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Clinical Trial Results:
An Open-Label, Prospective, Randomized, Controlled, Multi-Center Study Assessing Fixed Dose Versus Concentration Controlled Cellcept® Regimens for Patients Following a Single Organ Renal Transplantation in Combination With Full Dose and Reduced Dose Calcineurin Inhibitors

Summary
EudraCT number	2016-001043-39
Trial protocol	Outside EU/EEA
Global end of trial date	22 Sep 2007

Results information
Results version number	v1(current)
This version publication date	01 Jan 2017
First version publication date	01 Jan 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

ML17225

ISRCTN number

US NCT number

NCT00087581

WHO universal trial number (UTN)

Sponsor organisation name

F. Hoffmann-La Roche AG

Sponsor organisation address

Grenzacherstrasse 124, Basel, Switzerland, CH-4070

Public contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com

Scientific contact

Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

25 Mar 2008

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

22 Sep 2007

Was the trial ended prematurely?

Main objective of the trial

The primary objectives of the study were to compare the efficacy at 12 months post-transplant and the effects on renal function of a regimen of reduced concentration of calcineurin inhibitor (CNI), either cyclosporine or tacrolimus, and monitored mycophenolate mofetil (MMF/CellCept) to a regimen of standard concentrations of CNI and fixed-dose MMF.

Protection of trial subjects

The investigators have ensured that this study was conducted in full conformance with the principles of the “Declaration of Helsinki” or with the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. The study has fully adhered to the principles outlined in “Guideline for Good Clinical Practice” International Council for Harmonisation Tripartite Guideline (January 1997) or with local law if it afforded greater protection to the participant. The investigators have additionally ensured that the basic principles of “Good Clinical Practice” as outlined in the current version of 21 Code of Federal Regulations, subchapter D, part 312, “Responsibilities of Sponsors and Investigators”; part 50, “Protection of Human Subjects”; and part 56, “Institutional Review Boards” were adhered to.

Background therapy

Evidence for comparator

Actual start date of recruitment

28 Jun 2004

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 720

Worldwide total number of subjects

720

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

635

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Screening details

Participants were screened for study participation starting 1 week prior through 24 hours following the transplantation procedure and were then randomized to one of the three treatment regimens (Group A, B, or C) in a 1:1:1 ratio within 24 hours after transplantation. Randomization was to be balanced within each center.

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

Group A: Monitored MMF + Reduced CNI

Arm description

Group A received concentration-controlled/monitored MMF with an oral CNI, either cyclosporine or tacrolimus, at reduced blood concentration. The initial dose of MMF was at least 1 gram twice a day (BID) in adults and 600 milligrams per meter-squared (mg/m^2) in pediatrics. Subsequent doses were adjusted to maintain blood mycophenolic acid (MPA) levels greater than or equal to (≥) 1.3 micrograms per milliliter (μg/mL) with cyclosporine or ≥1.9 μg/mL with tacrolimus, not to exceed 4 grams total per day. The selected CNI was dosed to maintain reduced blood concentrations. Cyclosporine target concentrations were as follows: Days 1–30, 250–325 nanograms per milliliter (ng/mL); Days 30–90, 125–165 ng/mL; Days 90 through end of study, 95–145 ng/mL. Tacrolimus target concentrations were as follows: Days 1–30, 8–12 ng/mL; Days 30–90, 4–6 ng/mL; Days 90 through end of study, 3–5 ng/mL.

Arm type

Experimental

Investigational medicinal product name

Mycophenolate mofetil

Investigational medicinal product code

Other name

CellCept®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

The initial dose was at least 1 gram BID in adults and 600 mg/m^2 in pediatrics. In Groups A and B, subsequent doses were adjusted to maintain blood MPA levels ≥1.3 μg/mL with cyclosporine or ≥1.9 μg/mL with tacrolimus. In Group C, subsequent doses were not to be adjusted, except in the case of unacceptable toxicity.

Investigational medicinal product name

Tacrolimus

Investigational medicinal product code

Other name

Prograf®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Tacrolimus was given as 1-mg and 5-mg capsules and dosed to maintain either reduced (Group A) or standard/full (Groups B and C) blood concentrations. Tacrolimus target concentrations were as follows: Days 1–30, 8–12 ng/mL; Days 30–90, 4–6 ng/mL (reduced), 8–10 ng/mL (full); Days 90 through end of study, 3–5 ng/mL (reduced), 6–8 ng/mL (full).

Investigational medicinal product name

Cyclosporine

Investigational medicinal product code

Other name

Neoral®

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Cyclosporine was given as 100-mg soft gelatin capsules and dosed to maintain either reduced (Group A) or standard/full (Groups B and C) blood concentrations. Cyclosporine target concentrations were as follows: Days 1–30, 250–325 ng/mL; Days 30–90, 125–165 ng/mL (reduced) or 250–270 ng/mL (full); Days 90 through end of study, 95–145 ng/mL (reduced) or 190–220 ng/mL (full).

Group B: Monitored MMF + Full CNI

Arm description

Group B received concentration-controlled/monitored MMF with an oral CNI, either cyclosporine or tacrolimus, at a standard/full blood concentration. The initial dose of MMF was at least 1 gram BID in adults and 600 mg/m^2 in pediatrics. Subsequent doses were adjusted to maintain blood MPA levels ≥1.3 μg/mL with cyclosporine or ≥1.9 μg/mL with tacrolimus, not to exceed 4 grams total per day. The selected CNI was dosed to maintain standard/full blood concentrations. Cyclosporine target concentrations were as follows: Days 1–30, 250–325 ng/mL; Days 30–90, 250–270 ng/mL; Days 90 through end of study, 190–220 ng/mL. Tacrolimus target concentrations were as follows: Days 1–30, 8–12 ng/mL; Days 30–90, 8–10 ng/mL; Days 90 through end of study, 6–8 ng/mL.

Arm type

Experimental

Investigational medicinal product name

Mycophenolate mofetil

Investigational medicinal product code

Other name

CellCept®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Tacrolimus

Investigational medicinal product code

Other name

Prograf®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Cyclosporine

Investigational medicinal product code

Other name

Neoral®

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Group C: Fixed MMF + Full CNI

Arm description

Group C received fixed-dose MMF with an oral CNI, either cyclosporine or tacrolimus, at a standard/full blood concentration. The dose of MMF was at least 1 gram BID in adults and 600 mg/m^2 in pediatrics, not to exceed 4 grams total per day. Subsequent doses were not to be adjusted, except in the case of unacceptable toxicity. The selected CNI was dosed to maintain standard/full blood concentrations. Cyclosporine target concentrations were as follows: Days 1–30, 250–325 ng/mL; Days 30–90, 250–270 ng/mL; Days 90 through end of study, 190–220 ng/mL. Tacrolimus target concentrations were as follows: Days 1–30, 8–12 ng/mL; Days 30–90, 8–10 ng/mL; Days 90 through end of study, 6–8 ng/mL.

Arm type

Experimental

Investigational medicinal product name

Mycophenolate mofetil

Investigational medicinal product code

Other name

CellCept®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Tacrolimus

Investigational medicinal product code

Other name

Prograf®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Cyclosporine

Investigational medicinal product code

Other name

Neoral®

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1	Group A: Monitored MMF + Reduced CNI	Group B: Monitored MMF + Full CNI	Group C: Fixed MMF + Full CNI
Started	243	237	240
Completed Treatment	180	150	153
Completed 24-Month Follow-Up	20	36	41
Completed	20	36	41
Not completed	223	201	199
Consent withdrawn by subject	18	24	15
Death	10	7	8
Refused treatment	3	-	4
Unspecified	144	117	131
Lost to follow-up	21	31	29
Administrative reason/other	24	17	12
Adverse event or intercurrent illness	3	5	-

Baseline characteristics

Top of page

Reporting group title

Group A: Monitored MMF + Reduced CNI

Reporting group description

Reporting group title

Group B: Monitored MMF + Full CNI

Reporting group description

Reporting group title

Group C: Fixed MMF + Full CNI

Reporting group description

Reporting group values	Group A: Monitored MMF + Reduced CNI	Group B: Monitored MMF + Full CNI	Group C: Fixed MMF + Full CNI	Total
Number of subjects	243	237	240	720
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	48.3 ( 12.8 )	48.8 ( 13.55 )	49.6 ( 13.2 )	-
Gender categorical
Units: Subjects
Female	80	78	77	235
Male	163	159	163	485

End points

Top of page

Reporting group title

Group A: Monitored MMF + Reduced CNI

Reporting group description

Reporting group title

Group B: Monitored MMF + Full CNI

Reporting group description

Reporting group title

Group C: Fixed MMF + Full CNI

Reporting group description

Primary: Percentage of Participants with Treatment Failure During 12 Months Post-Transplantation

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End point title

Percentage of Participants with Treatment Failure During 12 Months Post-Transplantation

End point description

Treatment failure was defined as any one event of biopsy-proven acute rejection (BPAR), graft loss (characterized as initiation of chronic dialysis, transplant nephrectomy, re-transplantation, or death with functioning graft), death, or loss to follow-up. BPAR was defined as oral temperature greater than (>) 100 degrees Fahrenheit, graft swelling/tenderness, serum creatinine rise >0.3 milligrams per deciliter (mg/dL), rising blood pressure, oliguria, reduced renal flow, and ultrasound findings consistent with rejection, in addition to histologic findings of tubular invasion obtained from renal allograft biopsy. The percentage of participants who experienced treatment failure at any time during the first 12 months post-transplantation was reported. The 95 percent (%) confidence interval (CI) was calculated using the exact method. Intent-to-Treat (ITT) Population: All participants randomized into the study.

