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Clinical Trial Results:
Evaluation of the Benefits and Risks in Maintenance Renal Transplant Recipients Following Conversion to Nulojix® (belatacept)-based Immunosuppression

Summary
EudraCT number	2012-001314-42
Trial protocol	SE AT DE FR
Global end of trial date	14 Oct 2019

Results information
Results version number	v1(current)
This version publication date	08 Nov 2020
First version publication date	08 Nov 2020
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

IM103-116

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée de la Hulpe 185, Brussels, Belgium, 1170

Public contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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

06 Dec 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

14 Oct 2019

Was the trial ended prematurely?

Main objective of the trial

To evaluate patient and functional graft survival in maintenance renal transplant recipients (6 - 60 months post-transplantation) converted from CNI to belatacept-based immunosuppression as compared to those continuing CNI based immunosuppression at 24 months post-randomization.

Protection of trial subjects

The study was conducted in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Mar 2013

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: 185

Country: Number of subjects enrolled

Argentina: 64

Country: Number of subjects enrolled

Colombia: 8

Country: Number of subjects enrolled

Austria: 14

Country: Number of subjects enrolled

France: 43

Country: Number of subjects enrolled

Germany: 96

Country: Number of subjects enrolled

Netherlands: 31

Country: Number of subjects enrolled

Norway: 1

Country: Number of subjects enrolled

Sweden: 1

Country: Number of subjects enrolled

Switzerland: 3

Worldwide total number of subjects

446

EEA total number of subjects

186

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)

370

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Screening details

631 Subjects Enrolled, 446 randomized and Treated

Period 1 title

Randomization

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Belatacept

Arm description

Participants who converted to belatacept treatment from CNI-Based

Arm type

Active comparator

Investigational medicinal product name

Belatacept

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solution for solution for injection

Routes of administration

Subcutaneous use, Intravascular use

Dosage and administration details

Injection 250 mg / vial

Investigational medicinal product name

Mycophenolate Mofetil

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravascular use

Dosage and administration details

will be administered according to the package insert. Daily MMF should be administered in 2 divided doses on a consistent schedule in relation to the time of day and meals. Intravenous dosing is permitted, if needed, due to inter-current illness or other cause, at the investigator’s discretion. The dose and schedule may be adjusted determined on the basis of laboratory values and subject tolerability

Investigational medicinal product name

Enteric-coated Mycophenolate sodium/ Mycophenolic Acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

will be administered according to the package insert. Daily EC-MPS/MPA should be administered in 2 divided doses on a consistent schedule in relation to the time of day and meals. Intravenous dosing is permitted, if needed, due to inter-current illness or other cause, at the investigator’s discretion. The dose and schedule may be adjusted determined on the basis of laboratory values and subject tolerability

Investigational medicinal product name

Corticosteroids

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects should be maintained on a stable daily dose of corticosteroids for the duration of the study unless a change in the medical condition of the subject warrants adjustment. Withdrawal of corticosteroids during the study is not permitted.

CNI-Based Regimen

Arm description

Participants who continued on CNI-Based regimens

Arm type

Active comparator

Investigational medicinal product name

Cyclosporine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravascular use

Dosage and administration details

doses should be adjusted to maintain trough serum concentrations in the range of 50 - 250 ng/mL

Investigational medicinal product name

Tacrolimus

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravascular use

Dosage and administration details

doses should be adjusted to maintain trough serum concentrations in the range of 4 - 11 ng/mL

Investigational medicinal product name

Mycophenolate Mofetil

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravascular use

Dosage and administration details

Investigational medicinal product name

Enteric-coated Mycophenolate sodium/ Mycophenolic Acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Corticosteroids

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1	Belatacept	CNI-Based Regimen
Started	223	223
Completed	221	222
Not completed	2	1
Not Treated	2	1

Period 2 title

Treatment Period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Belatacept

Arm description

Participants who converted to belatacept treatment from CNI-Based

Arm type

Active comparator

Investigational medicinal product name

Belatacept

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder and solution for solution for injection

Routes of administration

Intravascular use

Dosage and administration details

Injection 250 mg / vial

Investigational medicinal product name

Mycophenolate Mofeti

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravascular use

Dosage and administration details

Investigational medicinal product name

Enteric-coated Mycophenolate sodium/ Mycophenolic Acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Corticosteroids

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

CNI-Based Regimen

Arm description

Participants who continued on CNI-Based regimens

Arm type

Active comparator

Investigational medicinal product name

Tacrolimus

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravascular use

Dosage and administration details

doses should be adjusted to maintain trough serum concentrations in the range of 4 - 11 ng/mL

Investigational medicinal product name

Cyclosporine

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravascular use

Dosage and administration details

doses should be adjusted to maintain trough serum concentrations in the range of 50 - 250 ng/mL

