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Clinical Trial Results:
Clinical and laboratory evaluation of acute rejection, myocyte growth, repair and oxidative stress following de novo cardiac transplant: A comparison between Tacrolimus and Cyclosporine based immunoprophylactic regimens with mycophenolic acid therapeutic drug monitoring.

Summary
EudraCT number	2015-001041-83
Trial protocol	Outside EU/EEA
Global end of trial date	18 Jul 2008

Results information
Results version number	v1
This version publication date	20 Jun 2016
First version publication date	25 Jul 2015
Other versions	v2 , v3

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

FKC-009

ISRCTN number

US NCT number

NCT00157014

WHO universal trial number (UTN)

Sponsor organisation name

Astellas Pharma Inc

Sponsor organisation address

675 Cochrane Drive, Suite 500, Markham, Canada,

Public contact

Clinical Trial Disclosure, Astellas Pharma Canada, Inc, Astellas.resultsdisclosure@astellas.com

Scientific contact

Clinical Trial Disclosure, Astellas Pharma Canada, Inc, Astellas.resultsdisclosure@astellas.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?

Yes

Analysis stage

Final

Date of interim/final analysis

18 Jul 2008

Is this the analysis of the primary completion data?

Yes

Primary completion date

18 Jul 2008

Global end of trial reached?

Yes

Global end of trial date

18 Jul 2008

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the trial was to investigate changes in subcellular markers of growth, apoptosis, differentiation, survival, inflammation, and oxidative stress, in relationship with cellular acute rejection, in de novo cardiac transplant recipients receiving either tacrolimus or cyclosporine (CsA) as the primary immunosuppressant.

Protection of trial subjects

This clinical study was written, conducted and reported in accordance with the protocol, ICH GCP Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.

Background therapy

All patients received induction therapy per institutional protocol and adjunctive immunosuppression with mycophenolate mofetil (MMF). Study treatments (tacrolimus and CsA) were administered continuously beginning no earlier than pre-transplant and no later than 10 days post-transplant. Mycophenolate mofetil (MMF) was administered peri-operatively in a pre-operative dose of 1.0 g IV/PO. The post-operative dose of MMF was given within 6 hours of transplantation at 1.0g IV/P for one week post-transplant and then 1.0g PO BID throughout the study period. Methylprednisolone was administered pre-operatively for adult patients and intra-operatively for paediatric patients. Prednisone was administered daily and was tapered slowly throughout the study. It was administered orally daily in Weeks 1 to 4: 20 mg; Week 8: 10 mg ; Week 12: 7.5 mg ; Weeks 16 to 26: 5 mg ; Weeks 27 to 52; 0-5 mg. Prednisone was discontinued after Week 26 according to the investigator’s clinical judgment. During the study, all patients were treated with statins to control lipid profiles. The drug pravastatin and simvastatin were recommended as first-line statin therapy. Patients also received antihypertensive therapy with angiotensin-converting enzyme (ACE) inhibitors as standard per protocol medical management or prophylaxis of calcineurin inhibitor-induced hypertension. Patients also received ganciclovir either orally or IV for cytomegalovirus (CMV) prophylaxis at the discretion of the investigator.

Evidence for comparator

Tacrolimus (Tac, FK506) and cyclosporine (CsA) have played a major role in the control of acute rejection (AR) in all organ transplants. Tacrolimus-based immunoprophylaxis resulted in 50% less development of hypertension, lower cholesterol and low-density lipoprotein (LDL) - cholesterol, and better preservation of renal function in both cardiac and renal transplant recipients. The dosing of CsA, MMF, and corticosteroids was based on current standards of practice for the use of these products in immunoprophylaxis of cardiac transplant patients.

Actual start date of recruitment

10 May 2004

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 93

Country: Number of subjects enrolled

United States: 18

Worldwide total number of subjects

111

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)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Adult and pediatric (from birth) male and female de novo recipients of cadaveric heart transplants.

Screening details

Screening(pre-transplant)period was Day -180 to -1;transplant was Day 0;Randomization conducted Days 0-10 post-transplant;133 adults were screened;100 were randomized and 17 pediatric participants were screened; 11 randomized.Patients were assigned treatment with either tacrolimus or cyclosporine in a 1:1 ratio within 10 days post-transplantation.

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

Tacrolimus - Adult

Arm description

Adult primary cadaveric heart transplant recipients randomized to immunosuppression with Tacrolimus 0.05 – 0.10 mg/ kg/ day administered orally in 2 divided doses starting within 10 days of transplant.

Arm type

Experimental

Investigational medicinal product name

Tacrolimus-Adult Dose

Investigational medicinal product code

FK506

Other name

Prograf®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Adult Dose: Tacrolimus 0.05 to 0.10 mg/kg/day in 2 divided doses starting within 10 days of transplant supplied as 5-, 1-, or 0.5-mg capsules. Tacrolimus was administered on an empty stomach, 1 hour before or 2 hours after meals. Study treatments were administered continuously beginning no earlier than pre-transplant and no later than 10 days post-transplant.In the event that therapeutic levels could not be achieved with oral capsules in the immediate post-operative period, use of commercially–obtained tacrolimus intravenous (IV) solution (Prograf® IV 5mg/mL) was permitted.

Cyclosporine – Adult

Arm description

Adult primary cadaveric heart transplant recipients randomized to immunosuppression with Cyclosporine 3-5 mg/kg/day administered orally in 2 divided doses starting within 10 days of transplant.

Arm type

Experimental

Investigational medicinal product name

Cyclosporine-Adult

Investigational medicinal product code

Other name

Neoral

Pharmaceutical forms

Capsule, soft

Routes of administration

Oral use

Dosage and administration details

Adult Dose: Starting within 10 days of transplant supplied as 10-, 25-, 50-, or 100-mg capsules. Study treatments were administered continuously beginning no earlier than pre-transplant and no later than 10 days post-transplant. In the event that therapeutic levels could not be achieved with oral capsules in the immediate post-operative period, use of commercially–obtained CsA IV solution (Sandimmune® IV 50 mg/mL) was permitted.

Tacrolimus – Pediatric

Arm description

Pediatric primary cadaveric heart transplant transplant recipients randomized to immunosuppression with Tacrolimus 0.05-0.30 mg/kg/day administered orally in 2 or 3 divided doses starting within 10 days of transplant.

Arm type

Experimental

Investigational medicinal product name

Tacrolimus-Pediatric Dose

Investigational medicinal product code

FK506

Other name

Prograf®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Pediatric Dose: Oral Prograf® 0.05-0.30 mg/kg/day was given in two divided doses, beginning no earlier than pre-transplant and no later than day 10 post-transplant. Tacrolimus was administered on an empty stomach, 1 hour before or 2 hours after meals. Tacrolimus may have been administered via nasogastric tube. Intravenous administration of tacrolimus should have been undertaken only when therapeutic levels could be achieved via oral and enteric routes. Intravenous dosing of tacrolimus, if required, is by administration as a continuous 24-hour infusion. Tacrolimus IV solution should be diluted in 0.9% sodium chloride or 5% dextrose for injection and stored in a glass bottle or non-polyvinyl chloride (PVC) bag for no longer than 24 hours prior to infusion. Dose decreases for mild intolerance should be based on balancing other clinical assessments, e.g., acute rejection.

Cyclosporine – Pediatric

Arm description

Pediatric primary cadaveric heart transplant transplant recipients randomized to immunosuppression with Cyclosporine 6-10 mg/kg/day in 2 or 3 divided doses starting within 10 days of transplant.