End point type

Primary

End point timeframe

Month 12

End point values	Group A: Monitored MMF + Reduced CNI	Group B: Monitored MMF + Full CNI	Group C: Fixed MMF + Full CNI
Number of subjects analysed	243	237	240
Units: percentage of participants
number (confidence interval 95%)	22.6 (17.5 to 28.4)	28.3 (22.6 to 34.5)	27.9 (22.3 to 34.1)

Difference at 12 Months (Group A vs Group C)

Statistical analysis description

Analysis stratified by CNI type. Non-inferiority was determined on the basis of the upper limit of the 90% CI. The regimen administered to Group A was considered statistically non-inferior to the regimen in Group C if the upper limit of the CI was less than (<) 10.

Comparison groups

Group C: Fixed MMF + Full CNI v Group A: Monitored MMF + Reduced CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

non-inferiority

P-value

= 0.1825

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-5.3

Confidence interval

level

90%

sides

2-sided

lower limit

-11.8

upper limit

1.3

Primary: Percent Change from Baseline in Calculated Glomerular Filtration Rate (GFR) at 12 Months Post-Transplantation

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End point title

Percent Change from Baseline in Calculated Glomerular Filtration Rate (GFR) at 12 Months Post-Transplantation

End point description

GFR was calculated using the Nankivell equation: [6.7 divided by (÷) serum creatinine in millimoles per liter (mmol/L)] plus (+) [body weight in kilograms ÷ 4] + [serum urea in mmol/L ÷ 2] + [100 ÷ height in meters] + a value of 35 for males or 25 for females. The percent change in GFR from Baseline to Month 12 was calculated as [GFR at Month 12 minus (–) GFR at Baseline] divided by GFR at Baseline, multiplied by 100. The result was averaged among all participants. ITT Population.

End point type

Primary

End point timeframe

Baseline to Month 12

End point values	Group A: Monitored MMF + Reduced CNI	Group B: Monitored MMF + Full CNI	Group C: Fixed MMF + Full CNI
Number of subjects analysed	243	237	240
Units: percent change
arithmetic mean (standard deviation)	12.3 ( 47.43 )	5.4 ( 30.65 )	8.2 ( 35.88 )

Difference at 12 Months (Group A vs Group C)

Statistical analysis description

Analysis performed with terms for treatment and CNI type as factors.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3469

Method

ANOVA

Parameter type

Difference in least squares means

Point estimate

4.1

Confidence interval

level

95%

sides

2-sided

lower limit

-4.46

upper limit

12.66

Difference at 12 Months (Group A vs Group B)

Statistical analysis description

Analysis performed with terms for treatment and CNI type as factors.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1077

Method

ANOVA

Parameter type

Difference in least squares means

Point estimate

6.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1.48

upper limit

14.95

Secondary: Percentage of Participants with Treatment Failure During 6 and 20-24 Months Post-Transplantation

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End point title

Percentage of Participants with Treatment Failure During 6 and 20-24 Months Post-Transplantation

End point description

Treatment failure was defined as any one event of BPAR, graft loss (characterized as initiation of chronic dialysis, transplant nephrectomy, re-transplantation, or death with functioning graft), death, or loss to follow-up. BPAR was defined as oral temperature >100 degrees Fahrenheit, graft swelling/tenderness, serum creatinine rise >0.3 mg/dL, rising blood pressure, oliguria, reduced renal flow, and ultrasound findings consistent with rejection, in addition to histologic findings of tubular invasion obtained from renal allograft biopsy. The percentage of participants who experienced treatment failure at any time during the first 6 and 20-24 months post-transplantation was reported. ITT Population.

End point type

Secondary

End point timeframe

Months 6, 20-24

End point values	Group A: Monitored MMF + Reduced CNI	Group B: Monitored MMF + Full CNI	Group C: Fixed MMF + Full CNI
Number of subjects analysed	243	237	240
Units: percentage of participants
number (not applicable)
6 Months	18.9	21.5	21.7
20-24 Months	30.5	40.5	35

Difference at 6 Months (Group A vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[1]

P-value

= 0.4599

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-2.7

Confidence interval

level

90%

sides

2-sided

lower limit

-8.8

upper limit

3.3

Notes
[1] - Mantel-Haenszel general association test was performed.

Difference at 6 Months (Group B vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[2]

P-value

= 0.9362

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-0.1

Confidence interval

level

90%

sides

2-sided

lower limit

-6.3

upper limit

6.1

Notes
[2] - Mantel-Haenszel general association test was performed.

Difference at 6 Months (Group A vs Group B)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[3]

P-value

= 0.4961

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-2.6

Confidence interval

level

90%

sides

2-sided

lower limit

-8.6

upper limit

3.4

Notes
[3] - Mantel-Haenszel general association test was performed.

Difference at 20-24 Months (Group A vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[4]

P-value

= 0.2895

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-4.5

Confidence interval

level

90%

sides

2-sided

lower limit

-11.6

upper limit

2.5

Notes
[4] - Mantel-Haenszel general association test was performed.

Difference at 20-24 Months (Group B vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[5]

P-value

= 0.237

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

5.5

Confidence interval

level

90%

sides

2-sided

lower limit

-1.8

upper limit

12.8

Notes
[5] - Mantel-Haenszel general association test was performed.

Difference at 20-24 Months (Group A vs Group B)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[6]

P-value

= 0.0225

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-10.1

Confidence interval

level

90%

sides

2-sided

lower limit

-17.2

upper limit

-2.9

Notes
[6] - Mantel-Haenszel general association test was performed.

Secondary: Percentage of Participants with BPAR During 6, 12, and 20-24 Months Post-Transplantation

Top of page

End point title

Percentage of Participants with BPAR During 6, 12, and 20-24 Months Post-Transplantation

End point description

BPAR was defined as oral temperature >100 degrees Fahrenheit, graft swelling/tenderness, serum creatinine rise >0.3 mg/dL, rising blood pressure, oliguria, reduced renal flow, and ultrasound findings consistent with rejection, in addition to histologic findings of tubular invasion obtained from renal allograft biopsy. The percentage of participants with at least one BPAR episode during the first 6, 12, and 20-24 months post-transplantation was reported. ITT Population.

End point type

Secondary

End point timeframe

Months 6, 12, 20-24

End point values	Group A: Monitored MMF + Reduced CNI	Group B: Monitored MMF + Full CNI	Group C: Fixed MMF + Full CNI
Number of subjects analysed	243	237	240
Units: percentage of participants
number (not applicable)
6 Months	6.2	7.6	7.5
12 Months	6.2	9.7	9.6
20-24 Months	6.6	11	10

Difference at 6 Months (Group A vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[7]

P-value

= 0.5675

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-5.8

upper limit

3.2

Notes
[7] - Mantel-Haenszel general association test was performed.

Difference at 6 Months (Group B vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[8]

P-value

= 0.9929

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-4.6

upper limit

4.8

Notes
[8] - Mantel-Haenszel general association test was performed.

Difference at 6 Months (Group A vs Group B)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[9]

P-value

= 0.5616

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-1.4

Confidence interval

level

95%

sides

2-sided

lower limit

-6

upper limit

3.1

Notes
[9] - Mantel-Haenszel general association test was performed.

