RAD: Efficacy and Safety of Concentration-controlled Everolimus to Eliminate or to Reduce Tacrolimus Compared to Tacrolimus in de Novo Liver Transplant Recipients

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00622869
• Collaborator: (none)
• Enrollment: 719
• Locations: 91
• Arms: 3
• Duration (Months): 51
• Patients Per Site: 7.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This trial was designed to address important issues that impact recipients of liver allografts as well as clinicians, ie, renal function, reduction or discontinuation of tacrolimus early post-transplantation, and progression rate of fibrosis in hepatitis C virus (HCV) positive patients.

Condition or Disease	Intervention/Treatment	Phase
Liver Transplantation	Drug: Tacrolimus (reduced tacrolimus); Drug: Tacrolimus (tacrolimus elimination); Drug: Tacrolimus (tacrolimus control); Drug: Everolimus (reduced tacrolimus); Drug: Everolimus (tacrolimus elimination); Drug: Corticosteroids	Phase 3

Detailed Description

This 24-month study consisted of a screening period, a baseline period (3 to 7 days post-transplantation) followed by a run-in period that ended on the day of randomization at 30 days (± 5 days) post-transplantation. Patients were screened for eligibility prior to liver transplantation. Patients who had undergone successful liver transplantation were initiated on a tacrolimus-based regimen that included corticosteroids and entered the baseline period (between 3 and 7 days post-transplantation). At 30 (± 5) days post-transplantation, patients who met additional randomization inclusion/exclusion criteria were randomized into the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 719 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 24 Month, Multicenter, Open-label, Randomized, Controlled Study to Evaluate the Efficacy and Safety of Concentration-controlled Everolimus to Eliminate or to Reduce Tacrolimus Compared to Tacrolimus in de Novo Liver Transplant Recipients
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Apr 1, 2012
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Everolimus + reduced tacrolimus Low dose tacrolimus (tacrolimus reduced) + everolimus + corticosteroids.	Drug: Tacrolimus (reduced tacrolimus); After everolimus whole blood trough levels were confirmed to be in the target range of 3-8 ng/mL, tacrolimus tapering began, achieving a target tacrolimus whole blood trough level of 3-5 ng/mL by 3 weeks after randomization, a level which was maintained for the duration of the study.; Other Names: FK-506 fujimycin Prograf Advagraf Protopic ; Drug: Everolimus (reduced tacrolimus); Everolimus was started within 24 hours of randomization at a dose of 1.0 mg twice a day (bid, 2 mg daily dose). The dose was adjusted to maintain everolimus trough blood levels between 3-8 ng/mL for the duration of the study.; Other Names: RAD-001 Zortress Certican Afinitor ; Drug: Corticosteroids; For patients in all groups, corticosteroids were initiated at or prior to the time of transplantation according to local practice. Corticosteroids could be used for the duration of the study but could not be eliminated before Month 6.
Experimental: Tacrolimus elimination Low-dose tacrolimus (until Month 4, then tacrolimus eliminated) + everolimus + corticosteroids.	Drug: Tacrolimus (tacrolimus elimination); After everolimus whole blood trough levels were confirmed to be in the target range of 3-8 ng/mL, tacrolimus tapering began, achieving a target tacrolimus whole blood trough level of 3-5 ng/mL by 3 weeks after randomization. Tacrolimus elimination was started beginning at Month 4. Tacrolimus was tapered after everolimus whole blood trough levels were within the target range of 6-10 ng/mL. Tacrolimus was completely eliminated by the end of Month 4.; Other Names: FK-506 fujimycin Prograf Advagraf Protopic ; Drug: Everolimus (tacrolimus elimination); Everolimus was started within 24 hours of randomization at a dose of 1.0 mg twice a day (bid, 2 mg daily dose). The dose was adjusted to maintain everolimus trough blood levels between 3-8 ng/mL until Month 4; beginning with Month 4, the dose was adjusted to maintain everolimus trough blood levels between 6-10 ng/mL.; Other Names: RAD-001 Zortress Certican Afinitor ; Drug: Corticosteroids; For patients in all groups, corticosteroids were initiated at or prior to the time of transplantation according to local practice. Corticosteroids could be used for the duration of the study but could not be eliminated before Month 6.
Active Comparator: Tacrolimus control Control dose tacrolimus + corticosteroids.	Drug: Tacrolimus (tacrolimus control); Tacrolimus trough levels were targeted to be maintained at 8-12 ng/mL until Month 4. At Month 4, tacrolimus whole blood trough levels were decreased to a target trough level of 6-10 ng/mL for the remainder of the study.; Other Names: FK-506 fujimycin Prograf Advagraf Protopic ; Drug: Corticosteroids; For patients in all groups, corticosteroids were initiated at or prior to the time of transplantation according to local practice. Corticosteroids could be used for the duration of the study but could not be eliminated before Month 6.

