Canadian Cardiology de Novo Study: A Comparison Between Tacrolimus- and Cyclosporine- Based Immunoprophylactic Regimens

• Sponsor: Astellas Pharma Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00157014
• Collaborator: Astellas Pharma Canada, Inc. (Industry)
• Enrollment: 111
• Locations: 13
• Arms: 4
• Actual Duration (Months): 50.3
• Patients Per Site: 8.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the safety and efficacy of tacrolimus in de novo heart transplantation.

Condition or Disease	Intervention/Treatment	Phase
Heart Diseases; Heart Transplantation	Drug: Tacrolimus; Drug: Cyclosporine; Drug: Mycophenolate mofetil; Drug: Methylprednisolone; Drug: Prednisone	Phase 3

Detailed Description

Subcellular markers will be assessed in relationship to cellular acute rejection in de novo cardiac transplant recipients receiving either tacrolimus or cyclosporine as their primary immunosuppressant

Two parallel active arms.

Study Design

• Study Type: Interventional
• Actual Enrollment: 111 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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 MPA TDM
• Actual Study Start Date: May 10, 2004
• Actual Primary Completion Date: Jul 18, 2008
• Actual Study Completion Date: Jul 18, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tacrolimus - Adult Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Drug: Tacrolimus; Oral; Other Names: Prograf FK506 ; Drug: Mycophenolate mofetil; Intravenous and Oral; Other Names: CellCept ; Drug: Methylprednisolone; Intravenous; Drug: Prednisone; Oral
Active Comparator: Cyclosporine - Adult Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Drug: Cyclosporine; Oral; Drug: Mycophenolate mofetil; Intravenous and Oral; Other Names: CellCept ; Drug: Methylprednisolone; Intravenous; Drug: Prednisone; Oral
Experimental: Tacrolimus - Pediatric Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Drug: Tacrolimus; Oral; Other Names: Prograf FK506 ; Drug: Mycophenolate mofetil; Intravenous and Oral; Other Names: CellCept ; Drug: Methylprednisolone; Intravenous; Drug: Prednisone; Oral
Active Comparator: Cyclosporine - Pediatric Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Drug: Cyclosporine; Oral; Drug: Mycophenolate mofetil; Intravenous and Oral; Other Names: CellCept ; Drug: Methylprednisolone; Intravenous; Drug: Prednisone; Oral

Outcome Measures

Primary Outcome Measures

1. The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies [2 Weeks and 52 Weeks]

   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.

2. The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population) [2 Weeks and 52 Weeks]

   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.

Secondary Outcome Measures

1. Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: MCP-1 [Pre-Transplant and 52 Weeks]

   Change is defined as Week 52 assessment - Pre-Transplant assessment. MCP-1= monocyte chemoattractant protein-1

2. Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: s-ICAM [Pre-Transplant and 52 Weeks]

   Change is defined as Week 52 assessment - Pre-Transplant assessment. s-ICAM= soluble-intracellular adhesion molecule

3. Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: E-selectin [Pre-Transplant and 52 Weeks]

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

4. Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Homocysteine [Pre-Transplant and 52 Weeks]

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

5. Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: hsCRP [Pre-Transplant and 52 Weeks]

   Change is defined as Week 52 assessment - Pre-Transplant assessment. hsCRP= high-sensitivity C Reactive Protein

6. Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: F2 Isoprostanes [Pre-Transplant and 52 Weeks]

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

7. Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: T-bars [Pre-Transplant and 52 Weeks]

   Change is defined as Week 52 assessment - Pre-Transplant assessment. T-bars = thiobarbituric acid reactive substances

8. Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Nitrotyrosine [Pre-Transplant and 52 Weeks]

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

9. Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: GSH/GSSG [Pre-Transplant and 52 Weeks]

   Change is defined as Week 52 assessment - Pre-Transplant assessment. GSH/GSSG= ratio of reduced to oxidised glutathione

10. Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: BNP [Pre-Transplant and 52 Weeks]

    Change is defined as Week 52 assessment - Pre-Transplant assessment. BNP= Brain Natriuretic Peptide

11. Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Troponin T [Pre-Transplant and 52 Weeks]

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

12. Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Osteopontin [Pre-Transplant and 52 Weeks]

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

13. Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Fibrinogen [Pre-Transplant and 52 Weeks]

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

14. Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: IL-6 [Pre-Transplant and 52 Weeks]

    Change is defined as Week 52 assessment - Pre-Transplant assessment. IL= Interleukin

15. Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: IL-18 [Pre-Transplant and 52 Weeks]

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

16. Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Cystatin-C [Pre-Transplant and 52 Weeks]

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

17. Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria [52 Weeks]

    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. Patients may report more than one acute rejection.

18. Time to First Acute Rejection Episode Following de Novo Cardiac Transplant [52 Weeks]

    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.

19. Number of Patients Requiring Antilymphocyte Antibodies or Steroids for Treatment of Severe Acute Rejection [52 Weeks]

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

20. Number of Cardiac Rejection Episodes Requiring Treatment [52 Weeks]

    The number of rejection episodes requiring treatment (medications started/ stopped, non-medication treatment, or both) regardless of biopsy grade or presence of hemodynamic compromise.

21. Mean Cases of Acute Rejection (MCAR) Per Patient [52 Weeks]

    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.

22. Number of Patients With Successful Steroid Taper or Withdrawal at Weeks 26 and 52 [26 Weeks and 52 Weeks]

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

23. Number of Patients With Treatment Failure and Crossover for Treatment Failure [52 Weeks]

    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.

