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Clinical Trial Results:
A 12-month, multi-center, open-label, randomized, controlled study to evaluate efficacy/safety and evolution of renal function of everolimus in co-exposure with tacrolimus in de novo liver transplant recipients

Summary
EudraCT number	2011-003118-17
Trial protocol	DE
Global end of trial date	08 Aug 2017

Results information
Results version number	v1(current)
This version publication date	19 Aug 2018
First version publication date	19 Aug 2018
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

CRAD001HDE13

ISRCTN number

US NCT number

NCT01551212

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

08 Aug 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Aug 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to demonstrate that an immunosuppressive regimen based on EVR in co-exposure with TAC has superior efficacy compared to TAC alone on eGFR (Modification of Diet in Renal Disease Study Group-4 (MDRD-4) formula) at Month 12 in de novo liver transplant recipients.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

For patients in all groups, corticosteroids were initiated at or prior to the time of transplantation according to local practice. Corticosteroids may have been used for the duration of the study according to the investigator`s discretion, but may not have been eliminated sooner than 6 months post-transplantation.

Evidence for comparator

Actual start date of recruitment

24 May 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 333

Worldwide total number of subjects

333

EEA total number of subjects

333

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)

323

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

In total, 642 patients were screened for study eligibility at 15 study centers in Germany. 339 patients were randomized out of which 333 received study treatment and were included in the analyses.

Screening details

Patients were screened for eligibility prior to liver transplantation (LTx). The study treatment started after a run-in period that ended on the day of randomization, scheduled at Day 7-21 post-LTx. Patients may have been initiated on an optional induction therapy, MMF, TAC at investigators’ discretion.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Everolimus/Tacrolimus

Arm description

Tacrolimus minimization arm. Everolimus (C0-h: 3-8 ng/mL) + tacrolimus (C0-h: < 5 ng/mL)

Arm type

Experimental

Investigational medicinal product name

Everolimus

Investigational medicinal product code

RAD001

Other name

Certican

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tablets at dose strengths of 0.25mg, 0.5mg, 0.75mg or 1.0mg in blisters of 10 tablets. Dosing schedule according to blood levels

Tacrolimus

Arm description

Tacrolimus (C0-h: 6-10 ng/ml)

Arm type

Active comparator

Investigational medicinal product name

Tacrolimus

Investigational medicinal product code

Other name

Tacrolimus Hexal

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tablets at dose strength of 0.5 mg, 1 mg, or 5 mg

Number of subjects in period 1	Everolimus/Tacrolimus	Tacrolimus
Started	169	164
Full Anylsis Set (FAS)	169	164
Safety Set	169	164
Per Protocol Set (PP)	110 ^[1]	101 ^[2]
Completed	166	148
Not completed	3	16
Adverse event, serious fatal	2	4
Consent withdrawn by subject	-	7
Administrative problems	1	2
Graft loss/Retransplantation	-	1
Lost to follow-up	-	1
Protocol deviation	-	1

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Per Protocol Set (PP) - Randomized, received at least 1 dose of study drug and had no major protocol deviation
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Per Protocol Set (PP) - Randomized, received at least 1 dose of study drug and had no major protocol deviation

Baseline characteristics

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Reporting group title

Everolimus/Tacrolimus

Reporting group description

Tacrolimus minimization arm. Everolimus (C0-h: 3-8 ng/mL) + tacrolimus (C0-h: < 5 ng/mL)

Reporting group title

Tacrolimus

Reporting group description

Tacrolimus (C0-h: 6-10 ng/ml)

Reporting group values	Everolimus/Tacrolimus	Tacrolimus	Total
Number of subjects	169	164	333
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	166	157	323
From 65-84 years	3	7	10
85 years and over	0	0	0
Age Continuous
Units: Years
arithmetic mean (standard deviation)	53.68 ( 9.38 )	53.46 ( 9.64 )	-
Sex/Gender, Customized
Units: Subjects
Male\|	133	121	254
Female\|	36	43	79
Race/Ethnicity, Customized
Units: Subjects
Caucasian\|	168	157	325
Black\|	1	1	2
Asian\|	0	3	3
Other\|	0	3	3

End points

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Reporting group title

Everolimus/Tacrolimus

Reporting group description

Tacrolimus minimization arm. Everolimus (C0-h: 3-8 ng/mL) + tacrolimus (C0-h: < 5 ng/mL)

Reporting group title

Tacrolimus

Reporting group description

Tacrolimus (C0-h: 6-10 ng/ml)

Primary: Estimated glomerular filtration rate (GFR)

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End point title

Estimated glomerular filtration rate (GFR)

End point description

The estmated GFR was calculated using MDRD-4 formula (Modification of Diet in Renal Disease Study Group).