Investigational medicinal product name

Mycophenolate Mofeti

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravascular use

Dosage and administration details

Investigational medicinal product name

Enteric-coated Mycophenolate sodium/ Mycophenolic Acid

Investigational medicinal product code

Other name

Pharmaceutical forms

Coated tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Corticosteroids

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 2	Belatacept	CNI-Based Regimen
Started	221	222
Completed	195	186
Not completed	26	36
Adverse event, serious fatal	3	3
withdrew consent	1	2
request to discontinue	6	11
Adverse event, non-fatal	12	7
No longer meets study criteria	3	10
poor/non compliance	-	3
Lack of efficacy	1	-

Baseline characteristics

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Reporting group title

Belatacept

Reporting group description

Participants who converted to belatacept treatment from CNI-Based

Reporting group title

CNI-Based Regimen

Reporting group description

Participants who continued on CNI-Based regimens

Reporting group values	Belatacept	CNI-Based Regimen	Total
Number of subjects	223	223	446
Age categorical
Units: Subjects
Adults (18-64 years)	184	186	370
From 65-84 years	39	37	76
Age Continuous
Units: Years
median (standard deviation)	55.0 ( 11.3 )	54.0 ( 11.7 )	-
Sex: Female, Male
Units: Participants
Female	73	72	145
Male	150	151	301
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0
Asian	1	3	4
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	24	24	48
White	191	187	378
More than one race	0	0	0
Unknown or Not Reported	7	9	16
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	9	15	24
Not Hispanic or Latino	82	79	161
Unknown or Not Reported	132	129	261

End points

Top of page

Reporting group title

Belatacept

Reporting group description

Participants who converted to belatacept treatment from CNI-Based

Reporting group title

CNI-Based Regimen

Reporting group description

Participants who continued on CNI-Based regimens

Reporting group title

Belatacept

Reporting group description

Participants who converted to belatacept treatment from CNI-Based

Reporting group title

CNI-Based Regimen

Reporting group description

Participants who continued on CNI-Based regimens

Primary: Percentage of participants who survive with a functional graft at 24 months

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End point title

Percentage of participants who survive with a functional graft at 24 months

End point description

Percentage of participants who survive with a functional graft at 24 months post-randomization

End point type

Primary

End point timeframe

at 24 Months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	223	223
Units: Percentage
number (confidence interval 95%)	98.2 (95.5 to 99.5)	97.3 (95.2 to 99.4)

Difference between belatacept and CNI

Comparison groups

Belatacept v CNI-Based Regimen

Number of subjects included in analysis

446

Analysis specification

Pre-specified

Analysis type

Method

Parameter type

Proportion of Difference

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-8.6

upper limit

10.4

Secondary: Percentage of participants who survive with a functional graft at 12 months

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End point title

Percentage of participants who survive with a functional graft at 12 months

End point description

Percentage of participants who survive with a functional graft at 12 months post-randomization

End point type

Secondary

End point timeframe

at 12 Months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	223	223
Units: Percentage
number (confidence interval 95%)	98.7 (96.1 to 99.7)	99.1 (96.8 to 99.9)

difference between belatacept and CNI

Comparison groups

Belatacept v CNI-Based Regimen

Number of subjects included in analysis

446

Analysis specification

Pre-specified

Analysis type

^[1]

Method

Parameter type

Proportion of Difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-9.9

upper limit

Notes
[1] - difference between belatacept and CNI

Secondary: Number of participants with a Biopsy Proven Acute Rejection (BPAR)

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End point title

Number of participants with a Biopsy Proven Acute Rejection (BPAR)

End point description

The number of clinically suspected, biopsy proven acute rejection (AR) at 12 and 24 months post-randomization includes subjects with at least one cellular and/or humoral BPAR event.

End point type

Secondary

End point timeframe

at 12 and 24 Months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	223	223
Units: Participants
at 12 Months	18	4
at 24 Months	18	9

No statistical analyses for this end point

Secondary: Number of Participants with varying severity of BPAR

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End point title

Number of Participants with varying severity of BPAR

End point description

Number of participants in each severity of clinically suspected, biopsy proven acute rejection (AR) at 12 and 24 months post-randomization

End point type

Secondary

End point timeframe

at 12 and 24 months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	223	223
Units: participants
at 12 Months\|Mild Acute (IA)	2	2
at 24 Months\|Mild Acute (IA)	2	4
at 12 Months\|Mild Acute (IB)1	1	0
at 24 Months\|Mild Acute (IB)1	1	0
at 12 Months\|Moderate Acute (IIA)	7	0
at 24 Months\|Moderate Acute (IIA)	7	1
at 12 Months\|Moderate Acute (IIB)	6	0
at 24 Months\|Moderate Acute (IIB)	6	0
at 12 Months\|Severe Acute (III)	4	1
at 24 Months\|Severe Acute (III)	4	1