24. Changes in Circulating Markers of Inflammation and Oxidation: F2 Isoprostanes (Pediatric Population) [Pre-Transplant and 52 Weeks]

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

25. Changes in Circulating Markers of Inflammation and Oxidation: Nitrotyrosine (Pediatric Population) [Pre-Transplant and 52 Weeks]

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

26. Changes in Circulating Markers of Inflammation and Oxidation: hsCRP (Pediatric Population) [Pre-Transplant and 52 Weeks]

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

27. Changes in Circulating Markers of Inflammation and Oxidation: Cystatin-C (Pediatric Population) [Pre-Transplant and 52 Weeks]

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

28. Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (Pediatric Population) [52 Weeks]

    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. Patients may report more than one rejection episode.

29. Time to First Acute Rejection Episode Following de Novo Cardiac Transplant (Pediatric Population) [52 Weeks]

    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.

30. Number of Patients Requiring Antilymphocyte Antibodies or Steroids for Treatment of Severe Acute Rejection (Pediatric Population) [52 Weeks]

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

31. Number of Cardiac Rejection Episodes Requiring Treatment (Pediatric Population) [52 Weeks]

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

32. Mean Cases of Acute Rejection (MCAR) Per Patient (Pediatric Population) [52 Weeks]

    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.

33. Number of Patients With Successful Steroid Taper or Withdrawal at Weeks 26 and 52 (Pediatric Population) [26 Weeks and 52 Weeks]

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

34. Number of Patients With Treatment Failure and Crossover for Treatment Failure (Pediatric Population) [52 Weeks]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients (or their legal guardians) who are capable of understanding, and who have been fully informed of the purpose of the study and the risks of participation.

• Patients (or their legal guardians) who have signed and dated the Informed Consent form and are willing and able to follow the study protocol.

• Patients who are primary cadaveric heart transplant recipients.

• Males or females from birth.

• Female patients of child-bearing potential who have a current negative pregnancy test and agree to practice effective birth control, as judged by the investigator, while participating in the study. Prepubescent pediatric patients will not require pregnancy testing.

• Patients able to tolerate oral medication and who do not have a gastrointestinal condition likely to affect the absorption kinetics or metabolism of the oral study medications.

Exclusion Criteria:

• Previous organ transplant recipients.

• Multi-organ transplant recipients.

• Recipients of a heart from a donor with incompatible ABO blood type.

• Patients with significant graft dysfunction and/or significant de novo infection(s) at time of randomization

• Patients with known hypersensitivity to tacrolimus, cyclosporine, mycophenolate mofetil (MMF), daclizumab, prednisone, cremophor, polysorbate 80 and/or polyoxyl 60 hydrogenated castor oil (HCO-60).

• Patients who are pregnant or lactating or planning to become pregnant prior to completion of the study.

• Patients who have consumed an investigational product in the 30 days prior to transplantation or at any time during post-transplantation follow-up.

• Patients receiving cholestyramine or colestipol.

• Patients having any one of the following at enrolment:

1. History of malignancy, not chart-documented as cured or active malignancy (with exception of eradicable non-metastatic in-situ basal cell or squamous cell carcinoma).

2. Leukopenia (white cell count < 2500/cu mm).

3. Anemia (hemoglobin < 80 g/L).

4. Positive test for hepatitis B surface antigen and/or hepatitis C.

5. Historical positive test for human immunodeficiency virus (HIV).

6. Serum creatinine > 230 umol/l.

7. Continual elevation of AST and/or ALT to >= 3X the upper limit of normal.

8. Body mass index (weight in kg/height in m2) > 30.

• Undiagnosed diabetes mellitus as determined by 2 hour (2h) oral glucose tolerance test (OGTT) or fasting glucose test or uncontrolled diabetes mellitus at screening. In either case, the patient may be declared as no longer excluded by this criterion upon establishment of control of the diabetes through appropriate medical management.

• Blood glucose >= 11.1 mmol/L at pre-operative assessment.

• Patients having a significant disease, substance dependency, or disability that may prevent adherence to, or understanding of, the protocol and/or the investigator's instructions.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Los Angeles	California	United States	90095
2		Calgary	Alberta	Canada	T2N 2T9
3		Edmonton	Alberta	Canada	T6G 2B7
4		Edmonton	Alberta	Canada	T6G 2E1
5		Vancouver	British Columbia	Canada	V6Z 1Y6
6		Halifax	Nova Scotia	Canada	B3H 3A7
7		London	Ontario	Canada	N6A 5A5
8		Ottawa	Ontario	Canada	K1Y 4W7
9		Toronto	Ontario	Canada	M5G 1X8
10		Toronto	Ontario	Canada	M5G 2N2
11		Montreal	Quebec	Canada	H1T 1C8
12		Montreal	Quebec	Canada	H3A 1A1
13		Sainte-Foy	Quebec	Canada	G1V 4G5

Sponsors and Collaborators

• Astellas Pharma Inc
• Astellas Pharma Canada, Inc.

Investigators

• Study Director: Medical Monitor, Astellas Pharma Canada, Inc.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Link to Prescribing Information

Publications

None provided.