End point type

Primary

End point timeframe

month 12

End point values	Everolimus/Tacrolimus	Tacrolimus
Number of subjects analysed	169	164
Units: mL/min
arithmetic mean (standard deviation)	73.46 ( 25.57 )	71.95 ( 27.17 )

estmated GFR using ANCOVA

Comparison groups

Everolimus/Tacrolimus v Tacrolimus

Number of subjects included in analysis

333

Analysis specification

Pre-specified

Analysis type

P-value

= 0.097

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

4.09

Confidence interval

level

95%

sides

2-sided

lower limit

-0.74

upper limit

8.91

Secondary: Estimated GFR - PP Set

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End point title

Estimated GFR - PP Set

End point description

This was a sensitivity analysis for the primary outcome measure based on the per-protocol set of patients.

End point type

Secondary

End point timeframe

month 12

End point values	Everolimus/Tacrolimus	Tacrolimus
Number of subjects analysed	169	164
Units: mL/min
arithmetic mean (standard deviation)	74.83 ( 25.19 )	70.65 ( 24.91 )

estmated GFR using ANCOVA

Comparison groups

Everolimus/Tacrolimus v Tacrolimus

Number of subjects included in analysis

333

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0085

Method

ANCOVA

Parameter type

Mean difference (final values)

Point estimate

7.99

Confidence interval

level

95%

sides

2-sided

lower limit

2.06

upper limit

13.92

Secondary: Incidence of composite of treated biopsy proven acute rejection (BPAR), graft loss or death

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End point title

Incidence of composite of treated biopsy proven acute rejection (BPAR), graft loss or death

End point description

Incidence of composite of treated biopsy proven acute rejection (BPAR), graft loss or death at Month 12

End point type

Secondary

End point timeframe

12 months

End point values	Everolimus/Tacrolimus	Tacrolimus
Number of subjects analysed	169	164
Units: Percent of Patients
number (not applicable)	9.5	7.9

Incidence of BPAR, graft loss or death

Comparison groups

Everolimus/Tacrolimus v Tacrolimus

Number of subjects included in analysis

333

Analysis specification

Pre-specified

Analysis type

P-value

= 0.699

Method

Fisher exact

Confidence interval

Secondary: Incidence of HCV

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End point title

Incidence of HCV

End point description

Incidence of HCV (hepatitis C virus) assessed as treatment emergent adverse events of special interest

End point type

Secondary

End point timeframe

12 months

End point values	Everolimus/Tacrolimus	Tacrolimus
Number of subjects analysed	169	164
Units: Participants	6	12

No statistical analyses for this end point

Secondary: Incidence of HCV related fibrosis

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End point title

Incidence of HCV related fibrosis

End point description

Incidence of hepatitis C virus (HCV) related fibrosis assessed as treatment emergent adverse events of special interest

End point type

Secondary

End point timeframe

12 months

End point values	Everolimus/Tacrolimus	Tacrolimus
Number of subjects analysed	169	164
Units: Participants	1	0

No statistical analyses for this end point

Secondary: Incidence of de novo HCC malignancies

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End point title

Incidence of de novo HCC malignancies

End point description

Incidence of de novo Hepatocellular Carcinoma (HCC) malignancies assessed as treatment emergent adverse events of special interest

End point type

Secondary

End point timeframe

12 months

End point values	Everolimus/Tacrolimus	Tacrolimus
Number of subjects analysed	169	164
Units: Participants	0	2

No statistical analyses for this end point

Secondary: Incidence and severity of CMV viral infections.

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End point title

Incidence and severity of CMV viral infections.

End point description

Incidence and severity of cytomegalovirus (CMV) viral infections assessed as treatment emergent adverse events of special interest.

End point type

Secondary

End point timeframe

12 months

End point values	Everolimus/Tacrolimus	Tacrolimus
Number of subjects analysed	169	164
Units: Participants
No CMV viral infection	136	129
Asymptomatic	0	5
Mild	16	20
Moderate	13	9
Severe	4	1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.