No statistical analyses for this end point

Secondary: Mean change from baseline of Calculated Glomerular Filtration Rate (cGFR) - Percent Change

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End point title

Mean change from baseline of Calculated Glomerular Filtration Rate (cGFR) - Percent Change

End point description

Mean change from baseline cGFR as calculated by the 4-variable MDRD equation to 12 and 24 months post-randomization - Percent Change

End point type

Secondary

End point timeframe

at 12 and 24 months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	223	223
Units: mL/min/1.73m²
arithmetic mean (confidence interval 95%)
at 12 Months	13.2 (10.4 to 16.0)	-0.3 (-2.9 to 2.4)
at 24 Months	15.2 (11.9 to 18.6)	0.3 (-2.9 to 3.4)

No statistical analyses for this end point

Secondary: Mean change from baseline of Calculated Glomerular Filtration Rate (cGFR) - Adjusted Change

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End point title

Mean change from baseline of Calculated Glomerular Filtration Rate (cGFR) - Adjusted Change

End point description

Mean change from baseline cGFR as calculated by the 4-variable MDRD equation to 12 and 24 months post-randomization - Adjusted Change

End point type

Secondary

End point timeframe

at 12 and 24 months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	223	223
Units: mL/min/1.73m²
arithmetic mean (confidence interval 95%)
at 12 Months	5.6 (4.3 to 6.9)	-0.7 (-2.0 to 0.6)
at 24 Months	6.2 (4.7 to 7.7)	-1.0 (-2.6 to 0.5)

No statistical analyses for this end point

Secondary: Mean Calculated Glomerular Filtration Rate (cGFR)

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End point title

Mean Calculated Glomerular Filtration Rate (cGFR)

End point description

Mean cGFR by study visit, as calculated by the 4-variable MDRD equation.

End point type

Secondary

End point timeframe

up to 24 months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	223	223
Units: mL/min/1.73m²
arithmetic mean (confidence interval 95%)
Screening	49.8 (48.2 to 51.5)	49.7 (48.2 to 51.2)
Baseline	49.6 (48.0 to 51.2)	50.7 (49.2 to 52.2)
Month 3	53.0 (51.1 to 54.9)	50.2 (48.3 to 52.0)
Month 6	53.3 (51.3 to 55.3)	50.9 (49.1 to 52.7)
Month 9	53.7 (51.8 to 55.6)	50.7 (48.9 to 52.5)
Month 12	55.5 (53.4 to 57.6)	50.5 (48.7 to 52.4)
Month 18	56.5 (54.5 to 58.5)	51.3 (49.2 to 53.4)
Month 24	55.7 (53.7 to 57.7)	51.1 (49.0 to 53.2)

No statistical analyses for this end point

Secondary: Slope Analysis of cGFR

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End point title

Slope Analysis of cGFR

End point description

Slopes of cGFR as plotted from baseline as well as from Month 3, to Month 12 and Month 24 post-randomization

End point type

Secondary

End point timeframe

at 12 and 24 Months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	223	223
Units: mL/min/1.73m²/month
number (confidence interval 95%)
Baseline to 12 Months	0.241 (0.103 to 0.378)	0.004 (-0.137 to 0.145)
Month 3 to Month 12	0.281 (0.072 to 0.490)	-0.159 (-0.372 to 0.055)
Baseline to Month 24	0.685 (0.426 to 0.945)	-0.112 (-0.379 to 0.155)
Month 3 to Month 24	0.658 (0.332 to 0.984)	-0.277 (-0.614 to 0.060)

No statistical analyses for this end point

Secondary: Slope Analysis of 1/Serum Creatinine

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End point title

Slope Analysis of 1/Serum Creatinine

End point description

Slopes of 1/serum creatinine as plotted from baseline as well as from Month 3, to Month 12 and Month 24 post-randomization

End point type

Secondary

End point timeframe

at 12 and 24 Months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	223	223
Units: mL/min/1.73m²/month
number (confidence interval 95%)
Baseline to 12 Months	0.034 (0.016 to 0.051)	-0.003 (-0.020 to 0.015)
Month 3 to Month 12	0.033 (0.007 to 0.059)	-0.021 (-0.048 to 0.006)
Baseline to Month 24	0.00868 (0.00537 to 0.01199)	-0.00203 (-0.00544 to 0.00138)
Month 3 to Month 24	0.00814 (0.00412 to 0.01217)	-0.00425 (-0.00842 to -0.00009)

No statistical analyses for this end point

Secondary: Percentage of participants with > 5% and >10% improvement over baseline cGFR