• Responsible Party: Astellas Pharma Inc
• ClinicalTrials.gov Identifier: NCT00157014
• Other Study ID Numbers: FKC-009
• First Posted: Sep 12, 2005
• Last Update Posted: Jun 5, 2017
• Last Verified: Apr 1, 2017

• Keywords provided by Astellas Pharma Inc: Antirejection; Treatment Outcome; Immunosuppression; Treatment Effectiveness; Anti-rejection therapy
• Additional relevant MeSH terms: Heart Diseases; Cyclosporine; Mycophenolic Acid; Prednisone; Methylprednisolone; Tacrolimus; Cyclosporins

Study Results

Participant Flow

Recruitment Details	3 patients randomized to cyclosporine actually received tacrolimus and were included in the Treatment Exposure Population for tacrolimus. 2 patients randomized for tacrolimus were excluded from Treatment Exposure Population - 1 never received drug; 1 received incorrect drug without a waiver.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult	Tacrolimus - Pediatric	Cyclosporine - Pediatric
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Period Title: Overall Study
STARTED	52	46	5	6
COMPLETED	45	41	4	5
NOT COMPLETED	7	5	1	1

Baseline Characteristics

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult	Tacrolimus - Pediatric	Cyclosporine - Pediatric	Total
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Total of all reporting groups
Overall Participants	52	46	5	6	109
Age, Customized (Number) [Number]
0 - ˂ 2 Years	0 0%	0 0%	1 20%	1 16.7%	2 1.8%
2 - 10 Years	0 0%	0 0%	1 20%	2 33.3%	3 2.8%
10 - ˂ 18 Years	0 0%	0 0%	3 60%	3 50%	6 5.5%
18 - 49 Years	14 26.9%	18 39.1%	0 0%	0 0%	32 29.4%
50 - 59 Years	18 34.6%	15 32.6%	0 0%	0 0%	33 30.3%
60 - 69 Years	18 34.6%	12 26.1%	0 0%	0 0%	30 27.5%
70 Years and Older	2 3.8%	1 2.2%	0 0%	0 0%	3 2.8%
Sex/Gender, Customized (Number) [Number]
Male	43 82.7%	37 80.4%	0 0%	2 33.3%	82 75.2%
Female	9 17.3%	9 19.6%	5 100%	4 66.7%	27 24.8%
Race/Ethnicity, Customized (Number) [Number]
European descent/ White	48 92.3%	40 87%	5 100%	4 66.7%	97 89%
Black	2 3.8%	4 8.7%	0 0%	1 16.7%	7 6.4%
East Indian	2 3.8%	0 0%	0 0%	1 16.7%	3 2.8%
Latin American	0 0%	1 2.2%	0 0%	0 0%	1 0.9%
Aboriginal	0 0%	1 2.2%	0 0%	0 0%	1 0.9%

Outcome Measures

1. Primary Outcome

Title	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies
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.
Time Frame	2 Weeks and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
p-ERK ½ - Week 2	0.70 (0.500)	0.90 (0.641)
p-ERK ½ - Week 52	0.87 (0.539)	0.79 (0.674)
p-ERK ½ - Change from Week 2	0.05 (0.834)	-0.05 (0.662)
p-JNK - Week 2	1.10 (0.813)	1.23 (0.722)
p-JNK - Week 52	1.33 (0.890)	1.46 (0.792)
p-JNK - Change from Week 2	0.03 (1.188)	0.22 (0.957)
p-p38 MAPK - Week 2	0.48 (0.450)	0.54 (0.556)
p-p38 MAPK - Week 52	0.63 (0.664)	0.77 (0.717)
p-p38 MAPK - Change from Week 2	0.14 (0.733)	0.23 (0.828)

2. Primary Outcome

Title	The Change in the Markers of Growth, Apoptosis, Inflammation and Oxidation Measured in Endomyocardial Biopsies (Pediatric Population)
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.
Time Frame	2 Weeks and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Pediatric	Cyclosporine - Pediatric
Arm/Group Description	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Measure Participants	5	6
p-ERK ½ - Week 2	1.74 (0.972)	1.67 (0.682)
p-ERK ½ - Week 52	0.93 (0.184)	1.22 (0.633)
p-ERK ½ - Change from Week 2	-0.09 (0)	-0.27 (0.309)
p-JNK - Week 2	1.17 (0.420)	0.91 (0.430)
p-JNK - Week 52	0.57 (0.085)	0.82 (0.537)
p-JNK - Change from Week 2	-0.21 (0)	0.04 (0.189)
p-p38 MAPK - Week 2	0.83 (0.467)	0.43 (0.364)
p-p38 MAPK - Week 52	0.24 (0.014)	0.58 (0.432)
p-p38 MAPK - Change from Week 2	-0.04 (0)	0.34 (0.630)

3. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: MCP-1
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment. MCP-1= monocyte chemoattractant protein-1
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Pre-Transplant	233.05 (292.832)	193.63 (144.696)
Week 52	229.96 (263.084)	180.90 (145.067)
Change from Pre-Transplant at Week 52	42.92 (165.517)	-16.49 (126.586)

4. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: s-ICAM
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment. s-ICAM= soluble-intracellular adhesion molecule
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Pre-Transplant	766.58 (449.572)	674.46 (429.036)
Week 52	590.30 (369.942)	503.71 (305.531)
Change from Pre-Transplant at Week 52	-227.58 (366.136)	-183.96 (250.382)

5. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: E-selectin
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Pre-Transplant	90.40 (72.801)	98.96 (89.153)
Week 52	68.60 (51.911)	80.93 (70.383)
Change from Pre-Transplant at Week 52	-18.58 (48.247)	-19.16 (52.080)

6. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Homocysteine
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Pre-Transplant	14.2 (6.94)	15.9 (6.97)
Week 52	13.5 (4.19)	15.8 (5.33)
Change from Pre-Transplant at Week 52	0.3 (5.02)	0.7 (7.61)

7. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: hsCRP
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment. hsCRP= high-sensitivity C Reactive Protein
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Pre-Transplant	32.85 (50.859)	21.83 (33.547)
Week 52	3.01 (3.313)	3.95 (5.273)
Change from Pre-Transplant at Week 52	-34.32 (54.257)	-18.69 (35.354)

8. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: F2 Isoprostanes
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Pre-Transplant	52.03 (76.090)	53.94 (78.476)
Week 52	30.08 (25.905)	50.44 (68.416)
Change from Pre-Transplant at Week 52	-13.29 (40.543)	-3.43 (103.457)

9. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: T-bars
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment. T-bars = thiobarbituric acid reactive substances
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Pre-Transplant	3.78 (1.586)	3.91 (2.059)
Week 52	3.25 (1.365)	3.14 (1.198)
Change from Pre-Transplant at Week 52	-0.64 (1.724)	-0.77 (2.182)

10. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Nitrotyrosine
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Pre-Transplant	422.63 (393.554)	482.43 (390.702)
Week 52	451.88 (443.372)	368.95 (262.693)
Change from Pre-Transplant at Week 52	71.44 (332.351)	-99.79 (228.268)

11. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: GSH/GSSG
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment. GSH/GSSG= ratio of reduced to oxidised glutathione
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Pre-Transplant	55.07 (62.780)	58.83 (71.289)
Week 52	51.69 (55.721)	53.72 (55.264)
Change from Pre-Transplant at Week 52	-2.07 (70.036)	-5.55 (80.490)

12. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: BNP
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment. BNP= Brain Natriuretic Peptide
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Pre-Transplant	4314.8 (4861.78)	4240.8 (4673.72)
Week 52	670.1 (1053.21)	1856.8 (5077.26)
Change from Pre-Transplant at Week 52	-4018.4 (5043.28)	-1446.7 (6460.33)

13. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Troponin T
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Pre-Transplant	0.30 (0.686)	0.28 (0.878)
Week 52	0.03 (0.116)	0.04 (0.120)
Change from Pre-Transplant at Week 52	-0.32 (0.768)	-0.27 (0.958)

14. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Osteopontin
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Pre-Transplant	11.88 (9.528)	11.14 (12.278)
Week 52	8.77 (10.462)	10.49 (8.987)
Change from Pre-Transplant at Week 52	-2.22 (10.615)	0.20 (11.158)

15. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Fibrinogen
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Pre-Transplant	4.4 (1.27)	4.4 (1.23)
Week 52	3.4 (0.87)	3.8 (0.77)
Change from Pre-Transplant at Week 52	-1.1 (1.48)	-0.5 (1.23)

16. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: IL-6
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment. IL= Interleukin
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Pre-Transplant	3.36 (4.221)	2.54 (3.159)
Week 52	0.98 (0.743)	0.90 (0.651)
Change from Pre-Transplant at Week 52	-2.84 (4.635)	-1.56 (3.146)

17. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: IL-18
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Pre-Transplant	574.0 (291.89)	496.2 (246.90)
Week 52	534.6 (290.38)	427.2 (217.07)
Change from Pre-Transplant at Week 52	5.2 (289.66)	-71.0 (243.81)

18. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation, Oxidation, Growth, Apoptosis, Differentiation and Survival: Cystatin-C
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment.
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Pre-Transplant	1.21 (0.414)	1.29 (0.490)
Week 52	1.29 (0.533)	1.48 (0.714)
Change from Pre-Transplant at Week 52	0.06 (0.464)	0.27 (0.744)

19. Secondary Outcome

Title	Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria
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. Patients may report more than one acute rejection.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Total Acute Rejection Episodes	8	8
Acute Rejection Episodes with ISHLT Grade ≥3A	3	7
Acute Rejection Episodes w/ Hemodynamic Compromise	6	2

20. Secondary Outcome

Title	Time to First Acute Rejection Episode Following de Novo Cardiac Transplant
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.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	6	8
Mean (Standard Deviation) [Days]	55.0 (35.60)	35.60 (132.86)

21. Secondary Outcome

Title	Number of Patients Requiring Antilymphocyte Antibodies or Steroids for Treatment of Severe Acute Rejection
Description	Severe Acute Rejection is defined as rejection with ISHLT Grade 4.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Number [Patients]	0	0

22. Secondary Outcome

Title	Number of Cardiac Rejection Episodes Requiring Treatment
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.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Number [Rejection Episodes]	12	11

23. Secondary Outcome

Title	Mean Cases of Acute Rejection (MCAR) Per Patient
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.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Mean (Standard Deviation) [MCAR per patient]	0.15 (0.46)	0.17 (0.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tacrolimus - Adult, Cyclosporine - Adult
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4725
	Comments	No adjustments for multiple comparisons were performed.
	Method	Wilcoxon (Mann-Whitney)
	Comments

24. Secondary Outcome

Title	Number of Patients With Successful Steroid Taper or Withdrawal at Weeks 26 and 52
Description	A successful steroid taper or withdrawal was defined as steroids (prednisone) being discontinued or tapered to the suggested dose level after week 26.
Time Frame	26 Weeks and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Week 26	22	16
Week 52	33	29

25. Secondary Outcome

Title	Number of Patients With Treatment Failure and Crossover for Treatment Failure
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.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Adult	Cyclosporine - Adult
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant	Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant
Measure Participants	52	46
Treatment Failures	6	11
Crossover for Treatment Failures	2	8

26. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation and Oxidation: F2 Isoprostanes (Pediatric Population)
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Pediatric	Cyclosporine - Pediatric
Arm/Group Description	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Measure Participants	5	6
Pre-Transplant	106.06 (37.974)	104.68 (53.812)
Week 52	69.71 (38.620)	66.48 (33.298)
Change from Pre-Transplant at Week 52	-38.31 (47.563)	-30.07 (80.246)

27. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation and Oxidation: Nitrotyrosine (Pediatric Population)
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Pediatric	Cyclosporine - Pediatric
Arm/Group Description	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Measure Participants	5	6
Pre-Transplant	233.08 (211.491)	12701.21 (21666.231)
Week 52	5462.99 (7988.134)	41147.62 (37565.740)
Change from Pre-Transplant at Week 52	5148.42 (7849.554)	21514.62 (49626.968)

28. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation and Oxidation: hsCRP (Pediatric Population)
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Pediatric	Cyclosporine - Pediatric
Arm/Group Description	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Measure Participants	5	6
Pre-Transplant	30.46 (32.274)	12.08 (14.771)
Week 52	26.31 (45.109)	2.43 (1.348)
Change from Pre-Transplant at Week 52	-7.85 (78.126)	-13.94 (16.461)

29. Secondary Outcome

Title	Changes in Circulating Markers of Inflammation and Oxidation: Cystatin-C (Pediatric Population)
Description	Change is defined as Week 52 assessment - Pre-Transplant assessment
Time Frame	Pre-Transplant and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Pediatric	Cyclosporine - Pediatric
Arm/Group Description	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Measure Participants	5	6
Pre-Transplant	0.86 (0.248)	0.77 (0.194)
Week 52	0.87 (0.133)	0.84 (0.111)
Change from Pre-Transplant at Week 52	-0.11 (0.197)	-0.01 (0.108)

30. Secondary Outcome

Title	Number of Acute Rejection Episodes by International Society of Heart and Lung Transplantation (ISHLT) Criteria (Pediatric Population)
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. Patients may report more than one rejection episode.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Pediatric	Cyclosporine - Pediatric
Arm/Group Description	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Measure Participants	5	6
Total Acute Rejection Episodes	3	3
Acute Rejection Episodes with ISHLT Grade ≥3A	3	3
Acute Rejection Episodes w/ Hemodynamic Compromise	0	0

31. Secondary Outcome

Title	Time to First Acute Rejection Episode Following de Novo Cardiac Transplant (Pediatric Population)
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.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Pediatric	Cyclosporine - Pediatric
Arm/Group Description	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Measure Participants	3	3
Mean (Standard Deviation) [Days]	56.3 (27.06)	49.0 (15.62)

32. Secondary Outcome

Title	Number of Patients Requiring Antilymphocyte Antibodies or Steroids for Treatment of Severe Acute Rejection (Pediatric Population)
Description	Severe Acute Rejection was defined as rejection with ISHLT Grade 4.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Pediatric	Cyclosporine - Pediatric
Arm/Group Description	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Measure Participants	5	6
Number [Patients]	0	0

33. Secondary Outcome

Title	Number of Cardiac Rejection Episodes Requiring Treatment (Pediatric Population)
Description	A summary of rejection episodes requiring treatment regardless of biopsy grade or presence of hemodynamic compromise.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Pediatric	Cyclosporine - Pediatric
Arm/Group Description	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Measure Participants	5	6
Number [Rejection Episodes]	3	3

34. Secondary Outcome

Title	Mean Cases of Acute Rejection (MCAR) Per Patient (Pediatric Population)
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.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Pediatric	Cyclosporine - Pediatric
Arm/Group Description	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Measure Participants	5	6
Mean (Standard Deviation) [MCAR per patient]	0.60 (0.55)	0.50 (0.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tacrolimus - Adult, Cyclosporine - Adult
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8373
	Comments	No adjustments for multiple comparisons were performed.
	Method	Wilcoxon (Mann-Whitney)
	Comments

35. Secondary Outcome

Title	Number of Patients With Successful Steroid Taper or Withdrawal at Weeks 26 and 52 (Pediatric Population)
Description	A successful steroid taper or withdrawal was defined as steroids (prednisone) being discontinued or tapered to the suggested dose level after week 26.
Time Frame	26 Weeks and 52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Pediatric	Cyclosporine - Pediatric
Arm/Group Description	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Measure Participants	5	6
Week 26	2	3
Week 52	1	1

36. Secondary Outcome

Title	Number of Patients With Treatment Failure and Crossover for Treatment Failure (Pediatric Population)
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.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tacrolimus - Pediatric	Cyclosporine - Pediatric
Arm/Group Description	Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant	Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
Measure Participants	5	6
Treatment Failures	1	3
Crossover for Treatment Failures	0	3