Outcome Measures

Primary Outcome Measures

1. Incidence Rate of Composite Efficacy Failure From Randomization to Month 12 [Randomization to Month 12]

   Composite efficacy failure was defined as treated biopsy proven acute rejection (tBPAR), graft loss, or death. A BPAR was defined as an acute rejection confirmed by biopsy with a Rejection Activity Index (RAI) score ≥ 3. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, they received a graft re-transplant, or they died. The incidence rates of composite efficacy failure were estimated with a Kaplan-Meier product-limit formula.

Secondary Outcome Measures

1. Incidence Rate of Composite Efficacy Failure From Randomization to Month 24 [Randomization to Month 24]

   Composite efficacy failure was defined as treated biopsy proven acute rejection (tBPAR), graft loss, or death. The incidence rates of composite efficacy failure were estimated with a Kaplan-Meier product-limit formula.

2. Incidence Rate of Treated Biopsy Proven Acute Rejection (tBPAR) at Months 12 and 24 [Randomization to Month 24]

   tBPAR was defined as an acute rejection confirmed by biopsy with a Rejection Activity Index (RAI) score ≥ 3, which was treated with anti-rejection therapy. Liver biopsies were collected for all cases of suspected acute rejection preferably within 24 hours, at the latest within 48 hours, whenever clinically possible. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, they received a graft re-transplant, or they died. The incidence rates of tBPAR were estimated with a Kaplan-Meier product-limit formula.

3. Change in Renal Function From Randomization to Months 12 and 24 [Randomization to Month 24]

   Change in renal function was assessed by the estimated Glomerular Filtration Rate (eGFR) using the abbreviated (4 variables) Modification of Diet in Renal Disease (MDRD-4) formula which was developed by the MDRD Study Group and has been validated in patients with chronic kidney disease. The MDRD-4 formula used for the eGFR calculation is: eGFR (mL/min/1.73m^2) = 186.3*(C^-1.154)*(A^-0.203)*G*R, where C is the serum concentration of creatinine (mg/dL), A is age (years), G=0.742 when gender is female, otherwise G=1, R=1.21 when race is black, otherwise R=1. The changes in renal function were analyzed via analysis of covariance (ANCOVA) with treatment, pre-transplant hepatitis C virus status and randomization eGFR as covariates. Based on these ANCOVA analyses, the least-squares mean and standard errors of change were reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Ability and willingness to provide written informed consent and adhere to study regimen.

• Recipients who are 18-70 years of age of a primary liver transplant from a deceased donor.

• Recipients who have been initiated on an immunosuppressive regimen that contains corticosteroids and tacrolimus, 3-7 days post-transplantation.

• Confirmed recipient hepatitis C virus (HCV) status at Screening (either by antibody or by PCR (polymerase chain reaction).

• Allograft is functioning at an acceptable level by the time of randomization as defined by protocol specific laboratory values.

• Abbreviated Modification of Diet in Renal Disease estimated glomerular filtration rate (MDRD eGFR) ≥ 30 mL/min/1.73m2. Results obtained within 5 days prior to randomization are acceptable, however, no sooner than Day 25 post-transplantation.

• Verification of at least 1 tacrolimus trough level of ≥ 8 ng/mL in the week prior to randomization. Investigators should make adjustments in tacrolimus dosing to continue to target trough levels above 8 ng/mL prior to randomization.

Exclusion Criteria

• Patients who are recipients of multiple solid organ or islet cell tissue transplants, or have previously received an organ or tissue transplant. Patients who have a combined liver-kidney transplant.

• Recipients of a liver from a living donor, or of a split liver.

• History of malignancy of any organ system within the past 5 years whether or not there is evidence of local recurrence or metastases, other than non-metastatic basal or squamous cell carcinoma of the skin, or HCC (hepatocellular carcinoma) (see next criteria).

• Hepatocellular carcinoma that does not fulfill Milan criteria (1 nodule ≤ 5 cm, 2-3 nodules all < 3 cm) at the time of transplantation as per explant histology of the recipient liver.

• Any use of antibody induction therapy.

• Patients with a known hypersensitivity to the drugs used on study or their class, or to any of the excipients.

• Patients who are recipients of ABO incompatible transplant grafts.

• Recipients of organs from donors who test positive for Hepatitis B surface antigen or HIV are excluded.

• Patients who have any surgical or medical condition, which in the opinion of the investigator, might significantly alter the absorption, distribution, metabolism and excretion of study drug.