Adverse event reporting additional description

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

EVR/TAC group

Reporting group description

EVR/TAC group

Reporting group title

TAC group

Reporting group description

TAC group

Serious adverse events	EVR/TAC group	TAC group
Total subjects affected by serious adverse events
subjects affected / exposed	111 / 169 (65.68%)	101 / 164 (61.59%)
number of deaths (all causes)	3	4
number of deaths resulting from adverse events	1	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ACUTE MYELOID LEUKAEMIA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
CHRONIC MYELOID LEUKAEMIA
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATOCELLULAR CARCINOMA
subjects affected / exposed	0 / 169 (0.00%)	3 / 164 (1.83%)
occurrences causally related to treatment / all	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
LYMPHOMA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
PROSTATE CANCER
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SQUAMOUS CELL CARCINOMA OF SKIN
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
ANGIODYSPLASIA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ARTERY DISSECTION
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
DIABETIC VASCULAR DISORDER
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HAEMATOMA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HYPERTENSIVE CRISIS
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
INFERIOR VENA CAVA STENOSIS
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INTERNAL HAEMORRHAGE
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
LYMPHATIC FISTULA
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
subjects affected / exposed	2 / 169 (1.18%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
POOR PERIPHERAL CIRCULATION
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
THROMBOSIS
subjects affected / exposed	2 / 169 (1.18%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
VENA CAVA THROMBOSIS
subjects affected / exposed	2 / 169 (1.18%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
ABORTION SPONTANEOUS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
CHILLS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
IMPAIRED HEALING
subjects affected / exposed	1 / 169 (0.59%)	3 / 164 (1.83%)
occurrences causally related to treatment / all	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
INCARCERATED HERNIA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
MALAISE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MUCOSAL INFLAMMATION
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
MULTIPLE ORGAN DYSFUNCTION SYNDROME
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
NON-CARDIAC CHEST PAIN
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
OEDEMA PERIPHERAL
subjects affected / exposed	1 / 169 (0.59%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
PYREXIA
subjects affected / exposed	4 / 169 (2.37%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	1 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
SURGICAL FAILURE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
LIVER TRANSPLANT REJECTION
subjects affected / exposed	12 / 169 (7.10%)	9 / 164 (5.49%)
occurrences causally related to treatment / all	4 / 14	1 / 9
deaths causally related to treatment / all	0 / 0	1 / 1
Respiratory, thoracic and mediastinal disorders
ACUTE RESPIRATORY DISTRESS SYNDROME
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ASTHMA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DYSPNOEA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HAEMOPTYSIS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PLEURAL EFFUSION
subjects affected / exposed	4 / 169 (2.37%)	5 / 164 (3.05%)
occurrences causally related to treatment / all	1 / 4	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 1
PLEURISY
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONIA ASPIRATION
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMOTHORAX
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed	2 / 169 (1.18%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
RESPIRATORY FAILURE
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
DISORIENTATION
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
DEVICE OCCLUSION
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
ALANINE AMINOTRANSFERASE INCREASED
subjects affected / exposed	1 / 169 (0.59%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
ASPARTATE AMINOTRANSFERASE INCREASED
subjects affected / exposed	1 / 169 (0.59%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
BLOOD ALKALINE PHOSPHATASE INCREASED
subjects affected / exposed	2 / 169 (1.18%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BLOOD BILIRUBIN INCREASED
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
BLOOD CREATINE PHOSPHOKINASE INCREASED
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BLOOD CREATININE INCREASED
subjects affected / exposed	3 / 169 (1.78%)	3 / 164 (1.83%)
occurrences causally related to treatment / all	2 / 4	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
BLOOD POTASSIUM INCREASED
subjects affected / exposed	2 / 169 (1.18%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
C-REACTIVE PROTEIN INCREASED
subjects affected / exposed	0 / 169 (0.00%)	5 / 164 (3.05%)
occurrences causally related to treatment / all	0 / 0	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
CHEST X-RAY ABNORMAL
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GAMMA-GLUTAMYLTRANSFERASE INCREASED
subjects affected / exposed	3 / 169 (1.78%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GLUTAMATE DEHYDROGENASE INCREASED
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HAEMOGLOBIN DECREASED
subjects affected / exposed	2 / 169 (1.18%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATIC ARTERY FLOW DECREASED
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATIC ENZYME INCREASED
subjects affected / exposed	6 / 169 (3.55%)	7 / 164 (4.27%)
occurrences causally related to treatment / all	1 / 6	2 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
LIVER FUNCTION TEST INCREASED
subjects affected / exposed	3 / 169 (1.78%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
TRANSAMINASES INCREASED
subjects affected / exposed	2 / 169 (1.18%)	6 / 164 (3.66%)
occurrences causally related to treatment / all	0 / 3	2 / 6
deaths causally related to treatment / all	0 / 0	1 / 1
TROPONIN INCREASED