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End point title

Percentage of participants with > 5% and >10% improvement over baseline cGFR

End point description

Percentage of participants with > 5% and >10% improvement over baseline cGFR, at 12 and 24 months post-randomization

End point type

Secondary

End point timeframe

at 12 and 24 Months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	223	223
Units: Percentage
number (not applicable)
>5% improvement at 12 months	53.4	28.7
>10% improvement at 12 months	43.9	21.5
>5% improvement at 24 months	54.3	29.6
>10% improvement at 24 months	48.4	22.0

No statistical analyses for this end point

Secondary: Mean urine protein/ creatinine ratio (UPCR)

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End point title

Mean urine protein/ creatinine ratio (UPCR)

End point description

Urine protein/ creatinine ratio (UPCR) at baseline, 3, 6, 12 and 24 months post randomization

End point type

Secondary

End point timeframe

Up to 24 Months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	223	223
Units: mg/mmol
arithmetic mean (confidence interval 95%)
at Baseline	17.80 (16.03 to 19.58)	18.61 (15.08 to 22.14)
at 3 months	22.87 (19.88 to 25.86)	20.61 (15.50 to 25.73)
at 6 months	23.42 (19.71 to 27.12)	20.85 (15.36 to 26.35)
at 12 months	29.11 (21.86 to 36.35)	21.67 (17.70 to 25.65)
at 24 months	28.81 (23.71 to 33.91)	24.56 (19.01 to 30.10)

No statistical analyses for this end point

Secondary: Mean change from baseline in systolic and diastolic blood pressure

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End point title

Mean change from baseline in systolic and diastolic blood pressure

End point description

Mean change in systolic and diastolic blood pressure from baseline to 12 and 24 months post randomization

End point type

Secondary

End point timeframe

at 12 and 24 months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	223	223
Units: mmHg
arithmetic mean (confidence interval 90%)
Diastolic BP at 12 Months	-1.5 (-2.9 to 0.0)	-0.6 (-2.1 to 1.0)
Diastolic BP at 24 Months	-1.7 (-3.3 to 0.0)	0.5 (-1.3 to 2.3)
Systolic BP at 12 Months	-1.6 (-4.0 to 0.9)	0.1 (-2.5 to 2.8)
Systolic BP at 24 Months	-1.3 (-4.1 to 1.6)	1.2 (-1.7 to 4.1)

No statistical analyses for this end point

Secondary: Number of antihypertensive medications used to control hypertension

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End point title

Number of antihypertensive medications used to control hypertension

End point description

The total number of antihypertensive medications used to control hypertension

End point type

Secondary

End point timeframe

at baseline, 12 and 24 Months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	223	223
Units: Number of medications
arithmetic mean (full range (min-max))
at Baseline	2.1 (1 to 5)	2.2 (1 to 6)
at 12 Months	2.3 (1 to 7)	2.2 (1 to 6)
at 24 Mnths	2.3 (1 to 8)	2.3 (1 to 7)

No statistical analyses for this end point

Secondary: Number of participants with donor specific antibodies (DSA)

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End point title

Number of participants with donor specific antibodies (DSA)

End point description

Number of participants with donor specific antibodies (DSA) at Baseline/Day 1, and Months 12 and 24 post-randomization

End point type

Secondary

End point timeframe

at baseline, 12 and 24 months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	223	223
Units: Participants
Pre existing at baseline	10	26
De Novo at 12 Months	2	9
De Novo at 24 Months	2	14

No statistical analyses for this end point

Secondary: Mean number of symptom occurrence and Symptom Distress

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End point title

Mean number of symptom occurrence and Symptom Distress

End point description

The frequency of symptom occurrence and symptom distress as measured with the Modified Transplant Symptom Occurrence and Symptom Distress Scale-59R (MTSOSD-59R) at baseline, Week 6, and Months 3, 6, and 12 post-randomization. Higher scores in the MTSOSD-59R indicate a greater symptom and symptom distress burden than lower scores.

End point type

Secondary

End point timeframe

up to 12 Months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	221	222
Units: Scores on a scale
arithmetic mean (standard deviation)
Baseline symptom occurrence	87.8 ( 20.06 )	90.7 ( 21.04 )
Baseline symptom distress	28.7 ( 27.07 )	34.8 ( 28.30 )
week 6 symptom occurrence	79.0 ( 16.52 )	88.6 ( 21.36 )
week 6 symptom distress	19.8 ( 21.41 )	32.4 ( 29.55 )
Month 3 symptom occurrence	80.5 ( 16.74 )	89.9 ( 23.45 )
Month 3 symptom distress	21.4 ( 23.08 )	35.2 ( 32.04 )
month 6 symptom occurrence	80.5 ( 17.50 )	91.8 ( 23.72 )
month 6 symptom distress	22.4 ( 22.18 )	36.3 ( 31.39 )
month 12 symptom occurrence	82.3 ( 20.08 )	91.0 ( 22.33 )
month 12 symptom distress	25.8 ( 25.32 )	34.4 ( 30.82 )