• Women of child-bearing potential (WOCBP).

• Patients with any history of coagulopathy or medical condition requiring long-term anticoagulation which would preclude liver biopsy after transplantation. (Low dose aspirin treatment or interruption of chronic anticoagulant is allowed).

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Los Angeles	California	United States	90033
2	Novartis Investigative Site	Los Angeles	California	United States	90048
3	Novartis Investigative Site	Los Angeles	California	United States	90095
4	Novartis Investigative Site	San Francisco	California	United States	94143
5	Novartis Investigative Site	Aurora	Colorado	United States	80045
6	Novartis Investigative Site	Washington	District of Columbia	United States	20007-2197
7	Novartis Investigative Site	Tampa	Florida	United States	33606
8	Novartis Investigative Site	Atlanta	Georgia	United States	30309
9	Novartis Investigative Site	Chicago	Illinois	United States	60637
10	Novartis Investigative Site	Lexington	Kentucky	United States	40536-0293
11	Novartis Investigative Site	Detroit	Michigan	United States	48202-2689
12	Novartis Investigative Site	Rochester	Minnesota	United States	55905
13	Novartis Investigative Site	St. Louis	Missouri	United States	63110
14	Novartis Investigative Site	Newark	New Jersey	United States	07101
15	Novartis Investigative Site	New York	New York	United States	10016
16	Novartis Investigative Site	New York	New York	United States	10032
17	Novartis Investigative Site	Chapel Hill	North Carolina	United States	27599
18	Novartis Investigative Site	Durham	North Carolina	United States	27710
19	Novartis Investigative Site	Cleveland	Ohio	United States	44195
20	Novartis Investigative Site	Oklahoma City	Oklahoma	United States	73112
21	Novartis Investigative Site	Portland	Oregon	United States	97201-3098
22	Novartis Investigative Site	Philadelphia	Pennsylvania	United States	19107
23	Novartis Investigative Site	Charleston	South Carolina	United States	29425
24	Novartis Investigative Site	Nashville	Tennessee	United States	37232
25	Novartis Investigative Site	Dallas	Texas	United States	75208-2312
26	Novartis Investigative Site	Dallas	Texas	United States	75246
27	Novartis Investigative Site	Houston	Texas	United States	77030-2400
28	Novartis Investigative Site	Houston	Texas	United States	77030
29	Novartis Investigative Site	San Martin	Buenos Aires	Argentina	C1107BEA
30	Novartis Investigative Site	Rosario	Santa Fe	Argentina	C2000DSR
31	Novartis Investigative Site	Buenos Aires		Argentina	C1118AAT
32	Novartis Investigative Site	Buenos Aires		Argentina	C1181ACH
33	Novartis Investigative Site	Buenos Aires		Argentina	W3400ABH
34	Novartis Investigative Site	Camperdown	New South Wales	Australia	2050
35	Novartis Investigative Site	Bedford Park	South Australia	Australia	5042
36	Novartis Investigative Site	Heidelberg	Victoria	Australia	3084
37	Novartis Investigative Site	Nedlands	Western Australia	Australia	6009
38	Novartis Investigative Site	Gent		Belgium	9000
39	Novartis Investigative Site	Leuven		Belgium	3000
40	Novartis Investigative Site	Liege		Belgium	4000
41	Novartis Investigative Site	Rio de Janeiro	RJ	Brazil	21041-030
42	Novartis Investigative Site	Porto Alegre	RS	Brazil	90020-090
43	Novartis Investigative Site	Blumenau	SC	Brazil	89010-500
44	Novartis Investigative Site	Ribeirao Preto	SP	Brazil	14048-900
45	Novartis Investigative Site	São Paulo	SP	Brazil	01323-900
46	Novartis Investigative Site	Edmonton	Alberta	Canada	T6G 2B7
47	Novartis Investigative Site	Vancouver	British Columbia	Canada	V5Z 1M9
48	Novartis Investigative Site	London	Ontario	Canada	N6A 5A5
49	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2C4
50	Novartis Investigative Site	Bogotá		Colombia
51	Novartis Investigative Site	Cali		Colombia
52	Novartis Investigative Site	Medellín		Colombia
53	Novartis Investigative Site	Praha 4		Czech Republic	140 21
54	Novartis Investigative Site	Bordeaux Cedex		France	33076
55	Novartis Investigative Site	Clichy		France	92110
56	Novartis Investigative Site	Creteil		France	94010
57	Novartis Investigative Site	Lille		France	59000
58	Novartis Investigative Site	Marseille		France	13385
59	Novartis Investigative Site	Montpellier		France	34295
60	Novartis Investigative Site	Villejuif		France	94805
61	Novartis Investigative Site	Berlin		Germany	13353
62	Novartis Investigative Site	Essen		Germany	45147
63	Novartis Investigative Site	Hamburg		Germany	20246
64	Novartis Investigative Site	Heidelberg		Germany	69120
65	Novartis Investigative Site	Jena		Germany	07740
66	Novartis Investigative Site	Leipzig		Germany	04103
67	Novartis Investigative Site	Mainz		Germany	55131
68	Novartis Investigative Site	Regensburg		Germany	93053
69	Novartis Investigative Site	Budapest		Hungary	1082
70	Novartis Investigative Site	Dublin 4		Ireland
71	Novartis Investigative Site	Jerusalem		Israel	91120
72	Novartis Investigative Site	Tel-Aviv		Israel	64239
73	Novartis Investigative Site	Milano	MI	Italy	20162
74	Novartis Investigative Site	Modena	MO	Italy	41100
75	Novartis Investigative Site	Roma	RM	Italy	00161
76	Novartis Investigative Site	Torino	TO	Italy	10126
77	Novartis Investigative Site	Pisa		Italy	56124
78	Novartis Investigative Site	Rotterdam		Netherlands	3015 CE
79	Novartis Investigative Site	Moscow		Russian Federation	123182
80	Novartis Investigative Site	Moscow		Russian Federation	129010
81	Novartis Investigative Site	Barcelona	Cataluña	Spain	08035
82	Novartis Investigative Site	Barcelona	Cataluña	Spain	08036
83	Novartis Investigative Site	Hospitalet de Llobregat	Cataluña	Spain	08907
84	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46026
85	Novartis Investigative Site	Majadanonda	Madrid	Spain	28222
86	Novartis Investigative Site	Pamplona	Navarra	Spain	31002
87	Novartis Investigative Site	Baracaldo	País Vasco	Spain	48903
88	Novartis Investigative Site	Madrid		Spain	28007
89	Novartis Investigative Site	Stockholm		Sweden	141 86
90	Novartis Investigative Site	Edinburgh		United Kingdom	ED16 4SA
91	Novartis Investigative Site	London		United Kingdom	SE5 9RS