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
WHITE BLOOD CELL COUNT INCREASED
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
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
ABDOMINAL WOUND DEHISCENCE
subjects affected / exposed	3 / 169 (1.78%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ACCIDENTAL OVERDOSE
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ANASTOMOTIC STENOSIS
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
BILIARY ANASTOMOSIS COMPLICATION
subjects affected / exposed	8 / 169 (4.73%)	13 / 164 (7.93%)
occurrences causally related to treatment / all	0 / 9	0 / 13
deaths causally related to treatment / all	0 / 0	0 / 0
BRAIN CONTUSION
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
COMPLICATIONS OF TRANSPLANTED LIVER
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CONCUSSION
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
FALL
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
FEMUR FRACTURE
subjects affected / exposed	2 / 169 (1.18%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GRAFT LOSS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
INCARCERATED INCISIONAL HERNIA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INCISIONAL HERNIA
subjects affected / exposed	11 / 169 (6.51%)	4 / 164 (2.44%)
occurrences causally related to treatment / all	0 / 11	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
LUMBAR VERTEBRAL FRACTURE
subjects affected / exposed	2 / 169 (1.18%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
OVERDOSE
subjects affected / exposed	2 / 169 (1.18%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
PELVIC FRACTURE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
POST PROCEDURAL BILE LEAK
subjects affected / exposed	1 / 169 (0.59%)	3 / 164 (1.83%)
occurrences causally related to treatment / all	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
SPINAL COMPRESSION FRACTURE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SPINAL FRACTURE
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SUBARACHNOID HAEMORRHAGE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
THORACIC VERTEBRAL FRACTURE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
TRANSPLANT FAILURE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
ULNA FRACTURE
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
VASCULAR PSEUDOANEURYSM
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
WEANING FAILURE
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
WOUND DEHISCENCE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
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
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ATRIAL FIBRILLATION
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CARDIOGENIC SHOCK
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
CORONARY ARTERY DISEASE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MITRAL VALVE INCOMPETENCE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
PERICARDIAL EFFUSION
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SUPRAVENTRICULAR TACHYCARDIA
subjects affected / exposed	1 / 169 (0.59%)	3 / 164 (1.83%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
TACHYCARDIA
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
VENTRICULAR EXTRASYSTOLES
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
VENTRICULAR TACHYCARDIA
subjects affected / exposed	2 / 169 (1.18%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
CEREBROVASCULAR ACCIDENT
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
EPILEPSY
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HEMIPARESIS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
LACUNAR STROKE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
NERVOUS SYSTEM DISORDER
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PARAPARESIS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
POLYNEUROPATHY
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PRESYNCOPE
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SEIZURE
subjects affected / exposed	2 / 169 (1.18%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SYNCOPE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
TRANSIENT ISCHAEMIC ATTACK
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
TREMOR
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	4 / 169 (2.37%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	1 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
BONE MARROW TOXICITY
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
EVANS SYNDROME
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPOCHROMIC ANAEMIA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
IRON DEFICIENCY ANAEMIA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
LYMPHOCYTOSIS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PANCYTOPENIA
subjects affected / exposed	3 / 169 (1.78%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
THROMBOCYTOPENIA
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ear and labyrinth disorders
VERTIGO
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
MYDRIASIS
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
ABDOMINAL HERNIA
subjects affected / exposed	3 / 169 (1.78%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ABDOMINAL PAIN
subjects affected / exposed	2 / 169 (1.18%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
ABDOMINAL PAIN UPPER
subjects affected / exposed	2 / 169 (1.18%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
APHTHOUS ULCER
subjects affected / exposed	2 / 169 (1.18%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ASCITES
subjects affected / exposed	5 / 169 (2.96%)	5 / 164 (3.05%)
occurrences causally related to treatment / all	1 / 6	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
COLITIS
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DENTAL CARIES
subjects affected / exposed	2 / 169 (1.18%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DIARRHOEA
subjects affected / exposed	5 / 169 (2.96%)	4 / 164 (2.44%)
occurrences causally related to treatment / all	1 / 8	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
DUODENAL ULCER
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ENTEROCOLITIS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
FAECES DISCOLOURED
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GASTRIC ULCER HAEMORRHAGE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
GASTRITIS