Difference at 12 Months (Group A vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[10]

P-value

= 0.1663

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-3.4

Confidence interval

level

95%

sides

2-sided

lower limit

-8.2

upper limit

1.4

Notes
[10] - Mantel-Haenszel general association test was performed.

Difference at 12 Months (Group B vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[11]

P-value

= 0.9938

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-5.2

upper limit

5.4

Notes
[11] - Mantel-Haenszel general association test was performed.

Difference at 12 Months (Group A vs Group B)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[12]

P-value

= 0.1714

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-3.5

Confidence interval

level

95%

sides

2-sided

lower limit

-8.4

upper limit

1.3

Notes
[12] - Mantel-Haenszel general association test was performed.

Difference at 20-24 Months (Group A vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[13]

P-value

= 0.1754

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-3.4

Confidence interval

level

95%

sides

2-sided

lower limit

-8.3

upper limit

1.5

Notes
[13] - Mantel-Haenszel general association test was performed.

Difference at 20-24 Months (Group B vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[14]

P-value

= 0.7782

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-4.5

upper limit

6.5

Notes
[14] - Mantel-Haenszel general association test was performed.

Difference at 20-24 Months (Group A vs Group B)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[15]

P-value

= 0.105

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-4.4

Confidence interval

level

95%

sides

2-sided

lower limit

-9.4

upper limit

0.7

Notes
[15] - Mantel-Haenszel general association test was performed.

Secondary: Percentage of Participants by Number of BPAR Episodes During 6, 12, and 20-24 Months Post-Transplantation

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End point title

Percentage of Participants by Number of BPAR Episodes During 6, 12, and 20-24 Months Post-Transplantation

End point description

BPAR was defined as oral temperature >100 degrees Fahrenheit, graft swelling/tenderness, serum creatinine rise >0.3 mg/dL, rising blood pressure, oliguria, reduced renal flow, and ultrasound findings consistent with rejection, in addition to histologic findings of tubular invasion obtained from renal allograft biopsy. The percentage of participants with 0, 1, 2, or 3 BPAR episodes during the first 6, 12, and 20-20-24 months post-transplantation was reported. ITT Population.

End point type

Secondary

End point timeframe

Months 6, 12, 20-24

End point values	Group A: Monitored MMF + Reduced CNI	Group B: Monitored MMF + Full CNI	Group C: Fixed MMF + Full CNI
Number of subjects analysed	243	237	240
Units: percentage of participants
number (not applicable)
6 Months, 0 Episodes	93.8	92.4	92.5
6 Months, 1 Episode	5.8	6.8	7.1
6 Months, 2 Episodes	0.4	0.8	0.4
12 Months, 0 Episodes	93.8	90.3	90.4
12 Months, 1 Episode	5.3	8.9	8.8
12 Months, 2 Episodes	0	0.8	0.8
12 Months, 3 Episodes	0.8	0	0
20-24 Months, 0 Episodes	93.4	89	90
20-24 Months, 1 Episode	5.8	9.7	8.3
20-24 Months, 2 Episodes	0	0.8	1.3
20-24 Months, 3 Episodes	0.8	0.4	0.4

Difference at 6 Months (Group A vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[16]

P-value

= 0.8419

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[16] - Mantel-Haenszel general association test was performed.

Difference at 6 Months (Group B vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[17]

P-value

= 0.8157

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[17] - Mantel-Haenszel general association test was performed.

Difference at 6 Months (Group A vs Group B)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[18]

P-value

= 0.7703

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[18] - Mantel-Haenszel general association test was performed.

Overall Treatment Effect at 6 Months

Statistical analysis description

Analysis performed with terms for treatment and CNI type as factors.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

720

Analysis specification

Pre-specified

Analysis type

other ^[19]

P-value

= 0.5921

Method

Poisson regression model

Confidence interval

Notes
[19] - Generalized linear modeling assuming Poisson distribution was performed.

Difference at 12 Months (Group A vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[20]

P-value

= 0.105

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[20] - Mantel-Haenszel general association test was performed.

Difference at 12 Months (Group B vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[21]

P-value

= 0.9989

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[21] - Mantel-Haenszel general association test was performed.

Difference at 12 Months (Group A vs Group B)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[22]

P-value

= 0.1013

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[22] - Mantel-Haenszel general association test was performed.

Overall Treatment Effect at 12 Months

Statistical analysis description

Analysis performed with terms for treatment and CNI type as factors.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

720

Analysis specification

Pre-specified

Analysis type

other ^[23]

P-value

= 0.35

Method

Poisson regression model

Confidence interval

Notes
[23] - Generalized linear modeling assuming Poisson distribution was performed.

Difference at 20-24 Months (Group A vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[24]

P-value

= 0.2008

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[24] - Mantel-Haenszel general association test was performed.

Difference at 20-24 Months (Group B vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[25]

P-value

= 0.9437

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[25] - Mantel-Haenszel general association test was performed.

Difference at 20-24 Months (Group A vs Group B)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[26]

P-value

= 0.1848

Method

Cochran-Mantel-Haenszel

Confidence interval

Notes
[26] - Mantel-Haenszel general association test was performed.

Overall Treatment Effect at 20-24 Months

Statistical analysis description

Analysis performed with terms for treatment and CNI type as factors.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

720

Analysis specification

Pre-specified

Analysis type

other ^[27]

P-value

= 0.1912

Method

Poisson regression model

Confidence interval

Notes
[27] - Generalized linear modeling assuming Poisson distribution was performed.

Secondary: Percentage of Participants Treated for Acute Rejection (AR) During 6, 12, and 20-24 Months Post-Transplantation

Top of page

End point title

Percentage of Participants Treated for Acute Rejection (AR) During 6, 12, and 20-24 Months Post-Transplantation

End point description

AR was defined as oral temperature >100 degrees Fahrenheit, graft swelling/tenderness, serum creatinine rise >0.3 mg/dL, rising blood pressure, oliguria, reduced renal flow, and ultrasound findings consistent with rejection, but without confirmation from biopsy. The percentage of participants who received treatment for AR during the first 6, 12, and 20-24 months post-transplantation was reported. ITT Population. (99999 = endpoint not analyzed because no data were available from any participants.)

End point type

Secondary

End point timeframe

Months 6, 12, 20-24

End point values	Group A: Monitored MMF + Reduced CNI	Group B: Monitored MMF + Full CNI	Group C: Fixed MMF + Full CNI
Number of subjects analysed	243	237	240
Units: percentage of participants
number (not applicable)
6 Months	99999	99999	99999
12 Months	99999	99999	99999
20-24 Months	99999	99999	99999

No statistical analyses for this end point

Secondary: Percentage of Participants Who Experienced Graft Loss During 6, 12, and 20-24 Months Post-Transplantation

Top of page

End point title

Percentage of Participants Who Experienced Graft Loss During 6, 12, and 20-24 Months Post-Transplantation

End point description

Graft loss was characterized as initiation of chronic dialysis, transplant nephrectomy, re-transplantation, or death with functioning graft. The percentage of participants who experienced graft loss at any time during the first 6, 12, and 20-24 months post-transplantation was reported. ITT Population.

End point type

Secondary

End point timeframe

Months 6, 12, 20-24

End point values	Group A: Monitored MMF + Reduced CNI	Group B: Monitored MMF + Full CNI	Group C: Fixed MMF + Full CNI
Number of subjects analysed	243	237	240
Units: percentage of participants
number (not applicable)
6 Months	3.7	2.1	2.5
12 Months	4.9	3.4	5
20-24 Months	6.2	5.9	5.8

No statistical analyses for this end point

Secondary: Percentage of Participants Who Died During 6, 12, and 20-24 Months Post-Transplantation

Top of page

End point title

Percentage of Participants Who Died During 6, 12, and 20-24 Months Post-Transplantation

End point description

The percentage of participants who died from any cause during the first 6, 12, and 20-24 months post-transplantation was reported. ITT Population.

End point type

Secondary

End point timeframe

Months 6, 12, 20-24

End point values	Group A: Monitored MMF + Reduced CNI	Group B: Monitored MMF + Full CNI	Group C: Fixed MMF + Full CNI
Number of subjects analysed	243	237	240
Units: percentage of participants
number (not applicable)
6 Months	2.1	0.4	1.3
12 Months	3.3	1.7	3.3
20-24 Months	4.5	3	3.8

No statistical analyses for this end point

Secondary: Percentage of Participants Who Discontinued Treatment with MMF or Were Lost to Follow-Up During 6, 12, and 20-24 Months Post-Transplantation

Top of page

End point title

Percentage of Participants Who Discontinued Treatment with MMF or Were Lost to Follow-Up During 6, 12, and 20-24 Months Post-Transplantation

End point description

The collective percentage of participants who discontinued treatment with MMF and/or were lost to follow-up during the first 6, 12, and 20-24 months post-transplantation was reported. ITT Population.