Arm type

Active comparator

Investigational medicinal product name

Cyclosporine - Pediatric Dose

Investigational medicinal product code

Other name

Neoral®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Pediatric Dose: Pediatric patients: Administration of the Neoral® form of cyclosporine must start within the first 10 days post transplant. It will be given at a starting dose of 6-10 mg/kg per day orally in 2 or 3 divided doses based on actual body weight unless the patient has significant renal dysfunction. The dose will subsequently be adjusted to achieve the targeted blood levels. Intravenous dosing of cyclosporine, if required, is to be initiated as a continuous 24-hour infusion of 1-2 mg/kg over 24 hours. For IV administration 1 mg/kg of IV cyclosporine should be diluted in 0.9% sodium chloride for injection or 5% dextrose for injection and stored in a glass bottle for no greater than 24 hours prior to infusion. The cyclosporine dose should be decreased in the presence of adverse events as clinically warranted. Dose decreases for mild intolerance should be based on balancing other clinical assessments, for example, acute rejection.

Number of subjects in period 1 ^[1]	Tacrolimus - Adult	Cyclosporine – Adult	Tacrolimus – Pediatric	Cyclosporine – Pediatric
Started	51	49	5	6
Treatment Exposure Population	52	46	5	6
Completed	45	41	4	5
Not completed	7	8	1	1
Consent withdrawn by subject	1	-	-	-
Living in nursing home	-	1	-	-
Death	4	3	1	1
Other	2	-	-	-
Patient would not have received transplant	-	1	-	-
Physician Discretion	-	1	-	-
Patient withdrawn at invstigator's discretion	-	1	-	-
Medications withdrawn on request of family	-	1	-	-
Joined	1	0	0	0
Transferred in from other group/arm	1	-	-	-

Notes
[1] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
Justification: Three patients randomized to cyclosporine actually received tacrolimus and were included in the Treatment Exposure Population for tacrolimus. Two patients randomized for tacrolimus were excluded from Treatment Exposure Population – 1 never received drug; 1 received incorrect drug without a waiver.

Baseline characteristics

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Reporting group title

Overall Study

Reporting group description

Notes
[1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
Justification: Two patients randomized for tacrolimus were excluded from Treatment Exposure Population – 1 never received drug; 1 received incorrect drug without a waiver.

Reporting group values	Overall Study	Total
Number of subjects	109	109
Age, Customized
Units: Participants
0 - ˂ 2 Years	2	2
2 - 10 Years	3	3
10 - ˂ 18 Years	6	6
18 - 49 Years	32	32
50 - 59 Years	33	33
60 - 69 Years	30	30
70 Years and Older	3	3
Gender categorical
Units: Subjects
Female	27	27
Male	82	82
Race / Ethnicity
Units: Subjects
European descent/ White	97	97
Black	7	7
East Indian	3	3
Latin American	1	1
Aboriginal	1	1

End points

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Reporting group title

Tacrolimus - Adult

Reporting group description

Reporting group title

Cyclosporine – Adult

Reporting group description

Adult primary cadaveric heart transplant recipients randomized to immunosuppression with Cyclosporine 3-5 mg/kg/day administered orally in 2 divided doses starting within 10 days of transplant.

Reporting group title

Tacrolimus – Pediatric

Reporting group description

Reporting group title

Cyclosporine – Pediatric

Reporting group description

Pediatric primary cadaveric heart transplant transplant recipients randomized to immunosuppression with Cyclosporine 6-10 mg/kg/day in 2 or 3 divided doses starting within 10 days of transplant.

Subject analysis set title

Cyclosporine – Pediatric

Subject analysis set type

Intention-to-treat

Subject analysis set description

Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant

Subject analysis set title

Tacrolimus - Pediatric

Subject analysis set type

Intention-to-treat

Subject analysis set description

Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant

Subject analysis set title

Tacrolimus – Adult

Subject analysis set type

Full analysis

Subject analysis set description

Adults: 0.05 – 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant

Subject analysis set title

Cyclosporine - Adult

Subject analysis set type

Full analysis

Subject analysis set description

Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant

Primary: The change in the markers of growth, apoptosis, inflammation and oxidation measured in endomyocardial biopsies (TE)

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End point title

The change in the markers of growth, apoptosis, inflammation and oxidation measured in endomyocardial biopsies (TE) ^[1] ^[2]

End point description

The markers assessed were p-ERK ½ (phosphorylated extracellular signal-regulated kinase), p-JNK (phosphorylated jun N-terminal kinase) and p-p38 MAPK (phosphorylated mitogen-activated protein kinase). The data for each biopsy marker were expressed as a ratio of its densitometry / densitometry of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Change is defined as Week 52 assessment- Week 2 assessment. The number of participants analyzed per arm represents Treatment Exposure (TE) Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each marker is noted in the category titles, as "N".

End point type

Primary

End point timeframe

2 Weeks and 52 Weeks

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis provided.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: Densitometry / Densitometry of GAPDH
arithmetic mean (standard deviation)
p-ERK ½ - Week 2 (N=36; 37)	0.7 ( 0.5 )	0.9 ( 0.641 )
p-ERK ½ - Week 52 (N=30; 27)	0.87 ( 0.539 )	0.79 ( 0.674 )
p-ERK ½ - Change from Week 2 (N=26; 25)	0.05 ( 0.834 )	-0.05 ( 0.662 )
p-JNK - Week 2 (N=36; 37)	1.1 ( 0.813 )	1.23 ( 0.722 )
p-JNK - Week 52 (N=30; 27)	1.33 ( 0.89 )	1.46 ( 0.792 )
p-JNK - Change from Week 2 (N=26; 25)	0.03 ( 1.188 )	0.22 ( 0.957 )
p-p38 MAPK - Week 2 (N=35; 37)	0.48 ( 0.45 )	0.54 ( 0.556 )
p-p38 MAPK - Week 52 (N=28; 27)	0.63 ( 0.664 )	0.77 ( 0.717 )
p-p38 MAPK - Change from Week 2 (N=25; 25)	0.14 ( 0.733 )	0.23 ( 0.828 )

No statistical analyses for this end point

Primary: The change in the markers of growth, apoptosis, inflammation and oxidation measured in endomyocardial biopsies (Pediatric Population)

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End point title

The change in the markers of growth, apoptosis, inflammation and oxidation measured in endomyocardial biopsies (Pediatric Population) ^[3] ^[4]

End point description

The markers assessed were p-ERK ½, p-JNK and p-p38 MAPK.The data for each biopsy marker were expressed as a ratio of its densitometry / densitometry of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Change is defined as Week 52 assessment- Week 2 assessment. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each marker is noted in the category titles, as "N".

End point type

Primary

End point timeframe

2 Weeks and 52 Weeks

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis provided.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.