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROINTESTINAL ANGIODYSPLASIA HAEMORRHAGIC
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROINTESTINAL INFLAMMATION
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROINTESTINAL NECROSIS
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
IMPAIRED GASTRIC EMPTYING
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INCARCERATED INGUINAL HERNIA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INCARCERATED UMBILICAL HERNIA
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
INGUINAL HERNIA
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
INTESTINAL INFARCTION
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
INTESTINAL ISCHAEMIA
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
INTESTINAL PERFORATION
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INTRA-ABDOMINAL FLUID COLLECTION
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MESENTERIC VEIN THROMBOSIS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MESENTERIC VENOUS OCCLUSION
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
NAUSEA
subjects affected / exposed	3 / 169 (1.78%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	2 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PANCREATITIS
subjects affected / exposed	2 / 169 (1.18%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PANCREATITIS ACUTE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
SUBILEUS
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SWOLLEN TONGUE
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
UMBILICAL HERNIA
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
VOMITING
subjects affected / exposed	4 / 169 (2.37%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	2 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
ACUTE HEPATIC FAILURE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
BILE DUCT STENOSIS
subjects affected / exposed	5 / 169 (2.96%)	6 / 164 (3.66%)
occurrences causally related to treatment / all	0 / 6	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
BILE DUCT STONE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
BILIARY ISCHAEMIA
subjects affected / exposed	5 / 169 (2.96%)	4 / 164 (2.44%)
occurrences causally related to treatment / all	0 / 6	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
BILIARY TRACT DISORDER
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
BILOMA
subjects affected / exposed	2 / 169 (1.18%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
CHOLANGITIS
subjects affected / exposed	13 / 169 (7.69%)	7 / 164 (4.27%)
occurrences causally related to treatment / all	1 / 22	2 / 9
deaths causally related to treatment / all	0 / 1	0 / 1
CHOLANGITIS ACUTE
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CHOLELITHIASIS
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CHOLESTASIS
subjects affected / exposed	1 / 169 (0.59%)	4 / 164 (2.44%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 1
DRUG-INDUCED LIVER INJURY
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATIC ARTERY ANEURYSM
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
HEPATIC ARTERY STENOSIS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATIC ARTERY THROMBOSIS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
HEPATIC FAILURE
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (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
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATIC HAEMATOMA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATIC HAEMORRHAGE
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATIC INFARCTION
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATIC ISCHAEMIA
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
HEPATIC LESION
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATIC NECROSIS
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATIC STEATOSIS
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATITIS TOXIC
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATOTOXICITY
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
LIVER DISORDER
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
NON-ALCOHOLIC STEATOHEPATITIS
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (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
subjects affected / exposed	0 / 169 (0.00%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
VANISHING BILE DUCT SYNDROME
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
ANGIOEDEMA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DIABETIC FOOT
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PRURITUS
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
ACUTE KIDNEY INJURY
subjects affected / exposed	10 / 169 (5.92%)	8 / 164 (4.88%)
occurrences causally related to treatment / all	5 / 12	3 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
ALBUMINURIA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CYSTITIS HAEMORRHAGIC
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
IGA NEPHROPATHY
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
OLIGURIA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PRERENAL FAILURE
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PROTEINURIA
subjects affected / exposed	2 / 169 (1.18%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
RENAL FAILURE
subjects affected / exposed	1 / 169 (0.59%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	1 / 1	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
RENAL IMPAIRMENT
subjects affected / exposed	1 / 169 (0.59%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
GOITRE
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
TOXIC NODULAR GOITRE
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (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
BACK PAIN
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MUSCULOSKELETAL DISORDER
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
MYOPATHY
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
OSTEOCHONDROSIS
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
ABDOMINAL ABSCESS
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ABDOMINAL WALL ABSCESS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ABSCESS JAW
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ANAL ABSCESS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
APPENDICITIS
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ATYPICAL PNEUMONIA
