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Clinical Trial Results:
12 month, multi-center, open-label, prospective, randomized, parallel group study investigating a standard regimen in de novo kidney transplant patients versus a Certican® based regimen either in combination with Cyclosporin A or Tacrolimus

Summary
EudraCT number	2011-005238-21
Trial protocol	DE FR
Global end of trial date	23 Mar 2016

Results information
Results version number	v1(current)
This version publication date	06 Apr 2017
First version publication date	06 Apr 2017
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

CRAD001ADE44

ISRCTN number

US NCT number

NCT01843348

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,

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,

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

23 Mar 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

23 Mar 2016

Global end of trial reached?

Yes

Global end of trial date

23 Mar 2016

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study was to demonstrate non-inferiority in renal function assessed by glomerular filtration rate (Nankivell formula) in at least one of the Certican treatment regimens compared to the standard group at Month 12 post-transplantation in renal transplant patients

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

Evidence for comparator

Actual start date of recruitment

27 Dec 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: 442

Country: Number of subjects enrolled

France: 170

Worldwide total number of subjects

612

EEA total number of subjects

612

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)

449

From 65 to 84 years

163

85 years and over

Subject disposition

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Recruitment details

Screening details

In total 659 patients were screened, 655 patients were randomized and 612 patients were treated.

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

TAC+MPA

Arm description

Tacrolimus, Mycophenolic acid (MPA), corticosteroids and Simulect

Arm type

Active comparator

Investigational medicinal product name

Tacrolimus

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

0.5 mg, 1 mg or 5 mg capsules, dosing schedule: according to standard blood levels

Investigational medicinal product name

Enteric Coated Mycophenolate Sodium (EC-MPS)

Investigational medicinal product code

Other name

Mycophenolic Acid (MPA)

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Tablets: 180 mg or 360 mg. Dosing: duration of study 360 mg bid and no less than 360 mg daily dose

Investigational medicinal product name

Mycophenolate Mofetil (MMF)

Investigational medicinal product code

Other name

Mycophenolic Acid (MPA)

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Capsules: 250 or 500 mg. Dosing: duration of study 500 mg bid and no less than 500 mg total daily dose

TAC+Certican

Arm description

Tacrolimus, Certican, corticosteroids and Simulect

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

0.25 mg, 0.5 mg 0.75 mg or 1 mg tablets, dosing schedule: according to blood levels

CycA+Certican

Arm description

Cyclosporin A, Certican, corticosteroids and Simulect

Arm type

Experimental

Investigational medicinal product name

Basiliximab

Investigational medicinal product code

Other name

Simulect

Pharmaceutical forms

Concentrate for solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Lyophilisate in vials with ampoules of sterile water for injection (5 mL), one vial containing 20 mg lyophilisate given intravenously on the day of transplantation and on day four post-transplantation.

Investigational medicinal product name

Cyclosporin A

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

10 mg, 25 mg, 50 mg or 100 mg capsules, dosing schedule: according to standard blood levels

Number of subjects in period 1	TAC+MPA	TAC+Certican	CycA+Certican
Started	205	208	199
Safety analysis set (SAS)	204	208	198
Full analysis set (FAS)	205	208	199
Per protocol set (PPS)	147 ^[1]	111 ^[2]	80 ^[3]
Completed	182	168	158
Not completed	23	40	41
Adverse event, serious fatal	5	3	4
Consent withdrawn by subject	4	16	18
Graft loss/retransplantation	5	8	11
Various reasons	4	9	6
Lost to follow-up	5	4	2

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: Milestones were added to provide number of participants in the analysis sets.
[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: Milestones were added to provide number of participants in the analysis sets.
[3] - 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: Milestones were added to provide number of participants in the analysis sets.

Baseline characteristics

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Reporting group title

TAC+MPA

Reporting group description

Tacrolimus, Mycophenolic acid (MPA), corticosteroids and Simulect

Reporting group title

TAC+Certican

Reporting group description

Tacrolimus, Certican, corticosteroids and Simulect

Reporting group title

CycA+Certican

Reporting group description

Cyclosporin A, Certican, corticosteroids and Simulect

Reporting group values	TAC+MPA	TAC+Certican	CycA+Certican	Total
Number of subjects	205	208	199	612
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)	55.3 ( 12.09 )	54.3 ( 13.5 )	55.1 ( 12.61 )	-
Gender, Male/Female
Units: Subjects
Female	65	70	66	201
Male	140	138	133	411

End points

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Reporting group title

TAC+MPA

Reporting group description

Tacrolimus, Mycophenolic acid (MPA), corticosteroids and Simulect

Reporting group title

TAC+Certican

Reporting group description

Tacrolimus, Certican, corticosteroids and Simulect

Reporting group title

CycA+Certican

Reporting group description

Cyclosporin A, Certican, corticosteroids and Simulect

Subject analysis set title

Tac+Certican - Tac+MPA - difference between groups at Month 12

Subject analysis set type

Per protocol

Subject analysis set description

Analysis set is composed of Tac+Certican (111) - Tac+MPA (147) for a total of 258.

Subject analysis set title

CycA+Certican -Tac+MPA - difference between groups

Subject analysis set type

Per protocol

Subject analysis set description

Analysis set is composed of CycA+Certican (80) - Tac+MPA (147) for a total of 227

Primary: Glomular filtration rate (GFR) mL/min via Nankivell method at Month 12 - Standard Regimen vs Certican regimens

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End point title

Glomular filtration rate (GFR) mL/min via Nankivell method at Month 12 - Standard Regimen vs Certican regimens

End point description

To demonstrate non-inferiority in renal function assessed by glomerular filtration rate (Nankivell formula) in at least one of the Certican® treatment regimens compared to the standard regimen group at month 12 post-transplantation in renal transplant patients. Nankivell formula: GFR = 6.7/Scr + BW/4 – Surea/2 – 100/(height)² + C where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kg, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients. The eGFR is expressed in mL/min per 1.73m². If a patient was on dialysis at the time of urea or creatinine assessment, the eGFR was set to 0. Analysis set = per protocol set