End point type

Secondary

End point timeframe

Months 6, 12, 20-24

End point values	Group A: Monitored MMF + Reduced CNI	Group B: Monitored MMF + Full CNI	Group C: Fixed MMF + Full CNI
Number of subjects analysed	243	237	240
Units: percentage of participants
number (not applicable)
6 Months	19.3	28.3	30
12 Months	23.5	36.3	36.3
20-24 Months	23.9	36.7	36.7

Difference at 6 Months (Group A vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[28]

P-value

= 0.0068

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-10.7

Confidence interval

level

95%

sides

2-sided

lower limit

-18.3

upper limit

-3

Notes
[28] - Mantel-Haenszel general association test was performed.

Difference at 6 Months (Group B vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[29]

P-value

= 0.6777

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-9.9

upper limit

6.4

Notes
[29] - Mantel-Haenszel general association test was performed.

Difference at 6 Months (Group A vs Group B)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[30]

P-value

= 0.0206

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-8.9

Confidence interval

level

95%

sides

2-sided

lower limit

-16.5

upper limit

-1.3

Notes
[30] - Mantel-Haenszel general association test was performed.

Difference at 12 Months (Group A vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[31]

P-value

= 0.0022

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-12.8

Confidence interval

level

95%

sides

2-sided

lower limit

-20.9

upper limit

-4.7

Notes
[31] - Mantel-Haenszel general association test was performed.

Difference at 12 Months (Group B vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[32]

P-value

= 0.98

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-8.6

upper limit

8.7

Notes
[32] - Mantel-Haenszel general association test was performed.

Difference at 12 Months (Group A vs Group B)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[33]

P-value

= 0.0018

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-12.8

Confidence interval

level

95%

sides

2-sided

lower limit

-20.9

upper limit

-4.7

Notes
[33] - Mantel-Haenszel general association test was performed.

Difference at 20-24 Months (Group A vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[34]

P-value

= 0.0023

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-12.8

Confidence interval

level

95%

sides

2-sided

lower limit

-20.9

upper limit

-4.7

Notes
[34] - Mantel-Haenszel general association test was performed.

Difference at 20-24 Months (Group B vs Group C)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[35]

P-value

= 0.977

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-8.6

upper limit

8.7

Notes
[35] - Mantel-Haenszel general association test was performed.

Difference at 20-24 Months (Group A vs Group B)

Statistical analysis description

Analysis stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[36]

P-value

= 0.0018

Method

Cochran-Mantel-Haenszel

Parameter type

Difference in proportions

Point estimate

-12.8

Confidence interval

level

95%

sides

2-sided

lower limit

-21

upper limit

-4.7

Notes
[36] - Mantel-Haenszel general association test was performed.

Secondary: Time to First BPAR Episode During 6, 12, and 20-24 Months Post-Transplantation

Top of page

End point title

Time to First BPAR Episode During 6, 12, and 20-24 Months Post-Transplantation

End point description

Time to first BPAR episode was defined as the time from transplantation to the first documented BPAR episode. BPAR was defined as oral temperature >100 degrees Fahrenheit, graft swelling/tenderness, serum creatinine rise >0.3 mg/dL, rising blood pressure, oliguria, reduced renal flow, and ultrasound findings consistent with rejection, in addition to histologic findings of tubular invasion obtained from renal allograft biopsy. Median time to first BPAR episode during the first 6, 12, and 20-24 months post-transplantation was estimated by Kaplan-Meier analysis and expressed in days. ITT Population. Values entered as "99999" indicate that data could not be reported due to a high number of censored observations.

End point type

Secondary

End point timeframe

Months 6, 12, 20-24

End point values	Group A: Monitored MMF + Reduced CNI	Group B: Monitored MMF + Full CNI	Group C: Fixed MMF + Full CNI
Number of subjects analysed	243	237	240
Units: days
median (confidence interval 95%)
6 Months	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
12 Months	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
20-24 Months	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

Difference at 6 Months (Group A vs Group C)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[37]

P-value

= 0.5395

Method

Logrank

Confidence interval

Notes
[37] - Survival curves were plotted and compared by the log rank test.

Difference at 6 Months (Group B vs Group C)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[38]

P-value

= 0.961

Method

Logrank

Confidence interval

Notes
[38] - Survival curves were plotted and compared by the log rank test.

Difference at 6 Months (Group A vs Group B)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[39]

P-value

= 0.5659

Method

Logrank

Confidence interval

Notes
[39] - Survival curves were plotted and compared by the log rank test.

Difference at 12 Months (Group A vs Group C)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[40]

P-value

= 0.159

Method

Logrank

Confidence interval

Notes
[40] - Survival curves were plotted and compared by the log rank test.

Difference at 12 Months (Group B vs Group C)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[41]

P-value

= 0.9595

Method

Logrank

Confidence interval

Notes
[41] - Survival curves were plotted and compared by the log rank test.

Difference at 12 Months (Group A vs Group B)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[42]

P-value

= 0.1724

Method

Logrank

Confidence interval

Notes
[42] - Survival curves were plotted and compared by the log rank test.

Difference at 20-24 Months (Group A vs Group C)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[43]

P-value

= 0.1686

Method

Logrank

Confidence interval

Notes
[43] - Survival curves were plotted and compared by the log rank test.

Difference at 20-24 Months (Group B vs Group C)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[44]

P-value

= 0.8016

Method

Logrank

Confidence interval

Notes
[44] - Survival curves were plotted and compared by the log rank test.

Difference at 20-24 Months (Group A vs Group B)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[45]

P-value

= 0.0958

Method

Logrank

Confidence interval

Notes
[45] - Survival curves were plotted and compared by the log rank test.

Secondary: Time to Treatment Failure During 6, 12, and 20-24 Months Post-Transplantation

Top of page

End point title

Time to Treatment Failure During 6, 12, and 20-24 Months Post-Transplantation

End point description

Time to treatment failure was defined as time from transplantation to the first documented treatment failure event. Treatment failure was defined as any one event of BPAR, graft loss (characterized as initiation of chronic dialysis, transplant nephrectomy, re-transplantation, or death with functioning graft), death, or loss to follow-up. BPAR was defined as oral temperature >100 degrees Fahrenheit, graft swelling/tenderness, serum creatinine rise >0.3 mg/dL, rising blood pressure, oliguria, reduced renal flow, and ultrasound findings consistent with rejection, in addition to histologic findings of tubular invasion obtained from renal allograft biopsy. Median time to treatment failure during the first 6, 12, and 20-24 months post-transplantation was estimated by Kaplan-Meier analysis and expressed in days. ITT Population. Values entered as "99999" indicate that data could not be reported due to a high number of censored observations.

End point type

Secondary

End point timeframe

Months 6, 12, 20-24

End point values	Group A: Monitored MMF + Reduced CNI	Group B: Monitored MMF + Full CNI	Group C: Fixed MMF + Full CNI
Number of subjects analysed	243	237	240
Units: days
median (confidence interval 95%)
6 Months	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
12 Months	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
20-24 Months	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)

Difference at 6 Months (Group A vs Group C)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[46]

P-value

= 0.4827

Method

Logrank

Confidence interval

Notes
[46] - Survival curves were plotted and compared by the log rank test.

Difference at 6 Months (Group B vs Group C)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[47]

P-value

= 0.8816

Method

Logrank

Confidence interval

Notes
[47] - Survival curves were plotted and compared by the log rank test.

Difference at 6 Months (Group A vs Group B)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[48]

P-value

= 0.5702

Method

Logrank

Confidence interval

Notes
[48] - Survival curves were plotted and compared by the log rank test.

Difference at 12 Months (Group A vs Group C)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[49]

P-value

= 0.2243

Method

Logrank

Confidence interval

Notes
[49] - Survival curves were plotted and compared by the log rank test.

Difference at 12 Months (Group B vs Group C)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[50]

P-value

= 0.9133

Method

Logrank

Confidence interval

Notes
[50] - Survival curves were plotted and compared by the log rank test.