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00622869
• Other Study ID Numbers: CRAD001H2304; 2007-001821-85
• First Posted: Feb 25, 2008
• Last Update Posted: May 27, 2013
• Last Verified: May 1, 2013

• Keywords provided by Novartis Pharmaceuticals: Liver transplantation; everolimus; calcineurin inhibitors; tacrolimus; renal function; MDRD formula; progression of fibrosis
• Additional relevant MeSH terms: Everolimus; Tacrolimus

Study Results

Participant Flow

Arm/Group Title	Everolimus + Reduced Tacrolimus	Tacrolimus Elimination	Tacrolimus Control Arm
Arm/Group Description	Low dose tacrolimus (tacrolimus reduced) + everolimus + corticosteroids.	Low-dose tacrolimus (until Month 4, then tacrolimus eliminated) + everolimus + corticosteroids.	Control dose tacrolimus + corticosteroids.
Period Title: Overall Study
STARTED	245	231	243
COMPLETED	202	174	204
NOT COMPLETED	43	57	39

Baseline Characteristics

Arm/Group Title	Everolimus + Reduced Tacrolimus	Tacrolimus Elimination	Tacrolimus Control Arm	Total
Arm/Group Description	Low dose tacrolimus (tacrolimus reduced) + everolimus + corticosteroids.	Low-dose tacrolimus (until Month 4, then tacrolimus eliminated) + everolimus + corticosteroids.	Control dose tacrolimus + corticosteroids.	Total of all reporting groups
Overall Participants	245	231	243	719
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.6 (9.2)	53.2 (10.8)	54.5 (8.7)	53.8 (9.6)
Sex: Female, Male (Count of Participants)
Female	65 26.5%	67 29%	64 26.3%	196 27.3%
Male	180 73.5%	164 71%	179 73.7%	523 72.7%

Outcome Measures

1. Primary Outcome

Title	Incidence Rate of Composite Efficacy Failure From Randomization to Month 12
Description	Composite efficacy failure was defined as treated biopsy proven acute rejection (tBPAR), graft loss, or death. A BPAR was defined as an acute rejection confirmed by biopsy with a Rejection Activity Index (RAI) score ≥ 3. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, they received a graft re-transplant, or they died. The incidence rates of composite efficacy failure were estimated with a Kaplan-Meier product-limit formula.
Time Frame	Randomization to Month 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients.