End point type

Primary

End point timeframe

One year post transplant

End point values	TAC+MPA	TAC+Certican	CycA+Certican
Number of subjects analysed	147	111	80
Units: mL/min per 1.73m²
arithmetic mean (standard deviation)
Month 1 - Day 1 to 60 (146,111,78)	62.62 ( 16.931 )	60.54 ( 17.31 )	59.47 ( 16.754 )
Month 3 - Day 61 to 136 (143,108,79)	66.36 ( 16.672 )	61.21 ( 14.771 )	62.22 ( 16.196 )
Month 6 - Day 137 to 228 (142,108,76)	68.05 ( 16.994 )	62.76 ( 16.763 )	63.17 ( 16.789 )
Month 9 - Day 229 to 319 (140,106,77)	69.47 ( 16.251 )	64.68 ( 15.507 )	62.89 ( 14.947 )
Month12 - Day 320 to 450 (147,111, 80)	70.41 ( 16.514 )	63.34 ( 16.986 )	61.51 ( 16.942 )

CycA+Certican - TAC+MPA at Month 12

Statistical analysis description

The trial tests the null hypotheses that the treatment difference (investigational minus reference) in mean eGFR at re-assigned visit Month 12 is lower than the non-inferiority margin (Δ) of 7 mL/min per 1.73m2 versus the alternative that the treatment difference is equal to or greater than the non-inferiority margin

Comparison groups

TAC+MPA v CycA+Certican

Number of subjects included in analysis

227

Analysis specification

Pre-specified

Analysis type

^[1]

P-value

< 0.0001

Method

ANOVA

Parameter type

Least square mean

Point estimate

-9.35

Confidence interval

level

95%

sides

2-sided

lower limit

-13.82

upper limit

-4.88

Notes
[1] - Analysis of variance (ANOVA) with tx, center, donor type factors. Raw and adjusted means were presented with one-sided p-values for un-shifted and shifted hypothesis, respectively. Significance level = 2.5% (one-sided)

TAC+Certican - TAC + MPA at Month 12

Comparison groups

TAC+MPA v TAC+Certican

Number of subjects included in analysis

258

Analysis specification

Pre-specified

Analysis type

^[2]

P-value

= 0.0067 ^[3]

Method

ANOVA

Parameter type

Least squares mean

Point estimate

-5.56

Confidence interval

level

95%

sides

2-sided

lower limit

-9.56

upper limit

-1.55

Notes
[2] - The trial tests the null hypotheses that the treatment difference (investigational minus reference) in mean eGFR at re-assigned visit Month 12 is lower than the non-inferiority margin (Δ) of 7 mL/min per 1.73m2 versus the alternative that the treatment difference is equal to or greater than the non-inferiority margin
[3] - Analysis of variance (ANOVA) with tx, center, donor type factors. Raw and adjusted means were presented with one-sided p-values for un-shifted and shifted hypothesis, respectively. Significance level = 2.5% (one-sided)

Secondary: Percentage of participants with composite treatment failure endpoints - difference between groups at month 12

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End point title

Percentage of participants with composite treatment failure endpoints - difference between groups at month 12

End point description

Combined endpoint included: biopsy proven acute rejection (BPAR) defined as a rejection which was acute and proven by biopsy, graft loss (GL) defined as: allograft was presumed to be lost on the day the patient starts dialysis and not able to be removed from dialysis or death. Patients who prematurely discontinued the study: if the patient did not suffer from an event before discontinuation and reason was not related to efficacy, the patient was assessed as having had no event, otherwise the patient was assessed as having had an event. Full analysis set (FAS)

End point type

Secondary

End point timeframe

Month 12 post transplant

End point values	TAC+MPA	TAC+Certican	CycA+Certican	Tac+Certican - Tac+MPA - difference between groups at Month 12	CycA+Certican -Tac+MPA - difference between groups
Number of subjects analysed	205	208	199	413	404
Units: Percentage of participants
number (not applicable)
BPAR or graft loss or death	9.8	13	24.6	3.2	14.9
BPAR, graft loss, death, or loss of follow-up	15.6	22.6	32.7	7	17.1

TAC+Certican - TAC+MPA at Month 12

Statistical analysis description

TAC+Certican - TAC+MPA - difference between groups

Comparison groups

TAC+MPA v TAC+Certican

Number of subjects included in analysis

413

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Point estimate

0.032

Confidence interval

level

95%

sides

2-sided

lower limit

-0.029

upper limit

0.093

CycA+Certican -Tac+MPA at Month 12

Statistical analysis description

CycA+Certican -Tac+MPA - difference between groups

Comparison groups

TAC+MPA v CycA+Certican

Number of subjects included in analysis

404

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Point estimate

0.149

Confidence interval

level

95%

sides

2-sided

lower limit

0.076

upper limit

0.221

Secondary: Glomular filtration rate (GFR) via Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method at month 12 post transplant

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End point title

Glomular filtration rate (GFR) via Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method at month 12 post transplant

End point description

Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method = GFR=141 x min(Scr/κ, 1)α x max(Scr/κ, 1)1.209 x 0.993Age x 1.018 [if female] x 1.159 [if black] where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is 0.329 for females and 0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1. last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model

End point type

Secondary

End point timeframe

Month 12 post transplant

End point values	TAC+MPA	TAC+Certican	CycA+Certican
Number of subjects analysed	181	166	158
Units: mL/min per 1.73m²
least squares mean (confidence interval 95%)	51.62 (48.1 to 55.14)	44.42 (40.95 to 47.89)	42.44 (38.89 to 45.99)

No statistical analyses for this end point

Secondary: Glomular filtration rate (GFR) mL/min via Cockcroft- Gault method at month 12 post transplant

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End point title

Glomular filtration rate (GFR) mL/min via Cockcroft- Gault method at month 12 post transplant

End point description

Cockcroft-Gault formula: For men: GFR= ((140-age) × body weight in kg)∕(72 x serum creatinine in mg∕dl)For women: GFR= (0.85×(140-age) × body weight in kg)∕(72 x serum creatinine in mg/dl), ), last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model

End point type

Secondary

End point timeframe

Month 12 post transplant

End point values	TAC+MPA	TAC+Certican	CycA+Certican
Number of subjects analysed	174	162	151
Units: mL/min per 1.73m²
least squares mean (confidence interval 95%)	60.26 (55.85 to 64.68)	52.25 (47.88 to 56.61)	51.3 (46.85 to 55.74)

No statistical analyses for this end point

Secondary: Glomular filtration rate (GFR) via Modification of Diet in Renal Disease (MDRD) method at month 12 post transplant

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End point title

Glomular filtration rate (GFR) via Modification of Diet in Renal Disease (MDRD) method at month 12 post transplant