Difference at 12 Months (Group A vs Group B)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[51]

P-value

= 0.1835

Method

Logrank

Confidence interval

Notes
[51] - Survival curves were plotted and compared by the log rank test.

Difference at 20-24 Months (Group A vs Group C)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

other ^[52]

P-value

= 0.3022

Method

Logrank

Confidence interval

Notes
[52] - Survival curves were plotted and compared by the log rank test.

Difference at 20-24 Months (Group B vs Group C)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

other ^[53]

P-value

= 0.3349

Method

Logrank

Confidence interval

Notes
[53] - Survival curves were plotted and compared by the log rank test.

Difference at 20-24 Months (Group A vs Group B)

Statistical analysis description

Analysis comparing survival curves for treatment groups, stratified by CNI type.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI

Number of subjects included in analysis

480

Analysis specification

Pre-specified

Analysis type

other ^[54]

P-value

= 0.0397

Method

Logrank

Confidence interval

Notes
[54] - Survival curves were plotted and compared by the log rank test.

Secondary: Percent Change from Baseline in Calculated GFR at 3, 6, and 20-24 Months Post-Transplantation

Top of page

End point title

Percent Change from Baseline in Calculated GFR at 3, 6, and 20-24 Months Post-Transplantation

End point description

GFR was calculated using the Nankivell equation: [6.7 ÷ serum creatinine in mmol/L] + [body weight in kilograms ÷ 4] + [serum urea in mmol/L ÷ 2] + [100 ÷ height in meters] + a value of 35 for males or 25 for females. The percent change in GFR from Baseline to Months 3, 6, and 20-24 was calculated as [GFR at Month 3, 6, or 20-24 – GFR at Baseline] divided by GFR at Baseline, multiplied by 100. The result was averaged among all participants. ITT Population

End point type

Secondary

End point timeframe

Baseline to Months 3, 6, 20-24

End point values	Group A: Monitored MMF + Reduced CNI	Group B: Monitored MMF + Full CNI	Group C: Fixed MMF + Full CNI
Number of subjects analysed	243	237	240
Units: percent change
arithmetic mean (standard deviation)
3 Months	10.5 ( 43.63 )	3.8 ( 22.75 )	8.4 ( 26.67 )
6 Months	11.5 ( 45.91 )	5.5 ( 24.45 )	8.6 ( 27.26 )
20-24 Months	8.3 ( 47.27 )	0.6 ( 31.79 )	4.6 ( 37.89 )

Difference at 3 Months (Group A vs Group C)

Statistical analysis description

Analysis performed with terms for treatment and CNI type as factors.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5783

Method

ANOVA

Parameter type

Difference in least squares means

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-5.15

upper limit

9.21

Difference at 3 Months (Group A vs Groups B+C)

Statistical analysis description

Analysis performed with terms for treatment and CNI type as factors.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

720

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1369

Method

ANOVA

Parameter type

Difference in least squares means

Point estimate

4.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1.34

upper limit

9.74

Difference at 6 Months (Group A vs Group C)

Statistical analysis description

Analysis performed with terms for treatment and CNI type as factors.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4797

Method

ANOVA

Parameter type

Difference in least squares means

Point estimate

2.9

Confidence interval

level

95%

sides

2-sided

lower limit

-5.1

upper limit

10.82

Difference at 6 Months (Group A vs Group B+C)

Statistical analysis description

Analysis performed with terms for treatment and CNI type as factors.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

720

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1836

Method

ANOVA

Parameter type

Difference in least squares means

Point estimate

4.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.05

upper limit

10.36

Difference at 20-24 Months (Group A vs Group C)

Statistical analysis description

Analysis performed with terms for treatment and CNI type as factors.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

483

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4533

Method

ANOVA

Parameter type

Difference in least squares means

Point estimate

3.7

Confidence interval

level

95%

sides

2-sided

lower limit

-5.92

upper limit

13.24

Difference at 20-24 Months (Group A vs Group B+C)

Statistical analysis description

Analysis performed with terms for treatment and CNI type as factors.

Comparison groups

Group A: Monitored MMF + Reduced CNI v Group B: Monitored MMF + Full CNI v Group C: Fixed MMF + Full CNI

Number of subjects included in analysis

720

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1491

Method

ANOVA

Parameter type

Difference in least squares means

Point estimate

5.6

Confidence interval

level

95%

sides

2-sided

lower limit

-2.06

upper limit

13.27

Adverse events

Top of page

Timeframe for reporting adverse events

From Baseline until up to 30 days after the last dose (maximum up to 24 months)

Adverse event reporting additional description

Safety Population: All participants who received at least one dose of study medication and had at least one post-baseline safety assessment.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

10.1

Reporting group title

Group A: Monitored MMF + Reduced CNI

Reporting group description

Group A received concentration-controlled/monitored MMF with an oral CNI, either cyclosporine or tacrolimus, at reduced blood concentration. The initial dose of MMF was at least 1 gram BID in adults and 600 mg/m^2 in pediatrics. Subsequent doses were adjusted to maintain blood MPA levels ≥1.3 μg/mL with cyclosporine or ≥1.9 μg/mL with tacrolimus, not to exceed 4 grams total per day. The selected CNI was dosed to maintain reduced blood concentrations. Cyclosporine target concentrations were as follows: Days 1–30, 250–325 ng/mL; Days 30–90, 125–165 ng/mL; Days 90 through end of study, 95–145 ng/mL. Tacrolimus target concentrations were as follows: Days 1–30, 8–12 ng/mL; Days 30–90, 4–6 ng/mL; Days 90 through end of study, 3–5 ng/mL.