Adverse Events

Time Frame	After the initiation of study drug up to 30 days after the last dose of study drug.
Adverse Event Reporting Description	Treatment Emergent Adverse Events were reported. Within a preferred term, patients were counted once.
Arm/Group Title	Tacrolimus - Adult		Cyclosporine - Adult		Tacrolimus - Pediatric		Cyclosporine - Pediatric
Arm/Group Description	Adults: 0.05 - 0.10 mg/ kg/ day in 2 divided doses starting within 10 days of transplant		Adults: 3-5 mg/ kg/ day in 2 divided doses starting within 10 days of transplant		Pediatrics: 0.05 - 0.30 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant		Pediatrics: 6 - 10 mg/ kg/ day in 2-3 divided doses starting within 10 days of transplant
All Cause Mortality
	Tacrolimus - Adult		Cyclosporine - Adult		Tacrolimus - Pediatric		Cyclosporine - Pediatric
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Tacrolimus - Adult		Cyclosporine - Adult		Tacrolimus - Pediatric		Cyclosporine - Pediatric
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/52 (40.4%)		24/46 (52.2%)		3/5 (60%)		5/6 (83.3%)
Blood and lymphatic system disorders
Neutropenia	0/52 (0%)		2/46 (4.3%)		0/5 (0%)		0/6 (0%)
Pancytopenia	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Cardiac disorders
Atrial flutter	2/52 (3.8%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Atrioventricular block complete	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Cardiac arrest	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Cardiac failure congestive	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Cardiogenic shock	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Pericardial effusion	1/52 (1.9%)		2/46 (4.3%)		1/5 (20%)		1/6 (16.7%)
Pericarditis constrictive	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Right ventricular failure	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Supraventricular tachycardia	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Cardiac tamponade	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Ear and labyrinth disorders
Deafness unilateral	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Endocrine disorders
Adrenal mass	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Eye disorders
Blindness cortical	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Gastrointestinal disorders
Abdominal discomfort	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Abdominal pain	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Constipation	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Diarrhoea	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Dysphagia	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Gastrointestinal haemorrhage	2/52 (3.8%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Lower gastrointestinal haemorrhage	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Mouth ulceration	0/52 (0%)		2/46 (4.3%)		0/5 (0%)		0/6 (0%)
Pancreatic disorder	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Upper gastrointestinal haemorrhage	2/52 (3.8%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Vomiting	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
General disorders
Catheter related complication	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Chest pain	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Chills	1/52 (1.9%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Oedema peripheral	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Pyrexia	0/52 (0%)		2/46 (4.3%)		0/5 (0%)		0/6 (0%)
Hepatobiliary disorders
Cholelithiasis	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Immune system disorders
Heart transplant rejection	2/52 (3.8%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Transplant rejection	2/52 (3.8%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Infections and infestations
American trypanosomiasis	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Bronchopneumonia	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Cellulitis	0/52 (0%)		2/46 (4.3%)		0/5 (0%)		0/6 (0%)
Clostridium difficile colitis	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Cystitis	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Cytomegalovirus gastritis	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Cytomegalovirus infection	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Diverticulitis	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Klebsiella bacteraemia	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Lobar pneumonia	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Lung infection	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Mediastinitis	1/52 (1.9%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Pneumonia	1/52 (1.9%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Pyelonephritis acute	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Sepsis	0/52 (0%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Sinusitis	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Staphylococcal infection	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Viral infection	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Pneumonia klebsiella	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Injury, poisoning and procedural complications
Haemothorax	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Post procedural haematoma	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Wound dehiscence	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Metabolism and nutrition disorders
Hyperkalaemia	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Fluid overload	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/52 (1.9%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Back pain	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Bone pain	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Rotator cuff syndrome	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer stage III	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Gastrointestinal carcinoma	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Lung neoplasm malignant	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Lymphoproliferative disorder	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Nervous system disorders