End point description

Modification of Diet in Renal Disease (MDRD) = For men: GFR = 170 x (serum creatinine -0,999) x (age-0,176) x (urea nitrogen -0,17) x (albumin0,318) For women: GFR = 170 x (serum creatinine -0,999) x (age-0,176) x (urea nitrogen -0,17) x albumin0,318) x 0.762 with urea nitrogen = urea / 2.144. last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model

End point type

Secondary

End point timeframe

Month 12 post transplant

End point values	TAC+MPA	TAC+Certican	CycA+Certican
Number of subjects analysed	172	156	140
Units: mL/min per 1.73m²
least squares mean (confidence interval 95%)	53.24 (49.62 to 56.87)	45.72 (42.11 to 49.32)	43.47 (39.75 to 47.2)

No statistical analyses for this end point

Secondary: Percentage of participants with treatment failure endpoints at month 12

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End point title

Percentage of participants with treatment failure endpoints at month 12

End point description

Treatment failure endpoints: biopsy proven acute rejection (BPAR) defined as a rejection which was acute and proven by biopsy, graft loss (GL) defined as: allograft was presumed to be lost on the day the patient starts dialysis and not able to be removed from dialysis or death. Patients who prematurely discontinued the study: if the patient did not suffer from an event before discontinuation and reason was not related to efficacy, the patient was assessed as having had no event, otherwise the patient was assessed as having had an event. Full analysis set (FAS)

End point type

Secondary

End point timeframe

Month 12 post transplant

End point values	TAC+MPA	TAC+Certican	CycA+Certican
Number of subjects analysed	205	208	199
Units: Percentage of participants
number (not applicable)
Biopsy proven acute rejection (BPAR)	9.3	12	24.6
Treated BPAR (tBPAR)	8.8	11.5	23.6
Graft loss	5.4	6.3	9
Death	4.9	6.3	6.5

TAC+Certican - TAC+MPA at Month 12

Statistical analysis description

BPAR - treatment differences at Month 12

Comparison groups

TAC+MPA v TAC+Certican

Number of subjects included in analysis

413

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001

Method

Pearson’s chi-square test

Parameter type

Log odds ratio

Point estimate

0.028

Confidence interval

level

95%

sides

2-sided

lower limit

-0.032

upper limit

0.087

Secondary: Percent of participants with delayed graft function and slow graft function

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End point title

Percent of participants with delayed graft function and slow graft function

End point description

Delayed graft function (DGF) was defined as the need for dialysis within the first 7 days post-transplantation, excluding the first post-transplantation day. Slow graft function (SGF) was defined as a serum creatinine >3.0 mg/dL at Day 5 post-transplantation. Full analysis set

End point type

Secondary

End point timeframe

Post transplant to month 12

End point values	TAC+MPA	TAC+Certican	CycA+Certican
Number of subjects analysed	205	208	199
Units: Percent of participants
number (not applicable)
Delayed graft function (197,187,172)	17.8	20.3	22.1
Slow graft function (195,187,171)	46.2	48.7	49.7

No statistical analyses for this end point

Secondary: Percent of participants with delayed graft function by day

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End point title

Percent of participants with delayed graft function by day

End point description

Delayed graft function (DGF) was defined as the need for dialysis within the first 7 days post-transplantation, excluding the first post-transplantation day.

End point type

Secondary

End point timeframe

Post transplant up to day 7

End point values	TAC+MPA	TAC+Certican	CycA+Certican
Number of subjects analysed	35	38	38
Units: Percent of participants
number (not applicable)
day 1 (8,7,4)	22.9	18.4	10.5
day 2 (2,2,2)	5.7	5.3	5.3
day 3 (5,1,2)	14.3	2.6	5.3
day 4 (4,2,4)	11.4	5.3	10.5
day 5 (4,5,3)	11.4	13.2	7.9
day 6 (1,1,2)	2.9	2.6	5.3
day 7 (2,4,0)	5.7	10.5	0
>7 days (9,16,21)	25.7	42.1	55.3

No statistical analyses for this end point

Secondary: Percent of participants with viral infections

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End point title

Percent of participants with viral infections

End point description

Viral infections for BKV-Virus (Humane Polyomavirus 1) and Cytomegalovirus (CMV) 

End point type

Secondary

End point timeframe

Post transplant to month 12

End point values	TAC+MPA	TAC+Certican	CycA+Certican
Number of subjects analysed	204	208 ^[4]	198
Units: Percent of participants
number (not applicable)
Viral infections - CMV Missing	1	0	1
Viral infections - CMV Asymptomatic	7	1	1
Viral infections - CMV Mild	5	2	1
Viral infections - CMV Moderate	6	1	1
Viral infections - CMV Severe	1	0	0
Viral infections - BKV Asymptomatic	10	8	5
Viral infections - BKV Mild	5	7	3
Viral infections - BKV Moderate	7	2	1
Viral infections - BKV Severe	0	0	0

Notes
[4] - Number of subjects analyzed is 210: 2 pt rec'd TAC+Cert in error-analyzed w TAC+Cert

No statistical analyses for this end point

Secondary: Percent of participants with wound healing complications during study

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End point title

Percent of participants with wound healing complications during study

End point description

Information collected to report wound healing process which included percentage of participants with complications, fluid collections detected and occurrence of lymphoceles

End point type

Secondary

End point timeframe

Post transplant until individual reporting

End point values	TAC+MPA	TAC+Certican	CycA+Certican
Number of subjects analysed	204	208	198
Units: Percent of participants
number (not applicable)
Wound healing complication	14.3	19.1	22.2
Fluids detected	18.7	26.8	27.8
Occurrence of lymphoceles	11.8	18.2	21.8

No statistical analyses for this end point

Secondary: Duration of wound healing

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End point title

Duration of wound healing

End point description

A wound will be considered healed if all the suture material and staples are removed and the wound is intact. Number of participants is based on all patients of the respective treatment group in the safety set, excluding patients with no answer (unknown).