No statistical analyses for this end point

Secondary: Number of participants with an adverse event of special interest

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End point title

Number of participants with an adverse event of special interest

End point description

Number of participants with an adverse event of special interests. Adverse events of special interest include: Serious Infections, Post-Transplant Lymphoproliferative Disorder (PTLD), Progressive multifocal leukoencephalopathy (PML), Malignancies (other than PTLD) including non-melanoma skin carcinomas, Tuberculosis Infections, CNS infections, Viral Infections and Infusion related reactions.

End point type

Secondary

End point timeframe

24 Months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	221	222
Units: participants
Serious Infections	37	44
PTLD	1	0
PML	0	0
Malignancies	17	12
Tuberculosis infections	0	0
CNS Infections	0	0
Viral Infections	5	9
Infusion Related Reactions	13	0

No statistical analyses for this end point

Secondary: Number of participants with Marked Laboratory Abnormalities

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End point title

Number of participants with Marked Laboratory Abnormalities

End point description

Number of participants with Marked Laboratory Abnormalities

End point type

Secondary

End point timeframe

24 Months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	221	222
Units: Participants
Hemoglobin (Abnormal Low)	0	0
Hemoglobin (Abnormal high)	0	0
Platelet count (Abnormal low)	0	1
Leukocytes (Abnormal low)	0	0
Lymphocytes (Abnormal low)	29	10
Lymphocytes (Abnormal high)	0	0
Neutrophils Absolute (Abnormal low)	5	3
Alanine Aminotransferase (Abnormal High)	0	0
Alkaline Phosphatase (Abnormal High)	0	0
Aspartate Aminotransferase (Abnormal High)	0	1
Total Bilirubin (Abnormal High)	0	0
Creatine (Abnormal High)	5	4
Protein/Creatinine Ratio (Abnormal High)	0	0
Bicarbonate (Abnormal High)	0	1
Total Calcium (Abnormal low)	0	3
Total Calcium (Abnormal high)	1	2
Magnesium (Abnormal low)	0	0
Magnesium (Abnormal high)	0	0
Phosphorus (Abnormal Low)	14	12
Potassium (Abnormal low)	3	2
Potassium (Abnormal high)	1	5
Sodium (Abnormal low)	4	9
Sodium (Abnormal high)	0	1
Albumin (Abnormal low)	0	0
Total Cholesterol (Abnormal High)	13	17
Serum Glucose (Abnormal low)	0	0
Serum Glucose (Abnormal high)	18	18
Triglycerides (Abnormal high)	2	2
Uric Acid (Abnormal high)	15	30

No statistical analyses for this end point

Secondary: Mean change from baseline in vital signs: Heart Rate

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End point title

Mean change from baseline in vital signs: Heart Rate

End point description

The mean change from baseline in measured heart rate

End point type

Secondary

End point timeframe

at 12 and 24 months

End point values	Belatacept	CNI-Based Regimen
Number of subjects analysed	221	222
Units: beats per minute (bpm)
arithmetic mean (confidence interval 95%)
Change from baseline at 12 months	-1.8 (-3.3 to -0.2)	-0.6 (-2.2 to 1.0)
Change from baseline at 24 months	-1.9 (-3.5 to -0.3)	1.0 (-0.8 to 2.8)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were collected from start of treatment up to 30 days after last treatment dose.

Adverse event reporting additional description

Adverse events were calculated up to 24 months

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

22.0

Reporting group title

CNI-Based Regimen

Reporting group description

Subjects randomized to continued their CNI-based regimen, received doses targeted to achieve trough serum concentrations (C0 levels) of 50 - 250 nanograms per milliliter (ng/mL) Cyclosporine (CsA) or 4 - 11 ng/mL Tacrolimus (TAC).

Reporting group title

Belatacept

Reporting group description

Subjects received an infusion of belatacept, 5 milligrams per kilogram (mg/kg) intravenously (IV) on Days 1, 15, 29, 43, 57, and every 28 days thereafter. Each dose was based on the Day 1 body weight (baseline weight), and was not to be modified unless body weight increased or decreased by more than or equal to 10% from Day 1. The infusion solution was administered over a period of approximately 30 minutes. The Calcineurin Inhibitors (CNI) dose was tapered to 40% - 60% of the baseline dose by Day 15, 20% - 30% of the baseline dose by Day 22, and was then discontinued by Day 29 (± 3 days).