End point values	Tacrolimus – Pediatric	Cyclosporine – Pediatric
Number of subjects analysed	5	6
Units: Densitometry / Densitometry of GAPDH
arithmetic mean (standard deviation)
p-ERK ½ - Week 2 (N=3; 5)	1.74 ( 0.972 )	1.67 ( 0.682 )
p-ERK ½ - Week 52 (N= 2; 4)	0.93 ( 0.184 )	1.22 ( 0.633 )
p-ERK ½ - Change from Week 2 (N= 1; 3)	-0.09 ( 0 )	-0.27 ( 0.309 )
p-JNK - Week 2 (N=3; 5)	1.17 ( 0.42 )	0.91 ( 0.43 )
p-JNK - Week 52 (N= 2; 4)	0.57 ( 0.085 )	0.82 ( 0.537 )
p-JNK - Change from Week 2 (N=1; 3)	-0.21 ( 0 )	0.04 ( 0.189 )
p-p38 MAPK - Week 2 (N=3; 5)	0.83 ( 0.467 )	0.43 ( 0.364 )
p-p38 MAPK - Week 52 (N=2; 4)	0.24 ( 0.014 )	0.58 ( 0.432 )
p-p38 MAPK - Change from Week 2 (N=1; 3)	-0.04 ( 0 )	0.34 ( 0.63 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: MCP-1 (TE)

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End point title

Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: MCP-1 (TE) ^[5]

End point description

Change is defined as Week 52 assessment – Pre-Transplant assessment. MCP-1= monocyte chemoattractant protein-1. The number of participants analyzed per arm represents Treatment Exposure (TE) Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: pg/mL
arithmetic mean (standard deviation)
Pre-Transplant (N=48; 44)	233.05 ( 292.832 )	193.63 ( 144.696 )
Week 52 (N=42; 40)	229.96 ( 263.084 )	180.9 ( 145.067 )
Change from Pre-Transplant at Week 52 (N=42; 40)	42.92 ( 165.517 )	-16.49 ( 126.586 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: s-ICAM (TE)

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End point title

Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: s-ICAM (TE) ^[6]

End point description

Change is defined as Week 52 assessment - Pre-Transplant assessment. s-ICAM= soluble-intracellular adhesion molecule. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: ng/mL
arithmetic mean (standard deviation)
Pre-Transplant (N= 50; 45)	766.58 ( 449.572 )	674.46 ( 429.036 )
Week 52 (N= 41; 40)	590.3 ( 369.942 )	503.71 ( 305.531 )
Change from Pre-Transplant at Week 52 (N= 41; 40)	-227.58 ( 366.136 )	-183.96 ( 250.382 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: E-selectin (TE)

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End point title

Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: E-selectin (TE) ^[7]

End point description

Change is defined as Week 52 assessment - Pre-Transplant assessment. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: ng/mL
arithmetic mean (standard deviation)
Pre-Transplant (N= 50; 43)	90.4 ( 72.801 )	98.96 ( 89.153 )
Week 52 (N= 41; 40)	68.6 ( 51.911 )	80.93 ( 70.383 )
Change from Pre-Transplant at Week 52 (N= 41; 40)	-18.58 ( 48.247 )	-19.16 ( 52.08 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Homocysteine (TE)

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End point title

Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Homocysteine (TE) ^[8]

End point description

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: μmol/L
arithmetic mean (standard deviation)
Pre-Transplant (N= 50; 44)	14.2 ( 6.94 )	15.9 ( 6.97 )
Week 52 (N= 40; 40)	13.5 ( 4.19 )	15.8 ( 5.33 )
Change from Pre-Transplant at Week 52 (N= 40; 40)	0.3 ( 5.02 )	0.7 ( 7.61 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: hsCRP (TE)

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End point title

Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: hsCRP (TE) ^[9]

End point description

Change is defined as Week 52 assessment - Pre-Transplant assessment. hsCRP= high-sensitivity C Reactive Protein. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: mg/L
arithmetic mean (standard deviation)
Pre-Transplant (N= 49; 45)	32.85 ( 50.859 )	21.83 ( 33.547 )
Week 52 (N= 42; 40)	3.01 ( 3.313 )	3.95 ( 5.273 )
Change from Pre-Transplant at Week 52 (N= 42; 40)	-34.32 ( 54.257 )	-18.69 ( 35.354 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: F2 isoprostanes (TE)

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End point title

Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: F2 isoprostanes (TE) ^[10]

End point description

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: pg/mL
arithmetic mean (standard deviation)
Pre-Transplant (N= 48; 45)	52.03 ( 76.09 )	53.94 ( 78.476 )
Week 52 (N= 42; 40)	30.08 ( 25.905 )	50.44 ( 68.416 )
Change from Pre-Transplant at Week 52 (N= 42; 40)	-13.29 ( 40.543 )	-3.43 ( 103.457 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: T-bars (TE)

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End point title

Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: T-bars (TE) ^[11]

End point description

Change is defined as Week 52 assessment - Pre-Transplant assessment. T-bars = thiobarbituric acid reactive substances. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: nmol/mL
arithmetic mean (standard deviation)
Pre-Transplant (N= 50; 45)	3.78 ( 1.586 )	3.91 ( 2.059 )
Week 52 (N= 40; 39)	3.25 ( 1.365 )	3.14 ( 1.198 )
Change from Pre-Transplant at Week 52 (N= 40; 39)	-0.64 ( 1.724 )	-0.77 ( 2.182 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Nitrotyrosine (TE)

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End point title

Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Nitrotyrosine (TE) ^[12]

End point description

Change is defined as Week 52 assessment - Pre-Transplant assessment. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received (TE) regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: nM
arithmetic mean (standard deviation)
Pre-Transplant (N= 50; 45)	422.63 ( 393.554 )	482.43 ( 390.702 )
Week 52 (N= 41; 39)	451.88 ( 443.372 )	368.95 ( 262.693 )
Change from Pre-Transplant at Week 52 (N= 41; 39)	71.44 ( 332.351 )	-99.79 ( 228.268 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: GSH/GSSG (TE)

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End point title

Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: GSH/GSSG (TE) ^[13]

End point description

Change is defined as Week 52 assessment - Pre-Transplant assessment. GSH/GSSG= ratio of reduced to oxidised glutathione.The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: Ratio
arithmetic mean (standard deviation)
Pre-Transplant (N= 49; 45)	55.07 ( 62.78 )	58.83 ( 71.289 )
Week 52 (N= 39; 38)	51.69 ( 55.721 )	53.72 ( 55.264 )
Change from Pre-Transplant at Week 52 (N= 39; 38)	-2.07 ( 70.036 )	-5.55 ( 80.49 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: BNP (TE)

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End point title

Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: BNP (TE) ^[14]

End point description

Change is defined as Week 52 assessment - Pre-Transplant assessment. BNP= Brain Natriuretic Peptide. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: ng/L
arithmetic mean (standard deviation)
Pre-Transplant (N= 49; 44)	4314.8 ( 4861.78 )	4240.8 ( 4673.72 )
Week 52 (N= 42; 40)	670.1 ( 1053.21 )	1856.8 ( 5077.26 )
Change from Pre-Transplant at Week 52 (N= 42; 40)	-4018.4 ( 5043.28 )	-1446.7 ( 6460.33 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Troponin T (TE)

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End point title

Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Troponin T (TE) ^[15]

End point description

Change is defined as Week 52 assessment - Pre-Transplant assessment. The number of participants analyzed per arm represents Treatment Exposure (TE) Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: ug/L
arithmetic mean (standard deviation)
Pre-Transplant (N= 49; 44)	0.3 ( 0.686 )	0.28 ( 0.878 )
Week 52 (N= 42; 40)	0.03 ( 0.116 )	0.04 ( 0.12 )
Change from Pre-Transplant at Week 52 (N= 42; 40)	-0.32 ( 0.768 )	-0.27 ( 0.958 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Osteopontin (TE)

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End point title

Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Osteopontin (TE) ^[16]

End point description

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: ng/mL
arithmetic mean (standard deviation)
Pre-Transplant (N= 50; 44)	11.88 ( 9.528 )	11.14 ( 12.278 )
Week 52 (N= 41; 38)	8.77 ( 10.462 )	10.49 ( 8.987 )
Change from Pre-Transplant at Week 52 (N= 41; 38)	-2.22 ( 10.615 )	0.2 ( 11.158 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Fibrinogen (TE)

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End point title

Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Fibrinogen (TE) ^[17]

End point description

Change is defined as Week 52 assessment - Pre-Transplant assessment.