End point type

Secondary

End point timeframe

Post transplant until individual reporting

End point values	TAC+MPA	TAC+Certican	CycA+Certican
Number of subjects analysed	28	34	38
Units: days
arithmetic mean (standard deviation)	42.4 ( 41.13 )	54.1 ( 61.97 )	85.3 ( 62.7 )

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

19.0

Reporting group title

Tac+MPA

Reporting group description

Tac+MPA

Reporting group title

CycA+Certican

Reporting group description

CycA+Certican

Reporting group title

Tac+Certican

Reporting group description

Tac+Certican

Serious adverse events	Tac+MPA	CycA+Certican	Tac+Certican
Total subjects affected by serious adverse events
subjects affected / exposed	135 / 204 (66.18%)	144 / 198 (72.73%)	161 / 210 (76.67%)
number of deaths (all causes)	4	2	2
number of deaths resulting from adverse events	0	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell unclassifiable lymphoma high grade
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bowen's disease
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac myxoma
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac valve fibroelastoma
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clear cell renal cell carcinoma
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fibroma
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant melanoma
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Marrow hyperplasia
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mucinous adenocarcinoma of appendix
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neuroendocrine tumour
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Parathyroid tumour benign
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	1 / 204 (0.49%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal neoplasm
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cancer
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seminoma
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Arteriosclerosis
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriovenous fistula
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	2 / 204 (0.98%)	3 / 198 (1.52%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	5 / 204 (2.45%)	3 / 198 (1.52%)	9 / 210 (4.29%)
occurrences causally related to treatment / all	0 / 5	1 / 3	2 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	3 / 210 (1.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	3 / 204 (1.47%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphocele
subjects affected / exposed	12 / 204 (5.88%)	24 / 198 (12.12%)	19 / 210 (9.05%)
occurrences causally related to treatment / all	0 / 12	17 / 28	14 / 21
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphoedema
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphorrhoea
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pelvic venous thrombosis
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery aneurysm
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Phlebitis deep
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	0 / 204 (0.00%)	3 / 198 (1.52%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subclavian vein thrombosis
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vena cava thrombosis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Venous thrombosis
subjects affected / exposed	1 / 204 (0.49%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Renal transplant
subjects affected / exposed	4 / 204 (1.96%)	5 / 198 (2.53%)	5 / 210 (2.38%)
occurrences causally related to treatment / all	0 / 4	3 / 5	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Steroid therapy
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transurethral prostatectomy
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular anastomosis
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug intolerance
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperthermia
subjects affected / exposed	1 / 204 (0.49%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	2 / 204 (0.98%)	4 / 198 (2.02%)	5 / 210 (2.38%)
occurrences causally related to treatment / all	0 / 2	4 / 4	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Incarcerated hernia
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inflammation
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 204 (0.00%)	3 / 198 (1.52%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0
Oedema
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 204 (0.00%)	2 / 198 (1.01%)	4 / 210 (1.90%)
occurrences causally related to treatment / all	0 / 0	0 / 2	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral swelling
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic allograft nephropathy
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypersensitivity
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Kidney transplant rejection
subjects affected / exposed	8 / 204 (3.92%)	22 / 198 (11.11%)	19 / 210 (9.05%)
occurrences causally related to treatment / all	0 / 8	5 / 27	3 / 22
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal transplant failure
subjects affected / exposed	8 / 204 (3.92%)	11 / 198 (5.56%)	9 / 210 (4.29%)
occurrences causally related to treatment / all	0 / 9	1 / 12	1 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transplant rejection
subjects affected / exposed	8 / 204 (3.92%)	17 / 198 (8.59%)	5 / 210 (2.38%)
occurrences causally related to treatment / all	0 / 10	5 / 20	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	3 / 204 (1.47%)	3 / 198 (1.52%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endometriosis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pelvic haematoma
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostatitis
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	1 / 204 (0.49%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 3	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemothorax
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laryngeal cyst
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary congestion
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	4 / 204 (1.96%)	5 / 198 (2.53%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 4	0 / 6	1 / 1
deaths causally related to treatment / all	0 / 3	0 / 0	0 / 0
Pulmonary mass
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	3 / 210 (1.43%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 204 (0.00%)	3 / 198 (1.52%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Affective disorder
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Depressive symptom
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Disorientation
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mental disorder
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Product issues
Device leakage
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device occlusion
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	2 / 204 (0.98%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydrocholecystis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Portal vein thrombosis
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Anticoagulation drug level below therapeutic
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood creatine increased
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood creatinine decreased
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood creatinine increased
subjects affected / exposed	11 / 204 (5.39%)	19 / 198 (9.60%)	20 / 210 (9.52%)
occurrences causally related to treatment / all	0 / 11	5 / 22	6 / 22
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
C-reactive protein increased
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac monitoring
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Creatinine renal clearance decreased
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epstein-Barr virus antigen positive
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General physical condition abnormal
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Abdominal wound dehiscence
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anastomotic complication
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arterial injury
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriovenous fistula site complication
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriovenous fistula thrombosis
subjects affected / exposed	1 / 204 (0.49%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Complications of transplanted kidney