Reporting group title

Group C: Fixed MMF + Full CNI

Reporting group description

Reporting group title

Group B: Monitored MMF + Full CNI

Reporting group description

Serious adverse events	Group A: Monitored MMF + Reduced CNI	Group C: Fixed MMF + Full CNI	Group B: Monitored MMF + Full CNI
Total subjects affected by serious adverse events
subjects affected / exposed	116 / 238 (48.74%)	141 / 238 (59.24%)	118 / 233 (50.64%)
number of deaths (all causes)	11	9	7
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Multiple myeloma
subjects affected / exposed	0 / 238 (0.00%)	2 / 238 (0.84%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Bladder cancer
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ovarian epithelial cancer
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Diffuse large B-cell lymphoma stage III
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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 adenocarcinoma
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Lung cancer metastatic
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1
Lung squamous cell carcinoma stage unspecified
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 2
Prostate cancer
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Vascular disorders
Lymphocele
subjects affected / exposed	4 / 238 (1.68%)	4 / 238 (1.68%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	3 / 238 (1.26%)	1 / 238 (0.42%)	4 / 233 (1.72%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 238 (0.00%)	3 / 238 (1.26%)	4 / 233 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 238 (0.00%)	2 / 238 (0.84%)	3 / 233 (1.29%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	2 / 238 (0.84%)	1 / 238 (0.42%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	1 / 238 (0.42%)	2 / 238 (0.84%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Necrosis ischaemic
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Peripheral ischaemia
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Aneurysm
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aneurysm ruptured
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Arterial disorder
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Extremity necrosis
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Iliac artery thrombosis
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemia
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
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 arterial occlusive disease
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Thrombophlebitis
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular pseudoaneurysm
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Surgical and medical procedures
Wound drainage
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (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
Nephrectomy
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	4 / 238 (1.68%)	7 / 238 (2.94%)	4 / 233 (1.72%)
occurrences causally related to treatment / all	1 / 4	1 / 8	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	3 / 238 (1.26%)	3 / 238 (1.26%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (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
Chills
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Asthenia
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Catheter thrombosis
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Generalised oedema
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Hernia
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Soft tissue inflammation
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Iodine allergy
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Anaphylactic reaction
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Pancreas transplant rejection
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
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 rejection
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Gynaecomastia
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Epididymitis
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Prostatitis
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Vaginal haemorrhage
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	1 / 238 (0.42%)	2 / 238 (0.84%)	3 / 233 (1.29%)
occurrences causally related to treatment / all	1 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	1 / 1	0 / 1	0 / 0
Pulmonary oedema
subjects affected / exposed	4 / 238 (1.68%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	3 / 233 (1.29%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (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
Acute respiratory distress syndrome
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Pulmonary congestion
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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 arrest
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Respiratory distress
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Acute respiratory failure
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Asthma
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Atelectasis
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
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	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Status asthmaticus
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Psychiatric disorders
Mental status changes
subjects affected / exposed	2 / 238 (0.84%)	0 / 238 (0.00%)	0 / 233 (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
Anxiety
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Mania
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Bipolar disorder
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Confusional state
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Blood creatinine increased
subjects affected / exposed	18 / 238 (7.56%)	13 / 238 (5.46%)	9 / 233 (3.86%)
occurrences causally related to treatment / all	5 / 23	4 / 17	4 / 13
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood glucose increased
subjects affected / exposed	0 / 238 (0.00%)	2 / 238 (0.84%)	0 / 233 (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
Blood potassium increased
subjects affected / exposed	0 / 238 (0.00%)	2 / 238 (0.84%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urine output decreased
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cytomegalovirus antigen positive
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cytomegalovirus test
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug level below therapeutic
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemoglobin decreased
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
International normalised ratio increased
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Graft dysfunction
subjects affected / exposed	7 / 238 (2.94%)	16 / 238 (6.72%)	8 / 233 (3.43%)
occurrences causally related to treatment / all	0 / 7	1 / 16	1 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	4 / 238 (1.68%)	2 / 238 (0.84%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 4	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Perinephric collection
subjects affected / exposed	1 / 238 (0.42%)	2 / 238 (0.84%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subcutaneous haematoma
subjects affected / exposed	2 / 238 (0.84%)	1 / 238 (0.42%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seroma
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	1 / 233 (0.43%)
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	0 / 238 (0.00%)	1 / 238 (0.42%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Therapeutic agent toxicity
subjects affected / exposed	0 / 238 (0.00%)	2 / 238 (0.84%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Graft thrombosis
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (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
Perirenal haematoma
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (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
Subdural haematoma
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (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
Incisional hernia
subjects affected / exposed	0 / 238 (0.00%)	2 / 238 (0.84%)	0 / 233 (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
Ureteric anastomosis complication
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary anastomotic leak
subjects affected / exposed	0 / 238 (0.00%)	2 / 238 (0.84%)	0 / 233 (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
Post procedural urine leak
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Fall
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Incision site haematoma
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Post procedural haematoma
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative ileus
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Radiation pneumonitis
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Tendon rupture
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Urostomy complication
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound complication
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Wound secretion
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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 disorders
Myocardial infarction
subjects affected / exposed	7 / 238 (2.94%)	0 / 238 (0.00%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 7	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	6 / 233 (2.58%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	2 / 238 (0.84%)	2 / 238 (0.84%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 3	0 / 1
Cardiac failure congestive
subjects affected / exposed	1 / 238 (0.42%)	2 / 238 (0.84%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 238 (0.42%)	2 / 238 (0.84%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Tachycardia
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	3 / 233 (1.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	2 / 238 (0.84%)	0 / 238 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (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 acute
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Cardiomegaly
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Supraventricular tachycardia
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Arrhythmia
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Cardiogenic shock
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Intracardiac thrombus
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
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 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Palpitations
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Cerebrovascular accident
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Convulsion
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Depressed level of consciousness
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Encephalitis
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neurotoxicity
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Anoxic encephalopathy
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Complex regional pain syndrome
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
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 and lymphatic system disorders
Anaemia
subjects affected / exposed	4 / 238 (1.68%)	5 / 238 (2.10%)	4 / 233 (1.72%)
occurrences causally related to treatment / all	0 / 4	1 / 5	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Leukopenia
subjects affected / exposed	3 / 238 (1.26%)	5 / 238 (2.10%)	5 / 233 (2.15%)
occurrences causally related to treatment / all	3 / 3	5 / 5	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 238 (0.42%)	2 / 238 (0.84%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	1 / 1	1 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemolytic uraemic syndrome
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Pancytopenia
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Visual disturbance
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Gastrointestinal disorders
Vomiting
subjects affected / exposed	2 / 238 (0.84%)	4 / 238 (1.68%)	4 / 233 (1.72%)
occurrences causally related to treatment / all	0 / 2	4 / 4	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 238 (0.42%)	5 / 238 (2.10%)	3 / 233 (1.29%)
occurrences causally related to treatment / all	1 / 1	4 / 5	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	3 / 238 (1.26%)	3 / 238 (1.26%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	1 / 3	3 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 238 (0.42%)	3 / 238 (1.26%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 1	1 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	2 / 238 (0.84%)	0 / 238 (0.00%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 2	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	2 / 238 (0.84%)	1 / 238 (0.42%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 238 (0.84%)	1 / 238 (0.42%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	3 / 233 (1.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erosive oesophagitis
subjects affected / exposed	2 / 238 (0.84%)	0 / 238 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (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
Gastritis erosive
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (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
Oesophagitis
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	1 / 233 (0.43%)
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 obstruction
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 238 (0.00%)	2 / 238 (0.84%)	0 / 233 (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
Food poisoning
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Gastrointestinal necrosis
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Pancreatitis acute
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Rectal haemorrhage
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Colitis
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Diarrhoea haemorrhagic
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Dysphagia
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Gastric ulcer haemorrhage
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Haemorrhoids
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Necrotising oesophagitis
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophageal spasm
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophageal stenosis
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peritoneal effusion
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retroperitoneal effusion
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Retroperitoneal haemorrhage
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Retroperitoneal haematoma
subjects affected / exposed	1 / 238 (0.42%)	2 / 238 (0.84%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Biliary tract disorder
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Cholecystitis chronic
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Bile duct stone
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Ischaemic hepatitis
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
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
Skin ulcer
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (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
Dry gangrene
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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 and urinary disorders
Renal failure acute
subjects affected / exposed	2 / 238 (0.84%)	3 / 238 (1.26%)	6 / 233 (2.58%)
occurrences causally related to treatment / all	0 / 2	3 / 4	3 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal tubular necrosis
subjects affected / exposed	4 / 238 (1.68%)	5 / 238 (2.10%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	1 / 4	0 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	4 / 238 (1.68%)	2 / 238 (0.84%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 4	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	3 / 233 (1.29%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract disorder
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	4 / 233 (1.72%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 238 (0.42%)	3 / 238 (1.26%)	0 / 233 (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
Renal artery stenosis