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: g/L
arithmetic mean (standard deviation)
Pre-Transplant (N= 48; 44)	4.4 ( 1.27 )	4.4 ( 1.23 )
Week 52 (N= 40; 40)	3.4 ( 0.87 )	3.8 ( 0.77 )
Change from Pre-Transplant at Week 52 (N= 40; 40)	-1.1 ( 1.48 )	-0.5 ( 1.23 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: IL-6 (TE)

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End point title

Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: IL-6 (TE) ^[18]

End point description

Change is defined as Week 52 assessment - Pre-Transplant assessment. IL= Interleukin The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. The number of participants included in the calculation for each row is noted in the category titles, as "N".

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: pg/mL
arithmetic mean (standard deviation)
Pre-Transplant (N= 48; 45)	3.36 ( 4.221 )	2.54 ( 3.159 )
Week 52 (N= 42; 40)	0.98 ( 0.743 )	0.9 ( 0.651 )
Change from Pre-Transplant at Week 52 (N= 42; 40)	-2.84 ( 4.635 )	-1.56 ( 3.146 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: IL-18 (TE)

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End point title

Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: IL-18 (TE) ^[19]

End point description

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: pg/mL
arithmetic mean (standard deviation)
Pre-Transplant (N= 48; 45)	574 ( 291.89 )	496.2 ( 246.9 )
Week 52 (N= 40; 40)	534.6 ( 290.38 )	427.2 ( 217.07 )
Change from Pre-Transplant at Week 52 (N=40; 40)	5.2 ( 289.66 )	-71 ( 243.81 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Cystatin-C (TE)

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End point title

Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Cystatin-C (TE) ^[20]

End point description

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: mg/L
arithmetic mean (standard deviation)
Pre-Transplant (N= 49; 45)	1.21 ( 0.414 )	1.29 ( 0.49 )
Week 52 (N= 42; 40)	1.29 ( 0.533 )	1.48 ( 0.714 )
Change from Pre-Transplant at Week 52 (N= 42; 40)	0.06 ( 0.464 )	0.27 ( 0.744 )

No statistical analyses for this end point

Secondary: Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (TE)

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End point title

Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (TE) ^[21]

End point description

Acute rejection was defined as a rejection with ISHLT Grade ≥3A or by the presence of hemodynamic compromise. ISHLT Grades ≥3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. Patients may report more than one acute rejection.

End point type

Secondary

End point timeframe

52 Weeks

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: Rejection Episodes
number (not applicable)
Total Acute Rejection Episodes	8	8
Acute Rejection Episodes with ISHLT Grade ≥3A	3	7
Acute Rejection Episodes w/ Hemodynamic Compromise	6	2

No statistical analyses for this end point

Secondary: Time to first acute rejection episode following de novo cardiac transplant (TE)

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End point title

Time to first acute rejection episode following de novo cardiac transplant (TE) ^[22]

End point description

Acute Rejection was defined as a rejection with ISHLT Grade ≥3A or by the presence of hemodynamic compromise. ISHLT Grades ≥3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection. Time to first acute rejection is defined as: date of onset - date of transplant.The population analyzed represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation. Only participants who experienced acute rejection were included in the analysis.

End point type

Secondary

End point timeframe

52 Weeks

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Cyclosporine – Adult	Cyclosporine – Pediatric
Number of subjects analysed	8	6
Units: Days
arithmetic mean (standard deviation)	166.6 ( 132.86 )	55 ( 35.6 )

No statistical analyses for this end point

Secondary: Number of patients requiring antilymphocyte antibodies or steroids for treatment of severe acute rejection

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End point title

Number of patients requiring antilymphocyte antibodies or steroids for treatment of severe acute rejection ^[23]

End point description

Severe Acute Rejection is defined as rejection with ISHLT Grade 4.

End point type

Secondary

End point timeframe

52 Weeks

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: Patients
number (not applicable)	0	0

No statistical analyses for this end point

Secondary: Number of cardiac rejection episodes requiring treatment (TE)

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End point title

Number of cardiac rejection episodes requiring treatment (TE) ^[24]

End point description

The number of rejection episodes requiring treatment (medications started/ stopped, non-medication treatment, or both) regardless of biopsy grade or presence of hemodynamic compromise. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation.

End point type

Secondary

End point timeframe

52 Weeks

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: Rejection Episodes
number (not applicable)	12	11

No statistical analyses for this end point

Secondary: Mean cases of acute rejection (MCAR) per patient

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End point title

Mean cases of acute rejection (MCAR) per patient ^[25]

End point description

MCAR represents the average number of acute rejections among all patients in each treatment group. Results were based on rejection episodes with endomyocardial biopsies. Acute rejection was defined as a rejection with ISHLT Grade ≥3A or by the presence of hemodynamic compromise. ISHLT Grades ≥3A include: Multifocal Moderate Rejection; Diffuse, Borderline Severe Acute Rejection; and Severe Acute Rejection. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation.

End point type

Secondary

End point timeframe

52 Weeks

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: MCAR per patient
arithmetic mean (standard deviation)	0.15 ( 0.46 )	0.17 ( 0.38 )

Mean Cases of Acute Rejection (MCAR)

Comparison groups

Cyclosporine – Adult v Tacrolimus - Adult

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

P-value

= 0.4725 ^[26]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

Notes
[26] - No adjustments for multiple comparisons were performed.

Secondary: Number of patients with successful steroid taper or withdrawal at weeks 26 and 52 (TE)

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End point title

Number of patients with successful steroid taper or withdrawal at weeks 26 and 52 (TE)

End point description

A successful steroid taper or withdrawal was defined as steroids (prednisone) being discontinued or tapered to the suggested dose level after week 26. The number of participants analyzed per arm represents Treatment Exposure Population- defined as all patients receiving at least 1 dose of study medication summarized according to treatment received regardless of randomization allocation.

End point type

Secondary

End point timeframe

26 Weeks and 52 Weeks

End point values	Tacrolimus – Adult	Cyclosporine - Adult
Number of subjects analysed	52	46
Units: Patients
number (not applicable)
Week 26	22	16
Week 52	33	29

No statistical analyses for this end point

Secondary: Number of patients with treatment failure and crossover for treatment failure

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End point title

Number of patients with treatment failure and crossover for treatment failure ^[27]

End point description

Treatment failure was defined as death, re-transplantation, withdrawal due to an Adverse Event, or a switch of main immunosuppressant medication, whichever came first. Crossover was defined as a switch from originally administered primary immunosuppressant (tacrolimus or cyclosporine) to the alternate primary immunosuppressant.

End point type

Secondary

End point timeframe

52 Weeks

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to adult population which is why arms representing only adult population are selected for this endpoint.

End point values	Tacrolimus - Adult	Cyclosporine – Adult
Number of subjects analysed	52	46
Units: Patients
number (not applicable)
Treatment Failures	6	11
Crossover for Treatment Failures	2	8

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation and oxidation: F2 isoprostanes (Pediatric Population)

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End point title

Changes in circulating markers of inflammation and oxidation: F2 isoprostanes (Pediatric Population) ^[28]

End point description

Change is defined as Week 52 assessment - Pre-Transplant assessment

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.