subjects affected / exposed	18 / 204 (8.82%)	18 / 198 (9.09%)	22 / 210 (10.48%)
occurrences causally related to treatment / all	0 / 18	3 / 18	4 / 23
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Graft complication
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Graft haemorrhage
subjects affected / exposed	0 / 204 (0.00%)	4 / 198 (2.02%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Graft thrombosis
subjects affected / exposed	1 / 204 (0.49%)	2 / 198 (1.01%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	0 / 204 (0.00%)	3 / 198 (1.52%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	1 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Kidney rupture
subjects affected / exposed	0 / 204 (0.00%)	2 / 198 (1.01%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Perinephric collection
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Perirenal haematoma
subjects affected / exposed	2 / 204 (0.98%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	1 / 204 (0.49%)	3 / 198 (1.52%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural haematuria
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 204 (0.00%)	4 / 198 (2.02%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural urine leak
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seroma
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Shunt aneurysm
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Shunt blood flow excessive
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Shunt occlusion
subjects affected / exposed	2 / 204 (0.98%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Shunt thrombosis
subjects affected / exposed	3 / 204 (1.47%)	0 / 198 (0.00%)	3 / 210 (1.43%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transplant dysfunction
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Traumatic haematoma
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Traumatic haemothorax
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ureteric anastomosis complication
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular graft stenosis
subjects affected / exposed	2 / 204 (0.98%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	3 / 204 (1.47%)	4 / 198 (2.02%)	3 / 210 (1.43%)
occurrences causally related to treatment / all	0 / 4	3 / 4	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound necrosis
subjects affected / exposed	1 / 204 (0.49%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Abdominal wall anomaly
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital cystic kidney disease
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydrocele
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 204 (0.00%)	2 / 198 (1.01%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	2 / 204 (0.98%)	3 / 198 (1.52%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 2	1 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	4 / 204 (1.96%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradyarrhythmia
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	1 / 204 (0.49%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac flutter
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Cardiomyopathy
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiovascular disorder
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intracardiac thrombus
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Long QT syndrome
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mitral valve disease
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Balance disorder
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Monoparesis
subjects affected / exposed	0 / 204 (0.00%)	2 / 198 (1.01%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neuralgia
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Polyneuropathy
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post herpetic neuralgia
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sensory loss
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	1 / 204 (0.49%)	4 / 198 (2.02%)	3 / 210 (1.43%)
occurrences causally related to treatment / all	0 / 1	0 / 4	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemolytic uraemic syndrome
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Histiocytosis haematophagic
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	5 / 204 (2.45%)	2 / 198 (1.01%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 5	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphatic disorder
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrogenic anaemia
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	2 / 204 (0.98%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Splenic lesion
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Sudden hearing loss
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertigo
subjects affected / exposed	1 / 204 (0.49%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Eyelid oedema
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retinal detachment
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal hernia
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal wall haematoma
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anal sphincter atony
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis microscopic
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticular perforation
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 204 (0.49%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hernial eventration
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intra-abdominal haematoma
subjects affected / exposed	1 / 204 (0.49%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Localised intraabdominal fluid collection
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 204 (0.98%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophageal ulcer
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritoneal haemorrhage
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumoperitoneum
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retroperitoneal haematoma
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retroperitoneal haemorrhage
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 204 (0.00%)	2 / 198 (1.01%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Volvulus
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Actinic keratosis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angioedema
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin lesion
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stasis dermatitis
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	9 / 204 (4.41%)	7 / 198 (3.54%)	12 / 210 (5.71%)
occurrences causally related to treatment / all	0 / 10	2 / 9	3 / 13
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder pain
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder tamponade
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysuria
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Focal segmental glomerulosclerosis
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Glomerulonephritis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	2 / 204 (0.98%)	0 / 198 (0.00%)	4 / 210 (1.90%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Micturition disorder
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrocalcinosis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Obstructive uropathy
subjects affected / exposed	0 / 204 (0.00%)	3 / 198 (1.52%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postrenal failure
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Proteinuria
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	5 / 210 (2.38%)
occurrences causally related to treatment / all	0 / 0	1 / 1	3 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal artery dissection
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal artery stenosis
subjects affected / exposed	4 / 204 (1.96%)	2 / 198 (1.01%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 4	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cyst
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cyst haemorrhage
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 204 (0.49%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal haematoma
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal haemorrhage
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	2 / 204 (0.98%)	4 / 198 (2.02%)	8 / 210 (3.81%)