Serious adverse events	CNI-Based Regimen	Belatacept
Total subjects affected by serious adverse events
subjects affected / exposed	97 / 222 (43.69%)	108 / 221 (48.87%)
number of deaths (all causes)	5	4
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	5 / 222 (2.25%)	11 / 221 (4.98%)
occurrences causally related to treatment / all	4 / 6	6 / 11
deaths causally related to treatment / all	0 / 0	0 / 0
Bowen's disease
subjects affected / exposed	0 / 222 (0.00%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cholesteatoma
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Papillary thyroid cancer
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post transplant lymphoproliferative disorder
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer recurrent
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	5 / 222 (2.25%)	3 / 221 (1.36%)
occurrences causally related to treatment / all	3 / 5	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	1 / 222 (0.45%)	4 / 221 (1.81%)
occurrences causally related to treatment / all	0 / 1	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 222 (0.45%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Dry gangrene
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Extremity necrosis
subjects affected / exposed	0 / 222 (0.00%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 222 (0.00%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 222 (0.00%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	2 / 222 (0.90%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombophlebitis superficial
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 222 (0.00%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumatosis
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 222 (0.00%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Sudden death
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Immune system disorders
Chronic allograft nephropathy
subjects affected / exposed	2 / 222 (0.90%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Kidney transplant rejection
subjects affected / exposed	8 / 222 (3.60%)	19 / 221 (8.60%)
occurrences causally related to treatment / all	1 / 9	13 / 21
deaths causally related to treatment / all	0 / 0	0 / 0
Renal transplant failure
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Uterovaginal prolapse
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vulvar dysplasia
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	2 / 222 (0.90%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus polyp
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Depressive delusion
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Blood creatinine increased
subjects affected / exposed	2 / 222 (0.90%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Donor specific antibody present
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Norovirus test positive
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Animal bite
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula aneurysm
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site complication
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site haemorrhage
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula thrombosis
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Complications of transplanted kidney
subjects affected / exposed	2 / 222 (0.90%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 13	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ligament rupture
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Limb injury
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Overdose
subjects affected / exposed	0 / 222 (0.00%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural fever
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haematuria
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Shunt blood flow excessive
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Shunt occlusion
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Traumatic intracranial haemorrhage
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular pseudoaneurysm
subjects affected / exposed	1 / 222 (0.45%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound haemorrhage
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Graft loss
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Congenital, familial and genetic disorders
Congenital cystic kidney disease
subjects affected / exposed	0 / 222 (0.00%)	3 / 221 (1.36%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 222 (0.45%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 222 (0.45%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure chronic
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	3 / 222 (1.35%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 222 (0.45%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	2 / 222 (0.90%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Palpitations
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus bradycardia
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Carotid artery stenosis
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral artery stenosis
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neuropathy peripheral
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	3 / 222 (1.35%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Agranulocytosis
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymphocytosis
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Monocytosis
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombotic microangiopathy
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Angle closure glaucoma
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Retinal vein occlusion
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal hernia
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal incarcerated hernia
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Abdominal pain
subjects affected / exposed	1 / 222 (0.45%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis microscopic
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dental caries
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	6 / 222 (2.70%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	2 / 7	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorder
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 222 (0.90%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal stenosis
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal ulcer haemorrhage
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 222 (0.00%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct stone
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary dyskinesia
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic cyst
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Diabetic foot
subjects affected / exposed	1 / 222 (0.45%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperhidrosis
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	5 / 222 (2.25%)	4 / 221 (1.81%)
occurrences causally related to treatment / all	1 / 7	2 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder diverticulum
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Glomerulonephritis