End point values	Tacrolimus – Pediatric	Cyclosporine – Pediatric
Number of subjects analysed	5	6
Units: pg/mL
arithmetic mean (standard deviation)
Pre-Transplant (N= 5; 5)	106.06 ( 37.974 )	104.68 ( 53.812 )
Week 52 (N= 3; 4)	69.71 ( 38.62 )	66.48 ( 33.298 )
Change from Pre-Transplant at Week 52 (N= 3; 4)	-38.31 ( 47.563 )	-30.07 ( 80.246 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation and oxidation: nitrotyrosine (Pediatric Population)

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End point title

Changes in circulating markers of inflammation and oxidation: nitrotyrosine (Pediatric Population) ^[29]

End point description

Change is defined as Week 52 assessment - Pre-Transplant assessment

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.

End point values	Tacrolimus – Pediatric	Cyclosporine – Pediatric
Number of subjects analysed	5	6
Units: nM
arithmetic mean (standard deviation)
Pre-Transplant (N= 5; 5)	233.08 ( 211.491 )	12701.21 ( 21666.231 )
Week 52 (N= 3; 4)	5462.99 ( 7988.134 )	41147.62 ( 37565.74 )
Change from Pre-Transplant at Week 52 (N= 3; 4)	5148.42 ( 7849.554 )	21514.62 ( 49626.968 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation and oxidation: hsCRP (Pediatric Population)

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End point title

Changes in circulating markers of inflammation and oxidation: hsCRP (Pediatric Population) ^[30]

End point description

Change is defined as Week 52 assessment - Pre-Transplant assessment

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.

End point values	Tacrolimus – Pediatric	Cyclosporine – Pediatric
Number of subjects analysed	5	6
Units: mg/L
arithmetic mean (standard deviation)
Pre-Transplant (N= 5; 4)	30.46 ( 32.274 )	12.08 ( 14.771 )
Week 52 (N= 3; 4)	26.31 ( 45.109 )	2.43 ( 1.348 )
Change from Pre-Transplant at Week 52 (N= 3; 4)	-7.85 ( 78.126 )	-13.94 ( 16.461 )

No statistical analyses for this end point

Secondary: Changes in circulating markers of inflammation and oxidation: Cystatin-C (Pediatric Population)

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End point title

Changes in circulating markers of inflammation and oxidation: Cystatin-C (Pediatric Population) ^[31]

End point description

Change is defined as Week 52 assessment - Pre-Transplant assessment

End point type

Secondary

End point timeframe

Pre-Transplant and 52 Weeks

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.

End point values	Tacrolimus – Pediatric	Cyclosporine – Pediatric
Number of subjects analysed	5	6
Units: mg/L
arithmetic mean (standard deviation)
Pre-Transplant ( N= 5; 4)	0.86 ( 0.248 )	0.77 ( 0.194 )
Week 52 (N= 3; 4)	0.87 ( 0.133 )	0.84 ( 0.111 )
Change from Pre-Transplant at Week 52 (N= 3; 4)	-0.11 ( 0.197 )	-0.01 ( 0.108 )

No statistical analyses for this end point

Secondary: Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (Pediatric Population)

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End point title

Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (Pediatric Population) ^[32]

End point description

End point type

Secondary

End point timeframe

52 Weeks

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.

End point values	Cyclosporine – Pediatric	Tacrolimus - Pediatric
Number of subjects analysed	6	5
Units: Rejection Episodes
number (not applicable)
Total Acute Rejection Episodes	3	3
Acute Rejection Episodes with ISHLT Grade ≥3A	3	3
Acute Rejection Episodes w/ Hemodynamic Compromise	0	0

No statistical analyses for this end point

Secondary: Time to first acute rejection episode following de novo cardiac transplant (Pediatric Population)

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End point title

Time to first acute rejection episode following de novo cardiac transplant (Pediatric Population) ^[33]

End point description

End point type

Secondary

End point timeframe

52 Weeks

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.

End point values	Cyclosporine – Pediatric
Number of subjects analysed	3
Units: Days
arithmetic mean (standard deviation)	49 ( 15.62 )

No statistical analyses for this end point

Secondary: Number of patients requiring antilymphocyte antibodies or steroids for treatment of severe acute rejection (Pediatric Population)

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End point title

Number of patients requiring antilymphocyte antibodies or steroids for treatment of severe acute rejection (Pediatric Population) ^[34]

End point description

Severe Acute Rejection was defined as rejection with ISHLT Grade 4.

End point type

Secondary

End point timeframe

52 Weeks

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.

End point values	Tacrolimus – Pediatric	Cyclosporine – Pediatric
Number of subjects analysed	5	6
Units: Patients
number (not applicable)	0	0

No statistical analyses for this end point

Secondary: Number of cardiac rejection episodes requiring treatment (Pediatric Population)

Top of page

End point title

Number of cardiac rejection episodes requiring treatment (Pediatric Population) ^[35]

End point description

A summary of rejection episodes requiring treatment regardless of biopsy grade or presence of hemodynamic compromise.

End point type

Secondary

End point timeframe

52 Weeks

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.

End point values	Tacrolimus – Pediatric	Cyclosporine – Pediatric
Number of subjects analysed	5	6
Units: Rejection Episodes
number (not applicable)	3	3

No statistical analyses for this end point

Secondary: Mean cases of acute rejection (MCAR) per patient (Pediatric Population)

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End point title

Mean cases of acute rejection (MCAR) per patient (Pediatric Population) ^[36]

End point description

End point type

Secondary

End point timeframe

52 Weeks

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.

End point values	Tacrolimus – Pediatric	Cyclosporine – Pediatric
Number of subjects analysed	5	6
Units: MCAR per patient
arithmetic mean (standard deviation)	0.6 ( 0.55 )	0.5 ( 0.55 )

STATISTICAL_ANALYSIS_TITLE

Comparison groups

Tacrolimus – Pediatric v Cyclosporine – Pediatric

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.8373 ^[37]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

level

95%

Notes
[37] - No adjustments for multiple comparisons were performed.

Secondary: Number of patients with successful steroid taper or withdrawal at weeks 26 and 52 (Pediatric Population)

Top of page

End point title

Number of patients with successful steroid taper or withdrawal at weeks 26 and 52 (Pediatric Population) ^[38]

End point description

A successful steroid taper or withdrawal was defined as steroids (prednisone) being discontinued or tapered to the suggested dose level after week 26.

End point type

Secondary

End point timeframe

26 Weeks and 52 Weeks

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.

End point values	Tacrolimus – Pediatric	Cyclosporine – Pediatric
Number of subjects analysed	5	6
Units: Patients
number (not applicable)
Week 26	2	3
Week 52	1	1

No statistical analyses for this end point

Secondary: Number of patients with treatment failure and crossover for treatment failure (Pediatric Population)

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End point title

Number of patients with treatment failure and crossover for treatment failure (Pediatric Population) ^[39]

End point description

End point type

Secondary

End point timeframe

52 Weeks

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Summary statistical analysis is only applicable to pediatric population which is why arms representing only pediatric population are selected for this endpoint.

End point values	Cyclosporine – Pediatric	Tacrolimus - Pediatric
Number of subjects analysed	6	5
Units: Patients
number (not applicable)
Treatment Failures	3	1
Crossover for Treatment Failures	3	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

After the initiation of study drug up to 30 days after the last dose of study drug.