occurrences causally related to treatment / all	0 / 2	0 / 4	1 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal infarct
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal tubular disorder
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal tubular necrosis
subjects affected / exposed	0 / 204 (0.00%)	2 / 198 (1.01%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ureteral necrosis
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ureteric stenosis
subjects affected / exposed	1 / 204 (0.49%)	1 / 198 (0.51%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	2 / 204 (0.98%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary fistula
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	3 / 204 (1.47%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	1 / 204 (0.49%)	2 / 198 (1.01%)	5 / 210 (2.38%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinoma
subjects affected / exposed	1 / 204 (0.49%)	2 / 198 (1.01%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vesicoureteric reflux
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hyperparathyroidism
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Parathyroid gland enlargement
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypercreatinaemia
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscle haemorrhage
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal abscess
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aspergillus infection
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BK virus infection
subjects affected / exposed	3 / 204 (1.47%)	1 / 198 (0.51%)	3 / 210 (1.43%)
occurrences causally related to treatment / all	0 / 3	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacterial pyelonephritis
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	2 / 204 (0.98%)	2 / 198 (1.01%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Corona virus infection
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cryptosporidiosis infection
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cytomegalovirus colitis
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cytomegalovirus infection
subjects affected / exposed	11 / 204 (5.39%)	2 / 198 (1.01%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 13	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea infectious
subjects affected / exposed	4 / 204 (1.96%)	6 / 198 (3.03%)	6 / 210 (2.86%)
occurrences causally related to treatment / all	0 / 4	1 / 6	4 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterococcal infection
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterocolitis viral
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epididymitis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epstein-Barr virus infection
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	1 / 204 (0.49%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia infection
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	2 / 204 (0.98%)	2 / 198 (1.01%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 2	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	2 / 204 (0.98%)	3 / 198 (1.52%)	5 / 210 (2.38%)
occurrences causally related to treatment / all	0 / 2	1 / 3	4 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Graft infection
subjects affected / exposed	1 / 204 (0.49%)	1 / 198 (0.51%)	4 / 210 (1.90%)
occurrences causally related to treatment / all	0 / 1	2 / 2	3 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemophilus infection
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes simplex
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	2 / 204 (0.98%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infected lymphocele
subjects affected / exposed	1 / 204 (0.49%)	3 / 198 (1.52%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 1	3 / 3	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	2 / 204 (0.98%)	5 / 198 (2.53%)	5 / 210 (2.38%)
occurrences causally related to treatment / all	0 / 2	2 / 5	3 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	3 / 210 (1.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Kidney infection
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Klebsiella infection
subjects affected / exposed	0 / 204 (0.00%)	2 / 198 (1.01%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	2 / 204 (0.98%)	1 / 198 (0.51%)	3 / 210 (1.43%)
occurrences causally related to treatment / all	0 / 2	1 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mastitis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocarditis infectious
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Orchitis
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	1 / 204 (0.49%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	4 / 204 (1.96%)	8 / 198 (4.04%)	10 / 210 (4.76%)
occurrences causally related to treatment / all	0 / 4	6 / 8	6 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia fungal
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia legionella
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Polyomavirus-associated nephropathy
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	0 / 204 (0.00%)	2 / 198 (1.01%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	10 / 204 (4.90%)	8 / 198 (4.04%)	9 / 210 (4.29%)
occurrences causally related to treatment / all	0 / 12	7 / 12	6 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	5 / 210 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal abscess
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cyst infection
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 204 (0.49%)	1 / 198 (0.51%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rotavirus infection
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	5 / 210 (2.38%)
occurrences causally related to treatment / all	0 / 0	0 / 1	4 / 5
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Septic shock
subjects affected / exposed	2 / 204 (0.98%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Shunt infection
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ureteritis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	21 / 204 (10.29%)	16 / 198 (8.08%)	27 / 210 (12.86%)
occurrences causally related to treatment / all	0 / 27	9 / 24	16 / 38
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	9 / 204 (4.41%)	7 / 198 (3.54%)	6 / 210 (2.86%)
occurrences causally related to treatment / all	0 / 10	4 / 7	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Varicella zoster virus infection
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	2 / 204 (0.98%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Acidosis
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	2 / 204 (0.98%)	3 / 198 (1.52%)	3 / 210 (1.43%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	3 / 204 (1.47%)	4 / 198 (2.02%)	5 / 210 (2.38%)
occurrences causally related to treatment / all	0 / 3	0 / 4	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 204 (0.00%)	1 / 198 (0.51%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	5 / 204 (2.45%)	1 / 198 (0.51%)	3 / 210 (1.43%)
occurrences causally related to treatment / all	0 / 5	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	2 / 210 (0.95%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	0 / 210 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	3 / 210 (1.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypophosphataemia
subjects affected / exposed	1 / 204 (0.49%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 204 (0.00%)	0 / 198 (0.00%)	1 / 210 (0.48%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Tac+MPA	CycA+Certican	Tac+Certican
Total subjects affected by non serious adverse events
subjects affected / exposed	200 / 204 (98.04%)	196 / 198 (98.99%)	205 / 210 (97.62%)
Vascular disorders
Haematoma
subjects affected / exposed	10 / 204 (4.90%)	17 / 198 (8.59%)	16 / 210 (7.62%)
occurrences all number	10	19	17
Hypertension
subjects affected / exposed	52 / 204 (25.49%)	57 / 198 (28.79%)	62 / 210 (29.52%)
occurrences all number	61	65	78
Hypotension
subjects affected / exposed	13 / 204 (6.37%)	16 / 198 (8.08%)	11 / 210 (5.24%)
occurrences all number	14	16	13
Lymphocele
subjects affected / exposed	20 / 204 (9.80%)	31 / 198 (15.66%)	22 / 210 (10.48%)
occurrences all number	20	31	23
Surgical and medical procedures
Renal transplant
subjects affected / exposed	8 / 204 (3.92%)	17 / 198 (8.59%)	9 / 210 (4.29%)
occurrences all number	8	19	12
General disorders and administration site conditions