subjects affected / exposed	1 / 169 (0.59%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	1 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
BACTERAEMIA
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
BACTERIAL INFECTION
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
BILIARY ABSCESS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
BILIARY TRACT INFECTION
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
BRONCHOPULMONARY ASPERGILLOSIS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CELLULITIS
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CHOLANGITIS INFECTIVE
subjects affected / exposed	6 / 169 (3.55%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	1 / 23	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
CLOSTRIDIUM DIFFICILE INFECTION
subjects affected / exposed	2 / 169 (1.18%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CYTOMEGALOVIRUS COLITIS
subjects affected / exposed	1 / 169 (0.59%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
CYTOMEGALOVIRUS HEPATITIS
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CYTOMEGALOVIRUS INFECTION
subjects affected / exposed	6 / 169 (3.55%)	3 / 164 (1.83%)
occurrences causally related to treatment / all	3 / 6	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
CYTOMEGALOVIRUS SYNDROME
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
CYTOMEGALOVIRUS VIRAEMIA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DEVICE RELATED INFECTION
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
EMPYEMA
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ENTERITIS INFECTIOUS
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
ENTEROCOCCAL INFECTION
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
EPIDIDYMITIS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
EPSTEIN-BARR VIRUS INFECTION
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
ESCHERICHIA INFECTION
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
FEBRILE INFECTION
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
FOLLICULITIS
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
FUNGAL INFECTION
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROENTERITIS
subjects affected / exposed	3 / 169 (1.78%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROENTERITIS CLOSTRIDIAL
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROENTERITIS CRYPTOSPORIDIAL
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROENTERITIS ROTAVIRUS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROINTESTINAL INFECTION
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GASTROINTESTINAL VIRAL INFECTION
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HAEMATOMA INFECTION
subjects affected / exposed	2 / 169 (1.18%)	3 / 164 (1.83%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
HEPATITIS C
subjects affected / exposed	2 / 169 (1.18%)	5 / 164 (3.05%)
occurrences causally related to treatment / all	0 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
HERPES ZOSTER
subjects affected / exposed	0 / 169 (0.00%)	2 / 164 (1.22%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
HUMAN HERPESVIRUS 6 INFECTION
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INFECTED SEROMA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
INFECTION
subjects affected / exposed	4 / 169 (2.37%)	3 / 164 (1.83%)
occurrences causally related to treatment / all	2 / 4	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
LIVER ABSCESS
subjects affected / exposed	5 / 169 (2.96%)	4 / 164 (2.44%)
occurrences causally related to treatment / all	0 / 6	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1
LOCALISED INFECTION
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
LUNG INFECTION
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PARONYCHIA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
PERITONITIS
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
PERITONITIS BACTERIAL
subjects affected / exposed	2 / 169 (1.18%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PHARYNGEAL ABSCESS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PILONIDAL CYST
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	10 / 169 (5.92%)	7 / 164 (4.27%)
occurrences causally related to treatment / all	5 / 15	2 / 8
deaths causally related to treatment / all	0 / 0	0 / 1
PSEUDOMONAS INFECTION
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SCARLET FEVER
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
SEPSIS
subjects affected / exposed	2 / 169 (1.18%)	4 / 164 (2.44%)
occurrences causally related to treatment / all	1 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1
SEPTIC SHOCK
subjects affected / exposed	2 / 169 (1.18%)	3 / 164 (1.83%)
occurrences causally related to treatment / all	1 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	1 / 3
STAPHYLOCOCCAL INFECTION
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
TRANSPLANT ABSCESS
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	3 / 4
deaths causally related to treatment / all	0 / 0	1 / 1
URINARY TRACT INFECTION
subjects affected / exposed	2 / 169 (1.18%)	5 / 164 (3.05%)
occurrences causally related to treatment / all	0 / 2	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
VARICELLA
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
VIRAL INFECTION
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
VIRAL UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	2 / 169 (1.18%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
WOUND INFECTION
subjects affected / exposed	3 / 169 (1.78%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
WOUND INFECTION STAPHYLOCOCCAL
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
ACIDOSIS HYPERCHLORAEMIC
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
DEHYDRATION
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
DIABETIC COMPLICATION
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
FLUID RETENTION
subjects affected / exposed	1 / 169 (0.59%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
GOUT
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPERGLYCAEMIA
subjects affected / exposed	3 / 169 (1.78%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	1 / 4	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPERINSULINAEMIC HYPOGLYCAEMIA
subjects affected / exposed	0 / 169 (0.00%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPERKALAEMIA
subjects affected / exposed	3 / 169 (1.78%)	1 / 164 (0.61%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