subjects affected / exposed	2 / 238 (0.84%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ureteric stenosis
subjects affected / exposed	2 / 238 (0.84%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephritis interstitial
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	1 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Focal segmental glomerulosclerosis
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ureteric obstruction
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Azotaemia
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Dysuria
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Glomerulonephritis membranoproliferative
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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 vein thrombosis
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder neck obstruction
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Cystitis haemorrhagic
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oliguria
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Proteinuria
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
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 thrombosis
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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 failure
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
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 infarct
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	2 / 238 (0.84%)	1 / 238 (0.42%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (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
Muscular weakness
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Osteoarthritis
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Arthritis
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Flank pain
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Neuropathic arthropathy
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
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
Urinary tract infection
subjects affected / exposed	16 / 238 (6.72%)	12 / 238 (5.04%)	6 / 233 (2.58%)
occurrences causally related to treatment / all	10 / 20	8 / 15	1 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	6 / 238 (2.52%)	8 / 238 (3.36%)	5 / 233 (2.15%)
occurrences causally related to treatment / all	2 / 7	6 / 9	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	2 / 238 (0.84%)	3 / 238 (1.26%)	6 / 233 (2.58%)
occurrences causally related to treatment / all	1 / 2	3 / 3	2 / 7
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Wound infection
subjects affected / exposed	4 / 238 (1.68%)	2 / 238 (0.84%)	4 / 233 (1.72%)
occurrences causally related to treatment / all	0 / 4	0 / 2	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	2 / 238 (0.84%)	5 / 238 (2.10%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 2	1 / 5	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 238 (0.42%)	2 / 238 (0.84%)	6 / 233 (2.58%)
occurrences causally related to treatment / all	0 / 1	1 / 2	2 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 238 (0.84%)	4 / 238 (1.68%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 2	1 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	2 / 238 (0.84%)	1 / 238 (0.42%)	3 / 233 (1.29%)
occurrences causally related to treatment / all	2 / 2	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	2 / 238 (0.84%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Polyomavirus-associated nephropathy
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	3 / 233 (1.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 238 (0.00%)	2 / 238 (0.84%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
BK virus infection
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (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
Staphylococcal infection
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 238 (0.00%)	2 / 238 (0.84%)	0 / 233 (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
Gangrene
subjects affected / exposed	0 / 238 (0.00%)	2 / 238 (0.84%)	0 / 233 (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
Gastroenteritis viral
subjects affected / exposed	0 / 238 (0.00%)	2 / 238 (0.84%)	0 / 233 (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
Localised infection
subjects affected / exposed	0 / 238 (0.00%)	2 / 238 (0.84%)	0 / 233 (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
Subcutaneous abscess
subjects affected / exposed	0 / 238 (0.00%)	2 / 238 (0.84%)	0 / 233 (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
Abdominal sepsis
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Bacterial pyelonephritis
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Clostridial infection
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Genital herpes
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung infection pseudomonal
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Perinephric abscess
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Peritonitis bacterial
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal wall abscess
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Abscess
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Abscess neck
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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 graft site infection
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Bacillary angiomatosis
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Bronchitis
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Catheter related infection
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Catheter site cellulitis
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Cellulitis staphylococcal
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Cytomegalovirus viraemia
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erythema infectiosum
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Escherichia urinary tract infection
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Gastroenteritis pseudomonas
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Groin abscess
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Hepatitis B
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
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 virus infection
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Human polyomavirus infection
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Infected skin ulcer
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Infective thrombosis
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Klebsiella infection
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Nocardiosis
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophageal candidiasis
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Orchitis
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Skin infection
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Tuberculosis
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Wound infection pseudomonas
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	6 / 238 (2.52%)	6 / 238 (2.52%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 6	1 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 238 (0.00%)	6 / 238 (2.52%)	6 / 233 (2.58%)
occurrences causally related to treatment / all	0 / 0	1 / 6	5 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 238 (0.42%)	4 / 238 (1.68%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	2 / 238 (0.84%)	1 / 238 (0.42%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	1 / 2	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 238 (0.00%)	2 / 238 (0.84%)	2 / 233 (0.86%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	2 / 238 (0.84%)	0 / 238 (0.00%)	0 / 233 (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
Diabetic ketoacidosis
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (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
Hypercalcaemia
subjects affected / exposed	1 / 238 (0.42%)	1 / 238 (0.42%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fluid overload
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypovolaemia
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (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
Hypomagnesaemia
subjects affected / exposed	1 / 238 (0.42%)	0 / 238 (0.00%)	0 / 233 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	0 / 238 (0.00%)	1 / 238 (0.42%)	0 / 233 (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
Metabolic acidosis
subjects affected / exposed	0 / 238 (0.00%)	0 / 238 (0.00%)	1 / 233 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 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	Group A: Monitored MMF + Reduced CNI	Group C: Fixed MMF + Full CNI	Group B: Monitored MMF + Full CNI
Total subjects affected by non serious adverse events
subjects affected / exposed	224 / 238 (94.12%)	227 / 238 (95.38%)	222 / 233 (95.28%)
Vascular disorders
Hypertension
subjects affected / exposed	51 / 238 (21.43%)	49 / 238 (20.59%)	51 / 233 (21.89%)
occurrences all number	60	51	54
Hypotension
subjects affected / exposed	30 / 238 (12.61%)	26 / 238 (10.92%)	24 / 233 (10.30%)
occurrences all number	35	32	28
General disorders and administration site conditions
Oedema
subjects affected / exposed	79 / 238 (33.19%)	90 / 238 (37.82%)	82 / 233 (35.19%)
occurrences all number	99	121	104
Fatigue
subjects affected / exposed	38 / 238 (15.97%)	41 / 238 (17.23%)	38 / 233 (16.31%)
occurrences all number	40	46	40
Oedema peripheral
subjects affected / exposed	33 / 238 (13.87%)	29 / 238 (12.18%)	29 / 233 (12.45%)
occurrences all number	40	37	41
Pyrexia
subjects affected / exposed	26 / 238 (10.92%)	28 / 238 (11.76%)	26 / 233 (11.16%)
occurrences all number	30	35	30
Pain
subjects affected / exposed	24 / 238 (10.08%)	19 / 238 (7.98%)	20 / 233 (8.58%)
occurrences all number	34	26	26
Asthenia
subjects affected / exposed	16 / 238 (6.72%)	18 / 238 (7.56%)	10 / 233 (4.29%)
occurrences all number	19	18	11
Chest pain
subjects affected / exposed	12 / 238 (5.04%)	9 / 238 (3.78%)	17 / 233 (7.30%)
occurrences all number	14	10	18
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	30 / 238 (12.61%)	26 / 238 (10.92%)	28 / 233 (12.02%)
occurrences all number	33	31	30
Cough
subjects affected / exposed	21 / 238 (8.82%)	24 / 238 (10.08%)	22 / 233 (9.44%)
occurrences all number	23	27	23
Pharyngolaryngeal pain
subjects affected / exposed	10 / 238 (4.20%)	14 / 238 (5.88%)	11 / 233 (4.72%)
occurrences all number	12	17	11
Psychiatric disorders
Insomnia
subjects affected / exposed	46 / 238 (19.33%)	41 / 238 (17.23%)	35 / 233 (15.02%)
occurrences all number	49	46	37
Anxiety
subjects affected / exposed	12 / 238 (5.04%)	11 / 238 (4.62%)	11 / 233 (4.72%)
occurrences all number	12	11	12
Depression
subjects affected / exposed	11 / 238 (4.62%)	9 / 238 (3.78%)	13 / 233 (5.58%)
occurrences all number	11	9	13
Investigations
Blood creatinine increased
subjects affected / exposed	43 / 238 (18.07%)	33 / 238 (13.87%)	45 / 233 (19.31%)
occurrences all number	50	48	55
Weight increased
subjects affected / exposed	31 / 238 (13.03%)	29 / 238 (12.18%)	24 / 233 (10.30%)
occurrences all number	31	32	25
Urine output decreased
subjects affected / exposed	8 / 238 (3.36%)	8 / 238 (3.36%)	12 / 233 (5.15%)
occurrences all number	8	8	12
Injury, poisoning and procedural complications
Graft dysfunction
subjects affected / exposed	23 / 238 (9.66%)	20 / 238 (8.40%)	13 / 233 (5.58%)
occurrences all number	23	20	13
Incision site pain
subjects affected / exposed	15 / 238 (6.30%)	14 / 238 (5.88%)	12 / 233 (5.15%)
occurrences all number	16	14	12
Nervous system disorders
Tremor
subjects affected / exposed	38 / 238 (15.97%)	47 / 238 (19.75%)	46 / 233 (19.74%)
occurrences all number	44	52	52
Headache
subjects affected / exposed	25 / 238 (10.50%)	33 / 238 (13.87%)	30 / 233 (12.88%)
occurrences all number	29	47	33
Dizziness
subjects affected / exposed	22 / 238 (9.24%)	19 / 238 (7.98%)	15 / 233 (6.44%)
occurrences all number	25	25	18
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	81 / 238 (34.03%)	80 / 238 (33.61%)	59 / 233 (25.32%)
occurrences all number	92	90	62
Leukopenia
subjects affected / exposed	54 / 238 (22.69%)	65 / 238 (27.31%)	56 / 233 (24.03%)
occurrences all number	72	77	81
Thrombocytopenia
subjects affected / exposed	9 / 238 (3.78%)	13 / 238 (5.46%)	6 / 233 (2.58%)
occurrences all number	9	13	6
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	97 / 238 (40.76%)	94 / 238 (39.50%)	101 / 233 (43.35%)
occurrences all number	130	122	138
Constipation
subjects affected / exposed	54 / 238 (22.69%)	65 / 238 (27.31%)	65 / 233 (27.90%)
occurrences all number	63	74	69
Nausea
subjects affected / exposed	51 / 238 (21.43%)	53 / 238 (22.27%)	48 / 233 (20.60%)
occurrences all number	61	75	56
Vomiting
subjects affected / exposed	48 / 238 (20.17%)	37 / 238 (15.55%)	40 / 233 (17.17%)
occurrences all number	54	48	50
Abdominal pain
subjects affected / exposed	27 / 238 (11.34%)	29 / 238 (12.18%)	34 / 233 (14.59%)
occurrences all number	29	41	37
Dyspepsia
subjects affected / exposed	16 / 238 (6.72%)	26 / 238 (10.92%)	30 / 233 (12.88%)
occurrences all number	16	28	31
Abdominal distension
subjects affected / exposed	11 / 238 (4.62%)	14 / 238 (5.88%)	9 / 233 (3.86%)
occurrences all number	11	14	9
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	12 / 238 (5.04%)	17 / 238 (7.14%)	23 / 233 (9.87%)
occurrences all number	13	18	25
Rash
subjects affected / exposed	14 / 238 (5.88%)	16 / 238 (6.72%)	19 / 233 (8.15%)
occurrences all number	14	17	20
Alopecia
subjects affected / exposed	8 / 238 (3.36%)	12 / 238 (5.04%)	8 / 233 (3.43%)
occurrences all number	8	13	8
Renal and urinary disorders
Haematuria
subjects affected / exposed	24 / 238 (10.08%)	20 / 238 (8.40%)	27 / 233 (11.59%)
occurrences all number	25	21	28
Renal tubular necrosis
subjects affected / exposed	15 / 238 (6.30%)	10 / 238 (4.20%)	13 / 233 (5.58%)
occurrences all number	15	10	13
Dysuria
subjects affected / exposed	19 / 238 (7.98%)	13 / 238 (5.46%)	14 / 233 (6.01%)
occurrences all number	20	13	15
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	21 / 238 (8.82%)	24 / 238 (10.08%)	19 / 233 (8.15%)
occurrences all number	21	27	19
Pain in extremity
subjects affected / exposed	21 / 238 (8.82%)	21 / 238 (8.82%)	15 / 233 (6.44%)
occurrences all number	21	22	18
Muscle spasms
subjects affected / exposed	12 / 238 (5.04%)	15 / 238 (6.30%)	18 / 233 (7.73%)
occurrences all number	12	18	22
Osteopenia
subjects affected / exposed	14 / 238 (5.88%)	8 / 238 (3.36%)	11 / 233 (4.72%)
occurrences all number	15	8	12
Arthralgia
subjects affected / exposed	15 / 238 (6.30%)	9 / 238 (3.78%)	5 / 233 (2.15%)
occurrences all number	17	11	5
Infections and infestations
Urinary tract infection
subjects affected / exposed	29 / 238 (12.18%)	25 / 238 (10.50%)	35 / 233 (15.02%)
occurrences all number	44	34	54
Upper respiratory tract infection
subjects affected / exposed	21 / 238 (8.82%)	15 / 238 (6.30%)	12 / 233 (5.15%)
occurrences all number	23	15	12
Nasopharyngitis
subjects affected / exposed	16 / 238 (6.72%)	13 / 238 (5.46%)	13 / 233 (5.58%)
occurrences all number	18	18	13
Metabolism and nutrition disorders
Hypophosphataemia
subjects affected / exposed	56 / 238 (23.53%)	59 / 238 (24.79%)	61 / 233 (26.18%)
occurrences all number	61	64	67
Hyperkalaemia
subjects affected / exposed	58 / 238 (24.37%)	60 / 238 (25.21%)	51 / 233 (21.89%)
occurrences all number	70	81	66
Hypomagnesaemia
subjects affected / exposed	53 / 238 (22.27%)	52 / 238 (21.85%)	53 / 233 (22.75%)
occurrences all number	56	62	62
Hyperglycaemia
subjects affected / exposed	32 / 238 (13.45%)	33 / 238 (13.87%)	30 / 233 (12.88%)
occurrences all number	34	38	31
Hypokalaemia
subjects affected / exposed	26 / 238 (10.92%)	25 / 238 (10.50%)	36 / 233 (15.45%)
occurrences all number	26	29	38
Hyperlipidaemia
subjects affected / exposed	28 / 238 (11.76%)	27 / 238 (11.34%)	18 / 233 (7.73%)
occurrences all number	28	29	20
Hypocalcaemia
subjects affected / exposed	16 / 238 (6.72%)	18 / 238 (7.56%)	25 / 233 (10.73%)
occurrences all number	17	19	25
Diabetes mellitus
subjects affected / exposed	19 / 238 (7.98%)	12 / 238 (5.04%)	19 / 233 (8.15%)
occurrences all number	19	12	19
Hypercholesterolaemia
subjects affected / exposed	14 / 238 (5.88%)	15 / 238 (6.30%)	8 / 233 (3.43%)
occurrences all number	14	15	8
Hypoglycaemia
subjects affected / exposed	13 / 238 (5.46%)	14 / 238 (5.88%)	8 / 233 (3.43%)
occurrences all number	17	18	8
Hyperphosphataemia
subjects affected / exposed	13 / 238 (5.46%)	4 / 238 (1.68%)	9 / 233 (3.86%)
occurrences all number	13	4	10