Impaired healing
subjects affected / exposed	5 / 204 (2.45%)	15 / 198 (7.58%)	13 / 210 (6.19%)
occurrences all number	5	15	13
Oedema
subjects affected / exposed	11 / 204 (5.39%)	8 / 198 (4.04%)	9 / 210 (4.29%)
occurrences all number	12	9	11
Oedema peripheral
subjects affected / exposed	62 / 204 (30.39%)	99 / 198 (50.00%)	82 / 210 (39.05%)
occurrences all number	77	117	103
Immune system disorders
Kidney transplant rejection
subjects affected / exposed	8 / 204 (3.92%)	14 / 198 (7.07%)	9 / 210 (4.29%)
occurrences all number	8	18	9
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	11 / 204 (5.39%)	14 / 198 (7.07%)	15 / 210 (7.14%)
occurrences all number	13	14	17
Dyspnoea
subjects affected / exposed	21 / 204 (10.29%)	19 / 198 (9.60%)	22 / 210 (10.48%)
occurrences all number	23	24	24
Psychiatric disorders
Anxiety
subjects affected / exposed	8 / 204 (3.92%)	9 / 198 (4.55%)	15 / 210 (7.14%)
occurrences all number	8	10	16
Insomnia
subjects affected / exposed	41 / 204 (20.10%)	24 / 198 (12.12%)	39 / 210 (18.57%)
occurrences all number	44	25	40
Sleep disorder
subjects affected / exposed	22 / 204 (10.78%)	22 / 198 (11.11%)	21 / 210 (10.00%)
occurrences all number	26	31	23
Investigations
Blood creatinine increased
subjects affected / exposed	25 / 204 (12.25%)	26 / 198 (13.13%)	27 / 210 (12.86%)
occurrences all number	28	31	29
Blood glucose increased
subjects affected / exposed	6 / 204 (2.94%)	8 / 198 (4.04%)	15 / 210 (7.14%)
occurrences all number	6	8	16
C-reactive protein increased
subjects affected / exposed	9 / 204 (4.41%)	13 / 198 (6.57%)	15 / 210 (7.14%)
occurrences all number	9	14	19
Haemoglobin decreased
subjects affected / exposed	9 / 204 (4.41%)	9 / 198 (4.55%)	11 / 210 (5.24%)
occurrences all number	9	11	12
Injury, poisoning and procedural complications
Complications of transplanted kidney
subjects affected / exposed	28 / 204 (13.73%)	43 / 198 (21.72%)	36 / 210 (17.14%)
occurrences all number	28	47	37
Procedural pain
subjects affected / exposed	26 / 204 (12.75%)	21 / 198 (10.61%)	25 / 210 (11.90%)
occurrences all number	30	21	26
Wound complication
subjects affected / exposed	68 / 204 (33.33%)	56 / 198 (28.28%)	64 / 210 (30.48%)
occurrences all number	76	63	75
Cardiac disorders
Tachycardia
subjects affected / exposed	14 / 204 (6.86%)	10 / 198 (5.05%)	10 / 210 (4.76%)
occurrences all number	14	13	10
Nervous system disorders
Headache
subjects affected / exposed	15 / 204 (7.35%)	15 / 198 (7.58%)	25 / 210 (11.90%)
occurrences all number	15	18	30
Tremor
subjects affected / exposed	30 / 204 (14.71%)	9 / 198 (4.55%)	22 / 210 (10.48%)
occurrences all number	30	9	22
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	44 / 204 (21.57%)	58 / 198 (29.29%)	53 / 210 (25.24%)
occurrences all number	48	66	58
Leukopenia
subjects affected / exposed	34 / 204 (16.67%)	11 / 198 (5.56%)	17 / 210 (8.10%)
occurrences all number	35	11	20
Thrombocytopenia
subjects affected / exposed	8 / 204 (3.92%)	20 / 198 (10.10%)	20 / 210 (9.52%)
occurrences all number	8	20	22
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	16 / 204 (7.84%)	18 / 198 (9.09%)	18 / 210 (8.57%)
occurrences all number	17	19	20
Abdominal pain upper
subjects affected / exposed	14 / 204 (6.86%)	12 / 198 (6.06%)	19 / 210 (9.05%)
occurrences all number	16	14	22
Constipation
subjects affected / exposed	71 / 204 (34.80%)	81 / 198 (40.91%)	69 / 210 (32.86%)
occurrences all number	76	88	82
Diarrhoea
subjects affected / exposed	19 / 204 (9.31%)	6 / 198 (3.03%)	17 / 210 (8.10%)
occurrences all number	20	8	20
Dyspepsia
subjects affected / exposed	14 / 204 (6.86%)	9 / 198 (4.55%)	17 / 210 (8.10%)
occurrences all number	15	9	18
Flatulence
subjects affected / exposed	24 / 204 (11.76%)	25 / 198 (12.63%)	35 / 210 (16.67%)
occurrences all number	30	26	36
Nausea
subjects affected / exposed	46 / 204 (22.55%)	42 / 198 (21.21%)	44 / 210 (20.95%)
occurrences all number	55	49	49
Vomiting
subjects affected / exposed	27 / 204 (13.24%)	22 / 198 (11.11%)	22 / 210 (10.48%)
occurrences all number	31	23	23
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	3 / 204 (1.47%)	4 / 198 (2.02%)	11 / 210 (5.24%)
occurrences all number	3	4	12
Renal and urinary disorders
Dysuria
subjects affected / exposed	14 / 204 (6.86%)	14 / 198 (7.07%)	14 / 210 (6.67%)
occurrences all number	15	14	15
Haematuria
subjects affected / exposed	14 / 204 (6.86%)	13 / 198 (6.57%)	19 / 210 (9.05%)
occurrences all number	15	13	19
Leukocyturia
subjects affected / exposed	14 / 204 (6.86%)	8 / 198 (4.04%)	13 / 210 (6.19%)
occurrences all number	19	9	15
Nocturia
subjects affected / exposed	12 / 204 (5.88%)	14 / 198 (7.07%)	11 / 210 (5.24%)
occurrences all number	12	14	12
Pollakiuria
subjects affected / exposed	9 / 204 (4.41%)	9 / 198 (4.55%)	11 / 210 (5.24%)
occurrences all number	9	9	11
Proteinuria
subjects affected / exposed	24 / 204 (11.76%)	30 / 198 (15.15%)	26 / 210 (12.38%)
occurrences all number	24	31	26
Renal impairment
subjects affected / exposed	15 / 204 (7.35%)	8 / 198 (4.04%)	13 / 210 (6.19%)
occurrences all number	15	12	13
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	4 / 204 (1.96%)	11 / 198 (5.56%)	7 / 210 (3.33%)
occurrences all number	4	12	9
Back pain
subjects affected / exposed	17 / 204 (8.33%)	10 / 198 (5.05%)	16 / 210 (7.62%)
occurrences all number	17	13	17
Muscle spasms
subjects affected / exposed	9 / 204 (4.41%)	7 / 198 (3.54%)	11 / 210 (5.24%)
occurrences all number	9	7	12
Infections and infestations
BK virus infection
subjects affected / exposed	45 / 204 (22.06%)	18 / 198 (9.09%)	36 / 210 (17.14%)
occurrences all number	53	18	41
Bronchitis
subjects affected / exposed	13 / 204 (6.37%)	4 / 198 (2.02%)	5 / 210 (2.38%)
occurrences all number	18	4	5
Cytomegalovirus infection
subjects affected / exposed	33 / 204 (16.18%)	3 / 198 (1.52%)	11 / 210 (5.24%)
occurrences all number	40	3	11
Diarrhoea infectious
subjects affected / exposed	56 / 204 (27.45%)	29 / 198 (14.65%)	40 / 210 (19.05%)
occurrences all number	69	35	47
Nasopharyngitis
subjects affected / exposed	29 / 204 (14.22%)	21 / 198 (10.61%)	31 / 210 (14.76%)
occurrences all number	34	24	39
Urinary tract infection
subjects affected / exposed	81 / 204 (39.71%)	72 / 198 (36.36%)	74 / 210 (35.24%)
occurrences all number	135	119	140
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	24 / 204 (11.76%)	24 / 198 (12.12%)	33 / 210 (15.71%)
occurrences all number	25	24	34
Dyslipidaemia
subjects affected / exposed	2 / 204 (0.98%)	7 / 198 (3.54%)	11 / 210 (5.24%)
occurrences all number	2	7	12
Fluid overload
subjects affected / exposed	7 / 204 (3.43%)	13 / 198 (6.57%)	7 / 210 (3.33%)
occurrences all number	11	13	7
Hypercalcaemia
subjects affected / exposed	16 / 204 (7.84%)	13 / 198 (6.57%)	16 / 210 (7.62%)
occurrences all number	16	13	16
Hypercholesterolaemia
subjects affected / exposed	5 / 204 (2.45%)	17 / 198 (8.59%)	16 / 210 (7.62%)
occurrences all number	5	17	16
Hyperglycaemia
subjects affected / exposed	12 / 204 (5.88%)	25 / 198 (12.63%)	20 / 210 (9.52%)
occurrences all number	14	26	20
Hyperkalaemia
subjects affected / exposed	65 / 204 (31.86%)	58 / 198 (29.29%)	53 / 210 (25.24%)
occurrences all number	79	71	57
Hyperlipidaemia
subjects affected / exposed	8 / 204 (3.92%)	23 / 198 (11.62%)	13 / 210 (6.19%)
occurrences all number	8	23	13
Hyperphosphataemia
subjects affected / exposed	5 / 204 (2.45%)	12 / 198 (6.06%)	7 / 210 (3.33%)
occurrences all number	6	12	7
Hypertriglyceridaemia
subjects affected / exposed	3 / 204 (1.47%)	10 / 198 (5.05%)	13 / 210 (6.19%)
occurrences all number	3	11	13
Hyperuricaemia
subjects affected / exposed	20 / 204 (9.80%)	14 / 198 (7.07%)	10 / 210 (4.76%)
occurrences all number	20	14	10
Hypocalcaemia
subjects affected / exposed	20 / 204 (9.80%)	17 / 198 (8.59%)	27 / 210 (12.86%)
occurrences all number	21	17	29
Hypokalaemia
subjects affected / exposed	33 / 204 (16.18%)	41 / 198 (20.71%)	37 / 210 (17.62%)
occurrences all number	37	47	42
Hypophosphataemia
subjects affected / exposed	23 / 204 (11.27%)	30 / 198 (15.15%)	36 / 210 (17.14%)
occurrences all number	25	30	37
Iron deficiency
subjects affected / exposed	6 / 204 (2.94%)	10 / 198 (5.05%)	8 / 210 (3.81%)
occurrences all number	6	10	9
Metabolic acidosis
subjects affected / exposed	24 / 204 (11.76%)	21 / 198 (10.61%)	25 / 210 (11.90%)
occurrences all number	25	22	27
Vitamin D deficiency
subjects affected / exposed	21 / 204 (10.29%)	14 / 198 (7.07%)	20 / 210 (9.52%)
occurrences all number	21	14	20