HYPONATRAEMIA
subjects affected / exposed	1 / 169 (0.59%)	0 / 164 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	EVR/TAC group	TAC group
Total subjects affected by non serious adverse events
subjects affected / exposed	164 / 169 (97.04%)	153 / 164 (93.29%)
Vascular disorders
HYPERTENSION
subjects affected / exposed	28 / 169 (16.57%)	24 / 164 (14.63%)
occurrences all number	28	24
General disorders and administration site conditions
IMPAIRED HEALING
subjects affected / exposed	24 / 169 (14.20%)	10 / 164 (6.10%)
occurrences all number	24	10
OEDEMA PERIPHERAL
subjects affected / exposed	38 / 169 (22.49%)	15 / 164 (9.15%)
occurrences all number	44	16
PYREXIA
subjects affected / exposed	20 / 169 (11.83%)	9 / 164 (5.49%)
occurrences all number	29	10
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	14 / 169 (8.28%)	8 / 164 (4.88%)
occurrences all number	15	9
DYSPNOEA
subjects affected / exposed	9 / 169 (5.33%)	7 / 164 (4.27%)
occurrences all number	10	7
PLEURAL EFFUSION
subjects affected / exposed	20 / 169 (11.83%)	12 / 164 (7.32%)
occurrences all number	27	12
Psychiatric disorders
DEPRESSION
subjects affected / exposed	4 / 169 (2.37%)	10 / 164 (6.10%)
occurrences all number	4	10
INSOMNIA
subjects affected / exposed	1 / 169 (0.59%)	9 / 164 (5.49%)
occurrences all number	1	10
Investigations
BLOOD CREATININE INCREASED
subjects affected / exposed	21 / 169 (12.43%)	21 / 164 (12.80%)
occurrences all number	21	24
BODY TEMPERATURE INCREASED
subjects affected / exposed	6 / 169 (3.55%)	9 / 164 (5.49%)
occurrences all number	8	12
C-REACTIVE PROTEIN INCREASED
subjects affected / exposed	18 / 169 (10.65%)	9 / 164 (5.49%)
occurrences all number	18	9
GAMMA-GLUTAMYLTRANSFERASE INCREASED
subjects affected / exposed	10 / 169 (5.92%)	12 / 164 (7.32%)
occurrences all number	10	14
HEPATIC ENZYME INCREASED
subjects affected / exposed	9 / 169 (5.33%)	13 / 164 (7.93%)
occurrences all number	11	13
TRANSAMINASES INCREASED
subjects affected / exposed	9 / 169 (5.33%)	8 / 164 (4.88%)
occurrences all number	9	9
Injury, poisoning and procedural complications
INCISIONAL HERNIA
subjects affected / exposed	35 / 169 (20.71%)	10 / 164 (6.10%)
occurrences all number	35	10
PROCEDURAL PAIN
subjects affected / exposed	5 / 169 (2.96%)	9 / 164 (5.49%)
occurrences all number	5	10
Nervous system disorders
HEADACHE
subjects affected / exposed	48 / 169 (28.40%)	22 / 164 (13.41%)
occurrences all number	60	27
TREMOR
subjects affected / exposed	25 / 169 (14.79%)	23 / 164 (14.02%)
occurrences all number	25	23
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	22 / 169 (13.02%)	20 / 164 (12.20%)
occurrences all number	24	21
LEUKOPENIA
subjects affected / exposed	45 / 169 (26.63%)	12 / 164 (7.32%)
occurrences all number	49	13
THROMBOCYTOPENIA
subjects affected / exposed	25 / 169 (14.79%)	4 / 164 (2.44%)
occurrences all number	27	5
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	23 / 169 (13.61%)	17 / 164 (10.37%)
occurrences all number	26	19
ABDOMINAL PAIN UPPER
subjects affected / exposed	15 / 169 (8.88%)	11 / 164 (6.71%)
occurrences all number	16	13
APHTHOUS ULCER
subjects affected / exposed	11 / 169 (6.51%)	0 / 164 (0.00%)
occurrences all number	11	0
ASCITES
subjects affected / exposed	20 / 169 (11.83%)	13 / 164 (7.93%)
occurrences all number	20	15
CONSTIPATION
subjects affected / exposed	13 / 169 (7.69%)	10 / 164 (6.10%)
occurrences all number	13	10
DIARRHOEA
subjects affected / exposed	43 / 169 (25.44%)	39 / 164 (23.78%)
occurrences all number	60	41
NAUSEA
subjects affected / exposed	22 / 169 (13.02%)	13 / 164 (7.93%)
occurrences all number	26	15
VOMITING
subjects affected / exposed	16 / 169 (9.47%)	12 / 164 (7.32%)
occurrences all number	23	17
Hepatobiliary disorders
CHOLANGITIS
subjects affected / exposed	9 / 169 (5.33%)	2 / 164 (1.22%)
occurrences all number	11	2
HEPATIC CYST
subjects affected / exposed	10 / 169 (5.92%)	3 / 164 (1.83%)
occurrences all number	14	3
HEPATIC STEATOSIS
subjects affected / exposed	12 / 169 (7.10%)	8 / 164 (4.88%)
occurrences all number	13	8
Skin and subcutaneous tissue disorders
ALOPECIA
subjects affected / exposed	10 / 169 (5.92%)	5 / 164 (3.05%)
occurrences all number	10	5
PRURITUS
subjects affected / exposed	16 / 169 (9.47%)	10 / 164 (6.10%)
occurrences all number	16	13
Renal and urinary disorders
PROTEINURIA
subjects affected / exposed	26 / 169 (15.38%)	12 / 164 (7.32%)
occurrences all number	29	13
RENAL FAILURE
subjects affected / exposed	12 / 169 (7.10%)	15 / 164 (9.15%)
occurrences all number	13	16
RENAL IMPAIRMENT
subjects affected / exposed	7 / 169 (4.14%)	15 / 164 (9.15%)
occurrences all number	7	15
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	9 / 169 (5.33%)	8 / 164 (4.88%)
occurrences all number	9	9
BACK PAIN
subjects affected / exposed	17 / 169 (10.06%)	12 / 164 (7.32%)
occurrences all number	17	12
MUSCLE SPASMS
subjects affected / exposed	7 / 169 (4.14%)	9 / 164 (5.49%)
occurrences all number	7	9
PAIN IN EXTREMITY
subjects affected / exposed	11 / 169 (6.51%)	5 / 164 (3.05%)
occurrences all number	12	5
Infections and infestations
CYTOMEGALOVIRUS INFECTION
subjects affected / exposed	24 / 169 (14.20%)	28 / 164 (17.07%)
occurrences all number	33	34
URINARY TRACT INFECTION
subjects affected / exposed	30 / 169 (17.75%)	24 / 164 (14.63%)
occurrences all number	41	36
VIRAL UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	41 / 169 (24.26%)	29 / 164 (17.68%)
occurrences all number	53	36
Metabolism and nutrition disorders
DIABETES MELLITUS
subjects affected / exposed	11 / 169 (6.51%)	8 / 164 (4.88%)
occurrences all number	11	8
HYPERCHOLESTEROLAEMIA
subjects affected / exposed	30 / 169 (17.75%)	9 / 164 (5.49%)
occurrences all number	32	9
HYPERKALAEMIA
subjects affected / exposed	13 / 169 (7.69%)	17 / 164 (10.37%)
occurrences all number	14	18
HYPERLIPIDAEMIA
subjects affected / exposed	15 / 169 (8.88%)	2 / 164 (1.22%)
occurrences all number	15	2
HYPERTRIGLYCERIDAEMIA
subjects affected / exposed	18 / 169 (10.65%)	8 / 164 (4.88%)
occurrences all number	19	8
HYPERURICAEMIA
subjects affected / exposed	10 / 169 (5.92%)	8 / 164 (4.88%)
occurrences all number	10	8
HYPOKALAEMIA
subjects affected / exposed	11 / 169 (6.51%)	8 / 164 (4.88%)
occurrences all number	15	9
IRON DEFICIENCY
subjects affected / exposed	11 / 169 (6.51%)	5 / 164 (3.05%)
occurrences all number	11	5
VITAMIN D DEFICIENCY
subjects affected / exposed	11 / 169 (6.51%)	10 / 164 (6.10%)
occurrences all number	11	10