Cerebral infarction	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Cerebrovascular accident	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Convulsion	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Depressed level of consciousness	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Encephalopathy	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Hydrocephalus	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Partial seizures	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Syncope vasovagal	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Tension headache	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Cerebral haemorrhage	0/52 (0%)		0/46 (0%)		1/5 (20%)		0/6 (0%)
Convulsion	0/52 (0%)		0/46 (0%)		0/5 (0%)		2/6 (33.3%)
Psychiatric disorders
Confusional state	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Renal and urinary disorders
Nephropathy toxic	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Renal failure	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Renal failure acute	0/52 (0%)		3/46 (6.5%)		0/5 (0%)		1/6 (16.7%)
Renal impairment	1/52 (1.9%)		0/46 (0%)		1/5 (20%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Non-cardiogenic pulmonary oedema	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Pleural effusion	1/52 (1.9%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Pleuritic pain	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Pneumothorax	0/52 (0%)		1/46 (2.2%)		1/5 (20%)		0/6 (0%)
Pulmonary embolism	1/52 (1.9%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Respiratory alkalosis	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Respiratory failure	1/52 (1.9%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Acute respiratory distress syndrome	0/52 (0%)		0/46 (0%)		1/5 (20%)		0/6 (0%)
Skin and subcutaneous tissue disorders
Acne	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Vascular disorders
Deep vein thrombosis	2/52 (3.8%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Inferior vena caval occlusion	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Orthostatic hypotension	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Temporal arteritis	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Vascular pseudoaneurysm	0/52 (0%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Tacrolimus - Adult		Cyclosporine - Adult		Tacrolimus - Pediatric		Cyclosporine - Pediatric
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/52 (100%)		46/46 (100%)		5/5 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Aneamia	18/52 (34.6%)		15/46 (32.6%)		1/5 (20%)		2/6 (33.3%)
Leukocytosis	9/52 (17.3%)		9/46 (19.6%)		0/5 (0%)		0/6 (0%)
Leukopenia	12/52 (23.1%)		9/46 (19.6%)		0/5 (0%)		0/6 (0%)
Thrombocytopenia	5/52 (9.6%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Neutropenia	0/52 (0%)		0/46 (0%)		1/5 (20%)		1/6 (16.7%)
Cardiac disorders
Atrial fibrillation	6/52 (11.5%)		4/46 (8.7%)		0/5 (0%)		0/6 (0%)
Atrial flutter	3/52 (5.8%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Bradycardia	6/52 (11.5%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Fluid overload	4/52 (7.7%)		6/46 (13%)		0/5 (0%)		0/6 (0%)
Mitral valve incompetence	3/52 (5.8%)		2/46 (4.3%)		0/5 (0%)		0/6 (0%)
Oedema due to cardiac disease	3/52 (5.8%)		4/46 (8.7%)		0/5 (0%)		0/6 (0%)
Oedema peripheral	6/52 (11.5%)		14/46 (30.4%)		0/5 (0%)		0/6 (0%)
Palpitations	3/52 (5.8%)		6/46 (13%)		0/5 (0%)		0/6 (0%)
Pericardial effusion	5/52 (9.6%)		6/46 (13%)		1/5 (20%)		0/6 (0%)
Pulmonary oedema	3/52 (5.8%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Right ventricular dysfunction	4/52 (7.7%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Tricuspid valve incompetence	3/52 (5.8%)		2/46 (4.3%)		0/5 (0%)		0/6 (0%)
Arrhythmia	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Congenital, familial and genetic disorders
Becker's muscular dystrophy	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Eye disorders
Amblyopia	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Gastrointestinal disorders
Abdominal distension	4/52 (7.7%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Abdominal pain	6/52 (11.5%)		5/46 (10.9%)		1/5 (20%)		0/6 (0%)
Abdominal pain upper	3/52 (5.8%)		2/46 (4.3%)		0/5 (0%)		0/6 (0%)
Constipation	6/52 (11.5%)		13/46 (28.3%)		0/5 (0%)		0/6 (0%)
Diarrhoea	26/52 (50%)		8/46 (17.4%)		0/5 (0%)		1/6 (16.7%)
Dysphagia	4/52 (7.7%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Gingival hyperplasia	0/52 (0%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Mouth ulceration	0/52 (0%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Nausea	8/52 (15.4%)		15/46 (32.6%)		1/5 (20%)		0/6 (0%)
Vomiting	3/52 (5.8%)		9/46 (19.6%)		2/5 (40%)		1/6 (16.7%)
Gastritis	0/52 (0%)		0/46 (0%)		1/5 (20%)		0/6 (0%)
Gingival hypertrophy	0/52 (0%)		0/46 (0%)		0/5 (0%)		3/6 (50%)
Tooth discolouration	0/52 (0%)		0/46 (0%)		1/5 (20%)		0/6 (0%)
General disorders
Asthenia	5/52 (9.6%)		2/46 (4.3%)		0/5 (0%)		0/6 (0%)
Chest pain	4/52 (7.7%)		2/46 (4.3%)		0/5 (0%)		0/6 (0%)
Chills	1/52 (1.9%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Fatigue	2/52 (3.8%)		7/46 (15.2%)		0/5 (0%)		0/6 (0%)
Hyperthermia	2/52 (3.8%)		4/46 (8.7%)		0/5 (0%)		0/6 (0%)
Influenza like illness	3/52 (5.8%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Oedema peripheral	14/52 (26.9%)		6/46 (13%)		0/5 (0%)		2/6 (33.3%)
Pyrexia	4/52 (7.7%)		4/46 (8.7%)		0/5 (0%)		2/6 (33.3%)
Oedema	0/52 (0%)		0/46 (0%)		2/5 (40%)		0/6 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Immune system disorders
Transplant rejection	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Infections and infestations
Bronchitis	4/52 (7.7%)		2/46 (4.3%)		0/5 (0%)		0/6 (0%)