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Were there any global substantial amendments to the protocol? Yes

08 Apr 2013

Amendment was to optimize patient safety and to enhance study performance and feasibility. Patient safety was optimized by limiting the risk of overexposure to Certican by change of starting dose. The Starting Dose was changed to 1.5 mg/day (2x 0.75mg).

13 Aug 2013

Amendment addresses exclusion criteria and visit assessments to be performed, enhances feasibility and patient safety. Exclusion criteria were changed in accordance to the informed consent and to add the term “total abstinence” to highly effective contraception methods. Further changes of the protocol comprised prevention of second blood drawings at baseline (not necessary), therefore enhanced safety for the patients

14 Jul 2014

Amendment was issued to update the investigator´s brochure. According to the investigator´s brochure contraception of 8 weeks after end of treatment was necessary as there was no data available that support a shorter time period. Informed consent was adapted according to these changes. In addition a higher recommended starting dose was recommended for patients receiving a combination of tacrolimus and Certican, due to different pharmacokinetics and to reach target everolimus trough level accurately timed

02 Feb 2015

Amendment was issued in response to German Health Authority’s request. The protocol was modified to implement most recent notifications for use of MPA based on the dear health care professional letter (DHCPL) that was sent out for CellCept by Roche 12-Dec-2014. In detail the study medication stopping rules were adopted to clearly follow the recommendations given in the DHCPL.

12 Jan 2016

Amendment 5 (12-Jan-2016) was issued in response to German Health Authority’s request, the protocol was modified to implement most recent notifications for use of MPA based on the dear health care professional letter (DHCPL) that was sent out for CellCept by Roche 10-Nov-2015

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:
12 month, multi-center, open-label, prospective, randomized, parallel group study investigating a standard regimen in de novo kidney transplant patients versus a Certican® based regimen either in combination with Cyclosporin A or Tacrolimus

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Glomular filtration rate (GFR) mL/min via Nankivell method at Month 12 - Standard Regimen vs Certican regimens

Primary: Glomular filtration rate (GFR) mL/min via Nankivell method at Month 12 - Standard Regimen vs Certican regimens

Secondary: Percentage of participants with composite treatment failure endpoints - difference between groups at month 12

Secondary: Percentage of participants with composite treatment failure endpoints - difference between groups at month 12

Secondary: Glomular filtration rate (GFR) via Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method at month 12 post transplant

Secondary: Glomular filtration rate (GFR) via Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method at month 12 post transplant

Secondary: Glomular filtration rate (GFR) mL/min via Cockcroft- Gault method at month 12 post transplant

Secondary: Glomular filtration rate (GFR) mL/min via Cockcroft- Gault method at month 12 post transplant

Secondary: Glomular filtration rate (GFR) via Modification of Diet in Renal Disease (MDRD) method at month 12 post transplant

Secondary: Glomular filtration rate (GFR) via Modification of Diet in Renal Disease (MDRD) method at month 12 post transplant

Secondary: Percentage of participants with treatment failure endpoints at month 12

Secondary: Percentage of participants with treatment failure endpoints at month 12

Secondary: Percent of participants with delayed graft function and slow graft function

Secondary: Percent of participants with delayed graft function and slow graft function

Secondary: Percent of participants with delayed graft function by day

Secondary: Percent of participants with delayed graft function by day

Secondary: Percent of participants with viral infections

Secondary: Percent of participants with viral infections

Secondary: Percent of participants with wound healing complications during study

Secondary: Percent of participants with wound healing complications during study

Secondary: Duration of wound healing

Secondary: Duration of wound healing

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Italy
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Outside EU/EEA

Clinical trials

Clinical Trial Results: 12 month, multi-center, open-label, prospective, randomized, parallel group study investigating a standard regimen in de novo kidney transplant patients versus a Certican® based regimen either in combination with Cyclosporin A or Tacrolimus

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Glomular filtration rate (GFR) mL/min via Nankivell method at Month 12 - Standard Regimen vs Certican regimens

Primary: Glomular filtration rate (GFR) mL/min via Nankivell method at Month 12 - Standard Regimen vs Certican regimens

Secondary: Percentage of participants with composite treatment failure endpoints - difference between groups at month 12

Secondary: Percentage of participants with composite treatment failure endpoints - difference between groups at month 12

Secondary: Glomular filtration rate (GFR) via Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method at month 12 post transplant

Secondary: Glomular filtration rate (GFR) via Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) method at month 12 post transplant

Secondary: Glomular filtration rate (GFR) mL/min via Cockcroft- Gault method at month 12 post transplant

Secondary: Glomular filtration rate (GFR) mL/min via Cockcroft- Gault method at month 12 post transplant

Secondary: Glomular filtration rate (GFR) via Modification of Diet in Renal Disease (MDRD) method at month 12 post transplant

Secondary: Glomular filtration rate (GFR) via Modification of Diet in Renal Disease (MDRD) method at month 12 post transplant

Secondary: Percentage of participants with treatment failure endpoints at month 12

Secondary: Percentage of participants with treatment failure endpoints at month 12

Secondary: Percent of participants with delayed graft function and slow graft function

Secondary: Percent of participants with delayed graft function and slow graft function

Secondary: Percent of participants with delayed graft function by day

Secondary: Percent of participants with delayed graft function by day

Secondary: Percent of participants with viral infections

Secondary: Percent of participants with viral infections

Secondary: Percent of participants with wound healing complications during study

Secondary: Percent of participants with wound healing complications during study

Secondary: Duration of wound healing

Secondary: Duration of wound healing

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
12 month, multi-center, open-label, prospective, randomized, parallel group study investigating a standard regimen in de novo kidney transplant patients versus a Certican® based regimen either in combination with Cyclosporin A or Tacrolimus