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Proteinuria
subjects affected / exposed	0 / 222 (0.00%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Renal artery stenosis
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal disorder
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary incontinence
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vesicoureteric reflux
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Hyperparathyroidism
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperthyroidism
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma muscle
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	2 / 222 (0.90%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Anal abscess
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial pyelonephritis
subjects affected / exposed	0 / 222 (0.00%)	3 / 221 (1.36%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 222 (0.45%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	3 / 222 (1.35%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic sinusitis
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cytomegalovirus infection
subjects affected / exposed	2 / 222 (0.90%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Enterococcal bacteraemia
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia infection
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gangrene
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	6 / 222 (2.70%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	1 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	1 / 222 (0.45%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis rotavirus
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic cyst infection
subjects affected / exposed	1 / 222 (0.45%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	0 / 222 (0.00%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Histoplasmosis disseminated
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Infected cyst
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infected lymphocele
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	2 / 222 (0.90%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	1 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Necrotising soft tissue infection
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal candidiasis
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oral candidiasis
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	1 / 222 (0.45%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	7 / 222 (3.15%)	5 / 221 (2.26%)
occurrences causally related to treatment / all	0 / 7	2 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia respiratory syncytial viral
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	1 / 222 (0.45%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 222 (0.45%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cyst infection
subjects affected / exposed	2 / 222 (0.90%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal graft infection
subjects affected / exposed	1 / 222 (0.45%)	2 / 221 (0.90%)
occurrences causally related to treatment / all	0 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 222 (0.90%)	4 / 221 (1.81%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic candida
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	8 / 222 (3.60%)	7 / 221 (3.17%)
occurrences causally related to treatment / all	1 / 17	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	3 / 222 (1.35%)	6 / 221 (2.71%)
occurrences causally related to treatment / all	1 / 3	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection
subjects affected / exposed	2 / 222 (0.90%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bk virus infection
subjects affected / exposed	2 / 222 (0.90%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	1 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cytomegalovirus chorioretinitis
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Medical device site infection
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 222 (0.45%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	3 / 222 (1.35%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemia
subjects affected / exposed	0 / 222 (0.00%)	1 / 221 (0.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ketoacidosis
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Steroid diabetes
subjects affected / exposed	1 / 222 (0.45%)	0 / 221 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	CNI-Based Regimen	Belatacept
Total subjects affected by non serious adverse events
subjects affected / exposed	167 / 222 (75.23%)	174 / 221 (78.73%)
Investigations
Blood creatinine increased
subjects affected / exposed	17 / 222 (7.66%)	20 / 221 (9.05%)
occurrences all number	20	23
Vascular disorders
Hypertension
subjects affected / exposed	21 / 222 (9.46%)	29 / 221 (13.12%)
occurrences all number	24	32
Nervous system disorders
Dizziness
subjects affected / exposed	8 / 222 (3.60%)	15 / 221 (6.79%)
occurrences all number	9	18
Headache
subjects affected / exposed	23 / 222 (10.36%)	27 / 221 (12.22%)
occurrences all number	29	35
Tremor
subjects affected / exposed	12 / 222 (5.41%)	6 / 221 (2.71%)
occurrences all number	13	6
General disorders and administration site conditions
Fatigue
subjects affected / exposed	15 / 222 (6.76%)	23 / 221 (10.41%)
occurrences all number	16	30
Oedema peripheral
subjects affected / exposed	35 / 222 (15.77%)	22 / 221 (9.95%)
occurrences all number	40	26
Pyrexia
subjects affected / exposed	17 / 222 (7.66%)	20 / 221 (9.05%)
occurrences all number	18	31
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	13 / 222 (5.86%)	12 / 221 (5.43%)
occurrences all number	13	12
Diarrhoea
subjects affected / exposed	61 / 222 (27.48%)	47 / 221 (21.27%)
occurrences all number	77	63
Nausea
subjects affected / exposed	11 / 222 (4.95%)	15 / 221 (6.79%)
occurrences all number	11	15
Vomiting
subjects affected / exposed	13 / 222 (5.86%)	10 / 221 (4.52%)
occurrences all number	17	12
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	21 / 222 (9.46%)	31 / 221 (14.03%)
occurrences all number	23	41
Oropharyngeal pain
subjects affected / exposed	12 / 222 (5.41%)	10 / 221 (4.52%)
occurrences all number	15	10
Psychiatric disorders
Insomnia
subjects affected / exposed	12 / 222 (5.41%)	9 / 221 (4.07%)
occurrences all number	12	10
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	23 / 222 (10.36%)	21 / 221 (9.50%)
occurrences all number	27	25
Back pain
subjects affected / exposed	22 / 222 (9.91%)	18 / 221 (8.14%)
occurrences all number	24	19
Musculoskeletal pain
subjects affected / exposed	12 / 222 (5.41%)	5 / 221 (2.26%)
occurrences all number	14	5
Pain in extremity
subjects affected / exposed	20 / 222 (9.01%)	11 / 221 (4.98%)
occurrences all number	21	11
Infections and infestations
Bronchitis
subjects affected / exposed	18 / 222 (8.11%)	23 / 221 (10.41%)
occurrences all number	19	32
Nasopharyngitis
subjects affected / exposed	50 / 222 (22.52%)	44 / 221 (19.91%)
occurrences all number	75	78
Upper respiratory tract infection
subjects affected / exposed	19 / 222 (8.56%)	18 / 221 (8.14%)
occurrences all number	29	22
Urinary tract infection
subjects affected / exposed	32 / 222 (14.41%)	38 / 221 (17.19%)
occurrences all number	75	72