Adverse event reporting additional description

Treatment Emergent Adverse Events were reported. Within a preferred term, participants were counted once.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

8.0

Reporting group title

Tacrolimus - Adult

Reporting group description

Adults: 0.05 – 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant

Reporting group title

Cyclosporine – Adult

Reporting group description

Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant

Reporting group title

Tacrolimus – Pediatric

Reporting group description

Pediatrics: 0.05 – 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant

Reporting group title

Cyclosporine – Pediatric

Reporting group description

Pediatrics: 6 – 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant

Serious adverse events	Tacrolimus - Adult	Cyclosporine – Adult	Tacrolimus – Pediatric	Cyclosporine – Pediatric
Total subjects affected by serious adverse events
subjects affected / exposed	21 / 52 (40.38%)	24 / 46 (52.17%)	3 / 5 (60.00%)	5 / 6 (83.33%)
number of deaths (all causes)	4	3	1	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer stage III
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal carcinoma
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lymphoproliferative disorder
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	2 / 52 (3.85%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inferior vena caval occlusion
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Temporal arteritis
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular pseudoaneurysm
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Catheter related complication
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chills
subjects affected / exposed	1 / 52 (1.92%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 52 (0.00%)	2 / 46 (4.35%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Heart transplant rejection
subjects affected / exposed	2 / 52 (3.85%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Transplant rejection
subjects affected / exposed	2 / 52 (3.85%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 3	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiogenic pulmonary oedema
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 52 (1.92%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 52 (1.92%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory alkalosis
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Haemothorax
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound dehiscence
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial flutter
subjects affected / exposed	2 / 52 (3.85%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Cardiac failure congestive
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	1 / 52 (1.92%)	2 / 46 (4.35%)	1 / 5 (20.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	1 / 1	0 / 2	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericarditis constrictive
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Right ventricular failure
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral infarction
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Convulsion
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	5 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Depressed level of consciousness
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydrocephalus
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Partial seizures
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope vasovagal
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tension headache
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	0 / 52 (0.00%)	2 / 46 (4.35%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Deafness unilateral
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Blindness cortical
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	2 / 52 (3.85%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mouth ulceration
subjects affected / exposed	0 / 52 (0.00%)	2 / 46 (4.35%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic disorder
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	2 / 52 (3.85%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholelithiasis
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephropathy toxic
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure acute
subjects affected / exposed	0 / 52 (0.00%)	3 / 46 (6.52%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	2 / 3	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Adrenal mass
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 52 (1.92%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
American trypanosomiasis
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 52 (0.00%)	2 / 46 (4.35%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cytomegalovirus gastritis
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cytomegalovirus infection
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Klebsiella bacteraemia
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lobar pneumonia
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mediastinitis
subjects affected / exposed	1 / 52 (1.92%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 52 (1.92%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 52 (0.00%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia klebsiella
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyperkalaemia
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fluid overload
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Tacrolimus - Adult	Cyclosporine – Adult	Tacrolimus – Pediatric	Cyclosporine – Pediatric
Total subjects affected by non serious adverse events
subjects affected / exposed	52 / 52 (100.00%)	46 / 46 (100.00%)	5 / 5 (100.00%)	6 / 6 (100.00%)
Vascular disorders
Hypertension
subjects affected / exposed	21 / 52 (40.38%)	26 / 46 (56.52%)	3 / 5 (60.00%)	4 / 6 (66.67%)
occurrences all number	25	29	3	4
Hypotension
subjects affected / exposed	13 / 52 (25.00%)	7 / 46 (15.22%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	15	10	0	0
Surgical and medical procedures
Removal of foreign body
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)
occurrences all number	0	0	1	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	5 / 52 (9.62%)	2 / 46 (4.35%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	5	2	0	0
Chest pain
subjects affected / exposed	4 / 52 (7.69%)	2 / 46 (4.35%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	4	2	0	0
Chills
subjects affected / exposed	1 / 52 (1.92%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	3	0	0
Fatigue
subjects affected / exposed	2 / 52 (3.85%)	7 / 46 (15.22%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	4	10	0	0
Hyperthermia
subjects affected / exposed	2 / 52 (3.85%)	4 / 46 (8.70%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	4	0	0
Influenza like illness
subjects affected / exposed	3 / 52 (5.77%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	0	0	0
Oedema Peripheral
subjects affected / exposed	21 / 52 (40.38%)	21 / 46 (45.65%)	0 / 5 (0.00%)	2 / 6 (33.33%)
occurrences all number	32	24	0	2
Pyrexia
subjects affected / exposed	4 / 52 (7.69%)	4 / 46 (8.70%)	0 / 5 (0.00%)	2 / 6 (33.33%)
occurrences all number	5	5	0	3
Oedema
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	2 / 5 (40.00%)	0 / 6 (0.00%)
occurrences all number	0	1	2	0
Immune system disorders
Transplant rejection
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	2 / 52 (3.85%)	4 / 46 (8.70%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	5	0	0
Cough
subjects affected / exposed	9 / 52 (17.31%)	6 / 46 (13.04%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	12	8	0	0
Dyspnoea
subjects affected / exposed	8 / 52 (15.38%)	5 / 46 (10.87%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	11	7	0	0
Pleural effusion
subjects affected / exposed	10 / 52 (19.23%)	18 / 46 (39.13%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	11	21	0	0
Pneumothorax
subjects affected / exposed	5 / 52 (9.62%)	4 / 46 (8.70%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	5	4	0	0
Aspiration
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Respiratory distress
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Psychiatric disorders
Agitation
subjects affected / exposed	3 / 52 (5.77%)	4 / 46 (8.70%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	4	4	0	0
Anxiety
subjects affected / exposed	5 / 52 (9.62%)	5 / 46 (10.87%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	5	6	0	0
Confusional state
subjects affected / exposed	3 / 52 (5.77%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	1	0	0
Depression
subjects affected / exposed	6 / 52 (11.54%)	5 / 46 (10.87%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	6	5	0	1
Insomnia
subjects affected / exposed	8 / 52 (15.38%)	12 / 46 (26.09%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	9	12	0	1
Investigations
Blood creatinine increased
subjects affected / exposed	2 / 52 (3.85%)	5 / 46 (10.87%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	9	0	0
Cardiac murmur
subjects affected / exposed	3 / 52 (5.77%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	5	0	0
Hepatic enzyme increased
subjects affected / exposed	0 / 52 (0.00%)	4 / 46 (8.70%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	4	0	0
Weight decreased
subjects affected / exposed	0 / 52 (0.00%)	3 / 46 (6.52%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	0	3	1	0
Weight increased
subjects affected / exposed	10 / 52 (19.23%)	9 / 46 (19.57%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	10	9	1	0
Cytomegalovirus antigen positive
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Epstein-Barr virus antibody positive
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Glomerular filtration rate decreased
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
White blood cell count increased
subjects affected / exposed	1 / 52 (1.92%)	1 / 46 (2.17%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	0	1
Injury, poisoning and procedural complications
Incision site pain
subjects affected / exposed	5 / 52 (9.62%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	6	4	0	0
Joint sprain
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Wound
subjects affected / exposed	2 / 52 (3.85%)	0 / 46 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	2	0	0	1
Congenital, familial and genetic disorders
Becker's muscular dystrophy
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	6 / 52 (11.54%)	4 / 46 (8.70%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	8	5	0	0
Atrial flutter
subjects affected / exposed	3 / 52 (5.77%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	3	0	0