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Were there any global substantial amendments to the protocol? Yes

20 Jan 2012

Assessment schedule: Laboratory and GFR were shifted from Screening visit to baseline visit. Additional assessment in Screening visit: Menopausal status and a pregnancy test in all women of childbearing potential.

26 Sep 2012

To allow more patients to be randomized into this study in- and exclusion criteria were adapted. According to these adaptations the patient management was changed. In addition some editorial changes and changes regarding the statistical analysis were performed.

14 Jun 2013

Details of five sub-studies which were conducted in selected centers were added

19 Nov 2014

The protocol has been refined to clarify the mandatory usage of corticosteroids in this study. Additionally, Inclusion Criterion 3/Exclusion Criterion 11 has been adjusted to include total abstinence as acceptable contraception method. In addition some editorial changes were performed.

19 Aug 2015

Exclusion Criterion 5 (at randomization) has been adjusted to allow inclusion of patients with hemoglobin < 6.0 g/dL (transfusion of erythrocytes concentrate during or after transplantation are allowed according to investigator discretion.)

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results:
A 12-month, multi-center, open-label, randomized, controlled study to evaluate efficacy/safety and evolution of renal function of everolimus in co-exposure with tacrolimus in de novo liver transplant recipients

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Estimated glomerular filtration rate (GFR)

Primary: Estimated glomerular filtration rate (GFR)

Secondary: Estimated GFR - PP Set

Secondary: Estimated GFR - PP Set

Secondary: Incidence of composite of treated biopsy proven acute rejection (BPAR), graft loss or death

Secondary: Incidence of composite of treated biopsy proven acute rejection (BPAR), graft loss or death

Secondary: Incidence of HCV

Secondary: Incidence of HCV

Secondary: Incidence of HCV related fibrosis

Secondary: Incidence of HCV related fibrosis

Secondary: Incidence of de novo HCC malignancies

Secondary: Incidence of de novo HCC malignancies

Secondary: Incidence and severity of CMV viral infections.

Secondary: Incidence and severity of CMV viral infections.

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Substantial protocol amendments (globally)

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Clinical trials

Clinical Trial Results: A 12-month, multi-center, open-label, randomized, controlled study to evaluate efficacy/safety and evolution of renal function of everolimus in co-exposure with tacrolimus in de novo liver transplant recipients

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Estimated glomerular filtration rate (GFR)

Primary: Estimated glomerular filtration rate (GFR)

Secondary: Estimated GFR - PP Set

Secondary: Estimated GFR - PP Set

Secondary: Incidence of composite of treated biopsy proven acute rejection (BPAR), graft loss or death

Secondary: Incidence of composite of treated biopsy proven acute rejection (BPAR), graft loss or death

Secondary: Incidence of HCV

Secondary: Incidence of HCV

Secondary: Incidence of HCV related fibrosis

Secondary: Incidence of HCV related fibrosis

Secondary: Incidence of de novo HCC malignancies

Secondary: Incidence of de novo HCC malignancies

Secondary: Incidence and severity of CMV viral infections.

Secondary: Incidence and severity of CMV viral infections.

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A 12-month, multi-center, open-label, randomized, controlled study to evaluate efficacy/safety and evolution of renal function of everolimus in co-exposure with tacrolimus in de novo liver transplant recipients