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Were there any global substantial amendments to the protocol? Yes

19 Mar 2004

The definition of treatment failure was modified in the first protocol amendment. Additionally, a last observation carried forward approach would be used for GFR analysis for participants who discontinued or were lost to follow-up before the planned end of study. Planned interim analyses were added. The schedule of a few laboratory collections was also modified and exclusion criteria regarding concomitant medication use and cold ischemia time were changed.

18 Aug 2004

The method for GFR assessment was changed from direct measurement with cold iothalmate to a calculated estimate using the Nankivell equation. Additionally, the CNI trough ranges were modified to allow for greater exposure in the early post-transplantation period. Dosing and treatment guidelines were updated, specifically regarding corticosteroid use and management of cyclosporine and MMF dosing.

15 Nov 2005

Clarifications were added for the handling of discontinued participants as well as the length of Sponsor provision of study drug. Plans for validation of the electronic Case Report Form database were specified.

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: An Open-Label, Prospective, Randomized, Controlled, Multi-Center Study Assessing Fixed Dose Versus Concentration Controlled Cellcept® Regimens for Patients Following a Single Organ Renal Transplantation in Combination With Full Dose and Reduced Dose Calcineurin Inhibitors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants with Treatment Failure During 12 Months Post-Transplantation

Primary: Percentage of Participants with Treatment Failure During 12 Months Post-Transplantation

Primary: Percent Change from Baseline in Calculated Glomerular Filtration Rate (GFR) at 12 Months Post-Transplantation

Primary: Percent Change from Baseline in Calculated Glomerular Filtration Rate (GFR) at 12 Months Post-Transplantation

Secondary: Percentage of Participants with Treatment Failure During 6 and 20-24 Months Post-Transplantation

Secondary: Percentage of Participants with Treatment Failure During 6 and 20-24 Months Post-Transplantation

Secondary: Percentage of Participants with BPAR During 6, 12, and 20-24 Months Post-Transplantation

Secondary: Percentage of Participants with BPAR During 6, 12, and 20-24 Months Post-Transplantation

Secondary: Percentage of Participants by Number of BPAR Episodes During 6, 12, and 20-24 Months Post-Transplantation

Secondary: Percentage of Participants by Number of BPAR Episodes During 6, 12, and 20-24 Months Post-Transplantation

Secondary: Percentage of Participants Treated for Acute Rejection (AR) During 6, 12, and 20-24 Months Post-Transplantation

Secondary: Percentage of Participants Treated for Acute Rejection (AR) During 6, 12, and 20-24 Months Post-Transplantation

Secondary: Percentage of Participants Who Experienced Graft Loss During 6, 12, and 20-24 Months Post-Transplantation

Secondary: Percentage of Participants Who Experienced Graft Loss During 6, 12, and 20-24 Months Post-Transplantation

Secondary: Percentage of Participants Who Died During 6, 12, and 20-24 Months Post-Transplantation

Secondary: Percentage of Participants Who Died During 6, 12, and 20-24 Months Post-Transplantation

Secondary: Percentage of Participants Who Discontinued Treatment with MMF or Were Lost to Follow-Up During 6, 12, and 20-24 Months Post-Transplantation

Secondary: Percentage of Participants Who Discontinued Treatment with MMF or Were Lost to Follow-Up During 6, 12, and 20-24 Months Post-Transplantation

Secondary: Time to First BPAR Episode During 6, 12, and 20-24 Months Post-Transplantation

Secondary: Time to First BPAR Episode During 6, 12, and 20-24 Months Post-Transplantation

Secondary: Time to Treatment Failure During 6, 12, and 20-24 Months Post-Transplantation

Secondary: Time to Treatment Failure During 6, 12, and 20-24 Months Post-Transplantation

Secondary: Percent Change from Baseline in Calculated GFR at 3, 6, and 20-24 Months Post-Transplantation

Secondary: Percent Change from Baseline in Calculated GFR at 3, 6, and 20-24 Months Post-Transplantation

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
An Open-Label, Prospective, Randomized, Controlled, Multi-Center Study Assessing Fixed Dose Versus Concentration Controlled Cellcept® Regimens for Patients Following a Single Organ Renal Transplantation in Combination With Full Dose and Reduced Dose Calcineurin Inhibitors