Diverticulitis	0/52 (0%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Influenza	1/52 (1.9%)		4/46 (8.7%)		0/5 (0%)		0/6 (0%)
Nasopharyngitis	2/52 (3.8%)		6/46 (13%)		0/5 (0%)		0/6 (0%)
Pneumonia	6/52 (11.5%)		2/46 (4.3%)		0/5 (0%)		1/6 (16.7%)
Sinusitis	3/52 (5.8%)		2/46 (4.3%)		0/5 (0%)		0/6 (0%)
Staphylococcal infection	4/52 (7.7%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Upper respiratory tract infection	4/52 (7.7%)		6/46 (13%)		1/5 (20%)		2/6 (33.3%)
Urinary tract infection	6/52 (11.5%)		2/46 (4.3%)		0/5 (0%)		0/6 (0%)
Adenovirus infection	0/52 (0%)		0/46 (0%)		1/5 (20%)		0/6 (0%)
Clostridial infection	0/52 (0%)		0/46 (0%)		1/5 (20%)		0/6 (0%)
Gastroenteritis	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Lower respiratory tract infection	0/52 (0%)		0/46 (0%)		1/5 (20%)		0/6 (0%)
Oral herpes	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Otitis media	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Respiratory syncytial virus infection	0/52 (0%)		0/46 (0%)		1/5 (20%)		0/6 (0%)
Tooth abscess	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Viral upper repiratory tract infection	0/52 (0%)		0/46 (0%)		1/5 (20%)		0/6 (0%)
Wound infection pseudomonas	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Injury, poisoning and procedural complications
Incision site pain	5/52 (9.6%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Joint sprain	0/52 (0%)		0/46 (0%)		1/5 (20%)		0/6 (0%)
Wound	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Investigations
Blood creatinine increased	2/52 (3.8%)		5/46 (10.9%)		0/5 (0%)		0/6 (0%)
Cardiac murmur	3/52 (5.8%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Hepatic enzyme increased	0/52 (0%)		4/46 (8.7%)		0/5 (0%)		0/6 (0%)
Weight decreased	0/52 (0%)		3/46 (6.5%)		1/5 (20%)		0/6 (0%)
Weight increased	10/52 (19.2%)		9/46 (19.6%)		1/5 (20%)		0/6 (0%)
Cytomegalovirus antigen positive	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Epstein-Barr virus antibody positive	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Glomerular filtration rate decreased	0/52 (0%)		0/46 (0%)		1/5 (20%)		0/6 (0%)
White blood cell count increased	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Metabolism and nutrition disorders
Diabetes mellitus	6/52 (11.5%)		11/46 (23.9%)		0/5 (0%)		1/6 (16.7%)
Dyslipidaemia	3/52 (5.8%)		2/46 (4.3%)		0/5 (0%)		0/6 (0%)
Fluid overload	3/52 (5.8%)		4/46 (8.7%)		2/5 (40%)		0/6 (0%)
Gout	2/52 (3.8%)		5/46 (10.9%)		0/5 (0%)		0/6 (0%)
Hyperglycaemia	6/52 (11.5%)		3/46 (6.5%)		1/5 (20%)		0/6 (0%)
Hyperkalaemia	5/52 (9.6%)		7/46 (15.2%)		0/5 (0%)		2/6 (33.3%)
Hyperlipidaemia	5/52 (9.6%)		8/46 (17.4%)		0/5 (0%)		1/6 (16.7%)
Hypoglycaemia	6/52 (11.5%)		4/46 (8.7%)		0/5 (0%)		0/6 (0%)
Hypokalaemia	8/52 (15.4%)		6/46 (13%)		2/5 (40%)		2/6 (33.3%)
Hypomagnesaemia	13/52 (25%)		4/46 (8.7%)		2/5 (40%)		2/6 (33.3%)
Hypovolaemia	6/52 (11.5%)		4/46 (8.7%)		0/5 (0%)		0/6 (0%)
Fluid retention	0/52 (0%)		0/46 (0%)		1/5 (20%)		1/6 (16.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/52 (5.8%)		5/46 (10.9%)		0/5 (0%)		0/6 (0%)
Back pain	4/52 (7.7%)		5/46 (10.9%)		0/5 (0%)		0/6 (0%)
Muscle spasms	8/52 (15.4%)		8/46 (17.4%)		0/5 (0%)		0/6 (0%)
Musculoskeletal chest pain	2/52 (3.8%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Musculoskeletal pain	7/52 (13.5%)		2/46 (4.3%)		0/5 (0%)		0/6 (0%)
Myalgia	4/52 (7.7%)		6/46 (13%)		0/5 (0%)		0/6 (0%)
Pain in extremity	4/52 (7.7%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Nervous system disorders
Convulsion	3/52 (5.8%)		1/46 (2.2%)		0/5 (0%)		1/6 (16.7%)
Dizziness	6/52 (11.5%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Headache	11/52 (21.2%)		13/46 (28.3%)		1/5 (20%)		1/6 (16.7%)
Hypoaesthesia	1/52 (1.9%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Paraesthesia	3/52 (5.8%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Tremor	23/52 (44.2%)		13/46 (28.3%)		0/5 (0%)		1/6 (16.7%)
Syncope	0/52 (0%)		0/46 (0%)		0/5 (0%)		1/6 (16.7%)
Psychiatric disorders
Agitation	3/52 (5.8%)		4/46 (8.7%)		0/5 (0%)		0/6 (0%)
Anxiety	5/52 (9.6%)		5/46 (10.9%)		0/5 (0%)		0/6 (0%)
Confusional state	3/52 (5.8%)		1/46 (2.2%)		0/5 (0%)		0/6 (0%)
Depression	6/52 (11.5%)		5/46 (10.9%)		0/5 (0%)		1/6 (16.7%)
Insomnia	8/52 (15.4%)		12/46 (26.1%)		0/5 (0%)		1/6 (16.7%)
Renal and urinary disorders
Renal failure	11/52 (21.2%)		12/46 (26.1%)		0/5 (0%)		0/6 (0%)
Renal failure acute	4/52 (7.7%)		4/46 (8.7%)		0/5 (0%)		0/6 (0%)
Renal failure chronic	3/52 (5.8%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Renal impairment	0/52 (0%)		3/46 (6.5%)		0/5 (0%)		0/6 (0%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	2/52 (3.8%)		4/46 (8.7%)		0/5 (0%)		0/6 (0%)
Cough	9/52 (17.3%)		6/46 (13%)		0/5 (0%)		0/6 (0%)
Dyspnoea	8/52 (15.4%)		5/46 (10.9%)		0/5 (0%)		0/6 (0%)
Pleural effusion	10/52 (19.2%)		18/46 (39.1%)		0/5 (0%)		0/6 (0%)
Pneumothorax	5/52 (9.6%)		4/46 (8.7%)		0/5 (0%)		0/6 (0%)
Aspiration	0/52 (0%)		0/46 (0%)		1/5 (20%)		0/6 (0%)
Respiratory distress	0/52 (0%)		0/46 (0%)		1/5 (20%)		0/6 (0%)
Skin and subcutaneous tissue disorders
Acne	4/52 (7.7%)		6/46 (13%)		0/5 (0%)		0/6 (0%)
Hypertrichosis	1/52 (1.9%)		4/46 (8.7%)		0/5 (0%)		3/6 (50%)
Rash	3/52 (5.8%)		4/46 (8.7%)		0/5 (0%)		0/6 (0%)
Skin lesion	7/52 (13.5%)		2/46 (4.3%)		0/5 (0%)		0/6 (0%)
Skin ulcer	3/52 (5.8%)		0/46 (0%)		0/5 (0%)		0/6 (0%)
Surgical and medical procedures
Removal of foreign body	0/52 (0%)		0/46 (0%)		1/5 (20%)		1/6 (16.7%)
Vascular disorders
Hypertension	21/52 (40.4%)		26/46 (56.5%)		3/5 (60%)		4/6 (66.7%)
Hypotension	13/52 (25%)		7/46 (15.2%)		0/5 (0%)		0/6 (0%)

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Principal Investigators are NOT employed by the organization sponsoring the study.

Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data. Sponsor must receive a site's manuscript at least 30 days prior to publication to ensure that no confidential information of Sponsor is included in the document. Sponsor may delay the publication for an additional 60 days to seek patent protection.