Bradycardia
subjects affected / exposed	6 / 52 (11.54%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	6	3	0	0
Mitral valve incompetence
subjects affected / exposed	3 / 52 (5.77%)	2 / 46 (4.35%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	2	0	0
Oedema due to cardiac disease
subjects affected / exposed	3 / 52 (5.77%)	4 / 46 (8.70%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	5	4	0	0
Palpitations
subjects affected / exposed	3 / 52 (5.77%)	6 / 46 (13.04%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	7	0	0
Pericardial effusion
subjects affected / exposed	5 / 52 (9.62%)	6 / 46 (13.04%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	5	7	1	0
Pulmonary oedema
subjects affected / exposed	3 / 52 (5.77%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	1	0	0
Right ventricular dysfunction
subjects affected / exposed	4 / 52 (7.69%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	4	3	0	0
Tricuspid valve incompetence
subjects affected / exposed	3 / 52 (5.77%)	2 / 46 (4.35%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	2	0	0
Arrhythmia
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Nervous system disorders
Convulsion
subjects affected / exposed	3 / 52 (5.77%)	1 / 46 (2.17%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	3	1	0	3
Dizziness
subjects affected / exposed	6 / 52 (11.54%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	6	3	0	0
Headache
subjects affected / exposed	11 / 52 (21.15%)	13 / 46 (28.26%)	1 / 5 (20.00%)	1 / 6 (16.67%)
occurrences all number	16	15	1	1
Hypoaesthesia
subjects affected / exposed	1 / 52 (1.92%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	3	0	0
Paraesthesia
subjects affected / exposed	3 / 52 (5.77%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	5	3	0	0
Tremor
subjects affected / exposed	23 / 52 (44.23%)	13 / 46 (28.26%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	28	14	0	1
Syncope
subjects affected / exposed	1 / 52 (1.92%)	1 / 46 (2.17%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	0	1
Blood and lymphatic system disorders
Aneamia
subjects affected / exposed	18 / 52 (34.62%)	15 / 46 (32.61%)	1 / 5 (20.00%)	2 / 6 (33.33%)
occurrences all number	18	16	2	3
Leukocytosis
subjects affected / exposed	9 / 52 (17.31%)	9 / 46 (19.57%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	10	9	0	0
Leukopenia
subjects affected / exposed	12 / 52 (23.08%)	9 / 46 (19.57%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	15	9	0	0
Thrombocytopenia
subjects affected / exposed	5 / 52 (9.62%)	1 / 46 (2.17%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	7	1	0	0
Neutropenia
subjects affected / exposed	2 / 52 (3.85%)	2 / 46 (4.35%)	1 / 5 (20.00%)	1 / 6 (16.67%)
occurrences all number	2	4	1	1
Eye disorders
Amblyopia
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	4 / 52 (7.69%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	4	3	0	0
Abdominal pain
subjects affected / exposed	6 / 52 (11.54%)	5 / 46 (10.87%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	6	5	1	0
Abdominal pain upper
subjects affected / exposed	3 / 52 (5.77%)	2 / 46 (4.35%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	2	0	0
Constipation
subjects affected / exposed	6 / 52 (11.54%)	13 / 46 (28.26%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	7	13	0	0
Diarrhoea
subjects affected / exposed	26 / 52 (50.00%)	8 / 46 (17.39%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	36	10	0	1
Dysphagia
subjects affected / exposed	4 / 52 (7.69%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	5	0	0	0
Gingival hyperplasia
subjects affected / exposed	0 / 52 (0.00%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	4	0	0
Mouth ulceration
subjects affected / exposed	0 / 52 (0.00%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	3	0	0
Nausea
subjects affected / exposed	8 / 52 (15.38%)	15 / 46 (32.61%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	9	24	1	0
Vomiting
subjects affected / exposed	3 / 52 (5.77%)	9 / 46 (19.57%)	2 / 5 (40.00%)	1 / 6 (16.67%)
occurrences all number	4	9	2	2
Gastritis
subjects affected / exposed	2 / 52 (3.85%)	1 / 46 (2.17%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	2	1	1	0
Gingival hypertrophy
subjects affected / exposed	1 / 52 (1.92%)	1 / 46 (2.17%)	0 / 5 (0.00%)	3 / 6 (50.00%)
occurrences all number	1	1	0	3
Tooth discolouration
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 52 (0.00%)	2 / 46 (4.35%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	2	0	1
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	4 / 52 (7.69%)	6 / 46 (13.04%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	4	7	0	0
Hypertrichosis
subjects affected / exposed	1 / 52 (1.92%)	4 / 46 (8.70%)	0 / 5 (0.00%)	3 / 6 (50.00%)
occurrences all number	1	4	0	3
Rash
subjects affected / exposed	3 / 52 (5.77%)	4 / 46 (8.70%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	4	0	0
Skin lesion
subjects affected / exposed	7 / 52 (13.46%)	2 / 46 (4.35%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	7	2	0	0
Skin ulcer
subjects affected / exposed	3 / 52 (5.77%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	4	0	0	0
Renal and urinary disorders
Renal failure
subjects affected / exposed	11 / 52 (21.15%)	12 / 46 (26.09%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	14	13	0	0
Renal failure acute
subjects affected / exposed	4 / 52 (7.69%)	4 / 46 (8.70%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	4	4	0	0
Renal failure chronic
subjects affected / exposed	3 / 52 (5.77%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	0	0	0
Renal impairment
subjects affected / exposed	0 / 52 (0.00%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	3	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	3 / 52 (5.77%)	5 / 46 (10.87%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	5	0	0
Back pain
subjects affected / exposed	4 / 52 (7.69%)	5 / 46 (10.87%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	4	5	0	0
Muscle spasms
subjects affected / exposed	8 / 52 (15.38%)	8 / 46 (17.39%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	8	8	0	0
Musculoskeletal chest pain
subjects affected / exposed	2 / 52 (3.85%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	3	0	0
Musculoskeletal pain
subjects affected / exposed	7 / 52 (13.46%)	2 / 46 (4.35%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	7	2	0	0
Myalgia
subjects affected / exposed	4 / 52 (7.69%)	6 / 46 (13.04%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	5	7	0	0
Pain in extremity
subjects affected / exposed	4 / 52 (7.69%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	6	3	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	4 / 52 (7.69%)	2 / 46 (4.35%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	5	2	0	0
Diverticulitis
subjects affected / exposed	0 / 52 (0.00%)	3 / 46 (6.52%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	0	3	0	0
Influenza
subjects affected / exposed	1 / 52 (1.92%)	4 / 46 (8.70%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	1	4	0	0
Nasopharyngitis
subjects affected / exposed	2 / 52 (3.85%)	6 / 46 (13.04%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	7	0	0
Pneumonia
subjects affected / exposed	6 / 52 (11.54%)	2 / 46 (4.35%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	8	2	0	1
Sinusitis
subjects affected / exposed	3 / 52 (5.77%)	2 / 46 (4.35%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	2	0	0
Staphylococcal infection
subjects affected / exposed	4 / 52 (7.69%)	0 / 46 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	4	0	0	0
Upper respiratory tract infection
subjects affected / exposed	4 / 52 (7.69%)	6 / 46 (13.04%)	1 / 5 (20.00%)	2 / 6 (33.33%)
occurrences all number	4	6	1	2
Urinary tract infection
subjects affected / exposed	6 / 52 (11.54%)	2 / 46 (4.35%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	7	2	0	0
Adenovirus infection
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Clostridial infection
subjects affected / exposed	0 / 52 (0.00%)	1 / 46 (2.17%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	0	2	1	0
Gastroenteritis
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Lower respiratory tract infection
subjects affected / exposed	0 / 52 (0.00%)	2 / 46 (4.35%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	0	2	1	0
Oral herpes
subjects affected / exposed	1 / 52 (1.92%)	1 / 46 (2.17%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	1	0	1
Otitis media
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Respiratory syncytial virus infection
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Tooth abscess
subjects affected / exposed	1 / 52 (1.92%)	0 / 46 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	1	0	0	1
Viral upper repiratory tract infection
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Wound infection pseudomonas
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	0	0	0	1
Viral upper respiratory tract infection
subjects affected / exposed	0 / 52 (0.00%)	0 / 46 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	0	0	1	0
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	6 / 52 (11.54%)	11 / 46 (23.91%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	6	12	0	1
Dyslipidaemia
subjects affected / exposed	3 / 52 (5.77%)	2 / 46 (4.35%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	3	2	0	0
Fluid overload
subjects affected / exposed	7 / 52 (13.46%)	10 / 46 (21.74%)	2 / 5 (40.00%)	0 / 6 (0.00%)
occurrences all number	8	17	2	0
Gout
subjects affected / exposed	2 / 52 (3.85%)	5 / 46 (10.87%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	2	5	0	0
Hyperglycaemia
subjects affected / exposed	6 / 52 (11.54%)	3 / 46 (6.52%)	1 / 5 (20.00%)	0 / 6 (0.00%)
occurrences all number	6	3	1	0
Hyperkalaemia
subjects affected / exposed	5 / 52 (9.62%)	7 / 46 (15.22%)	0 / 5 (0.00%)	2 / 6 (33.33%)
occurrences all number	6	7	0	2
Hyperlipidaemia
subjects affected / exposed	5 / 52 (9.62%)	8 / 46 (17.39%)	0 / 5 (0.00%)	1 / 6 (16.67%)
occurrences all number	6	10	0	1
Hypoglycaemia
subjects affected / exposed	6 / 52 (11.54%)	4 / 46 (8.70%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	8	4	0	0
Hypokalaemia
subjects affected / exposed	8 / 52 (15.38%)	6 / 46 (13.04%)	2 / 5 (40.00%)	2 / 6 (33.33%)
occurrences all number	8	7	2	2
Hypomagnesaemia
subjects affected / exposed	13 / 52 (25.00%)	4 / 46 (8.70%)	2 / 5 (40.00%)	2 / 6 (33.33%)
occurrences all number	14	4	2	2
Hypovolaemia
subjects affected / exposed	6 / 52 (11.54%)	4 / 46 (8.70%)	0 / 5 (0.00%)	0 / 6 (0.00%)
occurrences all number	7	4	0	0
Fluid retention
subjects affected / exposed	2 / 52 (3.85%)	0 / 46 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)
occurrences all number	2	0	1	1

