pre-operative baseline to eGFR value calculated from the highest cystatin C level measured during post-operative days 1–3 (POD1–3) (i.e., minimal eGFR during POD1–3)

Secondary: Key secondary endpoint: Mortality and major post-operative complications (including renal) until day 90

Secondary: Key secondary endpoint: Mortality and major post-operative complications (including renal) until day 90

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

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Outside EU/EEA

Clinical trials

Clinical Trial Results: Prospective, randomised, controlled, double-blind, multi-centre, multinational study on the safety and efficacy of 6% Hydroxyethyl starch (HES) solution versus an electrolyte solution in patients undergoing elective abdominal surgery (PHOENICS)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in cystatin C-based estimated glomerular filtration rate (eGFR) from pre-operative baseline to eGFR value calculated from the highest cystatin C level measured during post-operative days 1–3 (POD1–3) (i.e., minimal eGFR during POD1–3)

Primary: Change in cystatin C-based estimated glomerular filtration rate (eGFR) from pre-operative baseline to eGFR value calculated from the highest cystatin C level measured during post-operative days 1–3 (POD1–3) (i.e., minimal eGFR during POD1–3)

Secondary: Key secondary endpoint: Mortality and major post-operative complications (including renal) until day 90

Secondary: Key secondary endpoint: Mortality and major post-operative complications (including renal) until day 90

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
Prospective, randomised, controlled, double-blind, multi-centre, multinational study on the safety and efficacy of 6% Hydroxyethyl starch (HES) solution versus an electrolyte solution in patients undergoing elective abdominal surgery (PHOENICS)