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Were there any global substantial amendments to the protocol? Yes

07 Jan 2013

Modification to the inclusion/exclusion criteria. Clarifications to the time and Events, and Pharmacokinetic Assessments Tables. Inclusion of Clinical criteria for suspicion of PTLD and procedures for monitoring. Update to list of Abbreviations. Minor edits and clarifications throughout the protocol, including table numbering.

04 Sep 2013

Modification to the inclusion/exclusion criteria. Clarification to the Time and Events and Pharmacokinetic Assessments Tables. Modification to the Renal Biopsy Requirements. Clarification of Live Vaccines for subjects. Addition of re-testing for screening creatinine labs. Minor edits and clarifications throughout the protocol, including table numbering.

20 Aug 2014

Modification to the inclusion/exclusion criteria. Modification to the MDRD formula, the definition of stable renal function and stable immunosuppression regimen. Addition of re-screening subjects. Extension of screening period. Decrease the frequency of body weight measurements. Minor edits and clarifications throughout the protocol.

07 Apr 2017

Modification to decrease target enrollment from 600 to 440 randomized subjects. The clarification of wording for the following: the CSPAR endpoint for consistency throughout the protocol; the requirement for daily dosing of maintenance corticosteroids throughout study participation; to indicate that protocol-specified tacrolimus trough levels being locally determined for patient management will also be captured in the clinical database; the timing for determination of post-belatacept infusion vital signs. Limitation of study participation by patients enrolled while receiving maintenance immunosuppression with tacrolimus plus mycophenolate sodium to approximately one-third (1/3) of all subjects. Provide a proviso to allow rescreening of patients who were screen failure earlier in the study. Update the definition of menopause; Correction of typographical errors and minor edits grammatical inconsistencies throughout the protocol.

30 May 2017

To correct two typographical errors on the last revised protocol version 04.

18 Apr 2018

Update definition of serious breach per company guidelines, clarify belatacept dosing instructions for skipping of doses to include possibility of dosing out of defined visit windows, addition of PML for some biomarker labs, Clarification of “end of infusion” definition, allow provision of central lab CNI trough values to sites.

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: Evaluation of the Benefits and Risks in Maintenance Renal Transplant Recipients Following Conversion to Nulojix® (belatacept)-based Immunosuppression

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of participants who survive with a functional graft at 24 months

Primary: Percentage of participants who survive with a functional graft at 24 months

Secondary: Percentage of participants who survive with a functional graft at 12 months

Secondary: Percentage of participants who survive with a functional graft at 12 months

Secondary: Number of participants with a Biopsy Proven Acute Rejection (BPAR)

Secondary: Number of participants with a Biopsy Proven Acute Rejection (BPAR)

Secondary: Number of Participants with varying severity of BPAR

Secondary: Number of Participants with varying severity of BPAR

Secondary: Mean change from baseline of Calculated Glomerular Filtration Rate (cGFR) - Percent Change

Secondary: Mean change from baseline of Calculated Glomerular Filtration Rate (cGFR) - Percent Change

Secondary: Mean change from baseline of Calculated Glomerular Filtration Rate (cGFR) - Adjusted Change

Secondary: Mean change from baseline of Calculated Glomerular Filtration Rate (cGFR) - Adjusted Change

Secondary: Mean Calculated Glomerular Filtration Rate (cGFR)

Secondary: Mean Calculated Glomerular Filtration Rate (cGFR)

Secondary: Slope Analysis of cGFR

Secondary: Slope Analysis of cGFR

Secondary: Slope Analysis of 1/Serum Creatinine

Secondary: Slope Analysis of 1/Serum Creatinine

Secondary: Percentage of participants with > 5% and >10% improvement over baseline cGFR

Secondary: Percentage of participants with > 5% and >10% improvement over baseline cGFR

Secondary: Mean urine protein/ creatinine ratio (UPCR)

Secondary: Mean urine protein/ creatinine ratio (UPCR)

Secondary: Mean change from baseline in systolic and diastolic blood pressure

Secondary: Mean change from baseline in systolic and diastolic blood pressure

Secondary: Number of antihypertensive medications used to control hypertension

Secondary: Number of antihypertensive medications used to control hypertension

Secondary: Number of participants with donor specific antibodies (DSA)

Secondary: Number of participants with donor specific antibodies (DSA)

Secondary: Mean number of symptom occurrence and Symptom Distress

Secondary: Mean number of symptom occurrence and Symptom Distress

Secondary: Number of participants with an adverse event of special interest

Secondary: Number of participants with an adverse event of special interest

Secondary: Number of participants with Marked Laboratory Abnormalities

Secondary: Number of participants with Marked Laboratory Abnormalities

Secondary: Mean change from baseline in vital signs: Heart Rate

Secondary: Mean change from baseline in vital signs: Heart Rate

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Evaluation of the Benefits and Risks in Maintenance Renal Transplant Recipients Following Conversion to Nulojix® (belatacept)-based Immunosuppression