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Were there any global substantial amendments to the protocol? No

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: Clinical and laboratory evaluation of acute rejection, myocyte growth, repair and oxidative stress following de novo cardiac transplant: A comparison between Tacrolimus and Cyclosporine based immunoprophylactic regimens with mycophenolic acid therapeutic drug monitoring.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: The change in the markers of growth, apoptosis, inflammation and oxidation measured in endomyocardial biopsies (TE)

Primary: The change in the markers of growth, apoptosis, inflammation and oxidation measured in endomyocardial biopsies (TE)

Primary: The change in the markers of growth, apoptosis, inflammation and oxidation measured in endomyocardial biopsies (Pediatric Population)

Primary: The change in the markers of growth, apoptosis, inflammation and oxidation measured in endomyocardial biopsies (Pediatric Population)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: MCP-1 (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: MCP-1 (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: s-ICAM (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: s-ICAM (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: E-selectin (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: E-selectin (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Homocysteine (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Homocysteine (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: hsCRP (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: hsCRP (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: F2 isoprostanes (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: F2 isoprostanes (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: T-bars (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: T-bars (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Nitrotyrosine (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Nitrotyrosine (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: GSH/GSSG (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: GSH/GSSG (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: BNP (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: BNP (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Troponin T (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Troponin T (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Osteopontin (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Osteopontin (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Fibrinogen (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Fibrinogen (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: IL-6 (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: IL-6 (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: IL-18 (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: IL-18 (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Cystatin-C (TE)

Secondary: Changes in circulating markers of inflammation, oxidation, growth, apoptosis, differentiation and survival: Cystatin-C (TE)

Secondary: Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (TE)

Secondary: Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (TE)

Secondary: Time to first acute rejection episode following de novo cardiac transplant (TE)

Secondary: Time to first acute rejection episode following de novo cardiac transplant (TE)

Secondary: Number of patients requiring antilymphocyte antibodies or steroids for treatment of severe acute rejection

Secondary: Number of patients requiring antilymphocyte antibodies or steroids for treatment of severe acute rejection

Secondary: Number of cardiac rejection episodes requiring treatment (TE)

Secondary: Number of cardiac rejection episodes requiring treatment (TE)

Secondary: Mean cases of acute rejection (MCAR) per patient

Secondary: Mean cases of acute rejection (MCAR) per patient

Secondary: Number of patients with successful steroid taper or withdrawal at weeks 26 and 52 (TE)

Secondary: Number of patients with successful steroid taper or withdrawal at weeks 26 and 52 (TE)

Secondary: Number of patients with treatment failure and crossover for treatment failure

Secondary: Number of patients with treatment failure and crossover for treatment failure

Secondary: Changes in circulating markers of inflammation and oxidation: F2 isoprostanes (Pediatric Population)

Secondary: Changes in circulating markers of inflammation and oxidation: F2 isoprostanes (Pediatric Population)

Secondary: Changes in circulating markers of inflammation and oxidation: nitrotyrosine (Pediatric Population)

Secondary: Changes in circulating markers of inflammation and oxidation: nitrotyrosine (Pediatric Population)

Secondary: Changes in circulating markers of inflammation and oxidation: hsCRP (Pediatric Population)

Secondary: Changes in circulating markers of inflammation and oxidation: hsCRP (Pediatric Population)

Secondary: Changes in circulating markers of inflammation and oxidation: Cystatin-C (Pediatric Population)

Secondary: Changes in circulating markers of inflammation and oxidation: Cystatin-C (Pediatric Population)

Secondary: Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (Pediatric Population)

Secondary: Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (Pediatric Population)

Secondary: Time to first acute rejection episode following de novo cardiac transplant (Pediatric Population)

Secondary: Time to first acute rejection episode following de novo cardiac transplant (Pediatric Population)

Secondary: Number of patients requiring antilymphocyte antibodies or steroids for treatment of severe acute rejection (Pediatric Population)

Secondary: Number of patients requiring antilymphocyte antibodies or steroids for treatment of severe acute rejection (Pediatric Population)

Secondary: Number of cardiac rejection episodes requiring treatment (Pediatric Population)

Secondary: Number of cardiac rejection episodes requiring treatment (Pediatric Population)

Secondary: Mean cases of acute rejection (MCAR) per patient (Pediatric Population)

Secondary: Mean cases of acute rejection (MCAR) per patient (Pediatric Population)

Secondary: Number of patients with successful steroid taper or withdrawal at weeks 26 and 52 (Pediatric Population)

Secondary: Number of patients with successful steroid taper or withdrawal at weeks 26 and 52 (Pediatric Population)

Clinical Trial Results:
Clinical and laboratory evaluation of acute rejection, myocyte growth, repair and oxidative stress following de novo cardiac transplant: A comparison between Tacrolimus and Cyclosporine based immunoprophylactic regimens with mycophenolic acid therapeutic drug monitoring.