Arm/Group Title	Everolimus + Reduced Tacrolimus	Tacrolimus Elimination	Tacrolimus Control Arm
Arm/Group Description	Low dose tacrolimus (tacrolimus reduced) + everolimus + corticosteroids.	Low-dose tacrolimus (until Month 4, then tacrolimus eliminated) + everolimus + corticosteroids.	Control dose tacrolimus + corticosteroids.
Measure Participants	245	231	243
Number [Percentage of participants]	6.7 2.7%	24.2 10.5%	9.7 4%

2. Secondary Outcome

Title	Incidence Rate of Composite Efficacy Failure From Randomization to Month 24
Description	Composite efficacy failure was defined as treated biopsy proven acute rejection (tBPAR), graft loss, or death. The incidence rates of composite efficacy failure were estimated with a Kaplan-Meier product-limit formula.
Time Frame	Randomization to Month 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients.

Arm/Group Title	Everolimus + Reduced Tacrolimus	Tacrolimus Elimination	Tacrolimus Control Arm
Arm/Group Description	Low dose tacrolimus (tacrolimus reduced) + everolimus + corticosteroids.	Low-dose tacrolimus (until Month 4, then tacrolimus eliminated) + everolimus + corticosteroids.	Control dose tacrolimus + corticosteroids.
Measure Participants	245	231	243
Number [Percentage]	10.3	26.0	12.5

3. Secondary Outcome

Title	Incidence Rate of Treated Biopsy Proven Acute Rejection (tBPAR) at Months 12 and 24
Description	tBPAR was defined as an acute rejection confirmed by biopsy with a Rejection Activity Index (RAI) score ≥ 3, which was treated with anti-rejection therapy. Liver biopsies were collected for all cases of suspected acute rejection preferably within 24 hours, at the latest within 48 hours, whenever clinically possible. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, they received a graft re-transplant, or they died. The incidence rates of tBPAR were estimated with a Kaplan-Meier product-limit formula.
Time Frame	Randomization to Month 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients.

Arm/Group Title	Everolimus + Reduced Tacrolimus	Tacrolimus Elimination	Tacrolimus Control Arm
Arm/Group Description	Low dose tacrolimus (tacrolimus reduced) + everolimus + corticosteroids.	Low-dose tacrolimus (until Month 4, then tacrolimus eliminated) + everolimus + corticosteroids.	Control dose tacrolimus + corticosteroids.
Measure Participants	245	231	243
Month 12	3.0	18.8	7.2
Month 24	4.8	19.9	7.7

4. Secondary Outcome

Title	Change in Renal Function From Randomization to Months 12 and 24
Description	Change in renal function was assessed by the estimated Glomerular Filtration Rate (eGFR) using the abbreviated (4 variables) Modification of Diet in Renal Disease (MDRD-4) formula which was developed by the MDRD Study Group and has been validated in patients with chronic kidney disease. The MDRD-4 formula used for the eGFR calculation is: eGFR (mL/min/1.73m^2) = 186.3*(C^-1.154)*(A^-0.203)*G*R, where C is the serum concentration of creatinine (mg/dL), A is age (years), G=0.742 when gender is female, otherwise G=1, R=1.21 when race is black, otherwise R=1. The changes in renal function were analyzed via analysis of covariance (ANCOVA) with treatment, pre-transplant hepatitis C virus status and randomization eGFR as covariates. Based on these ANCOVA analyses, the least-squares mean and standard errors of change were reported.
Time Frame	Randomization to Month 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized patients.

Arm/Group Title	Everolimus + Reduced Tacrolimus	Tacrolimus Elimination	Tacrolimus Control Arm
Arm/Group Description	Low dose tacrolimus (tacrolimus reduced) + everolimus + corticosteroids.	Low-dose tacrolimus (until Month 4, then tacrolimus eliminated) + everolimus + corticosteroids.	Control dose tacrolimus + corticosteroids.
Measure Participants	245	231	243
Month 12 (N=244, 231, 243)	-2.23 (1.54)	-1.51 (1.58)	-10.73 (1.54)
Month 24 (N=245, 231, 243)	-7.94 (1.53)	-4.19 (1.58)	-14.60 (1.54)

Adverse Events

Time Frame	Adverse events (AE) were followed until resolution or judged permanent. Serious AEs occurring after transplantation, until 30 days after study medication (SM) discontinuation, or > 4 weeks after study discontinuation if related to SM were reported.
Adverse Event Reporting Description	Safety population: All patients who received at least 1 dose of randomized study medication. Adverse events up to Month 24 were reported.
Arm/Group Title	Everolimus + Reduced Tacrolimus		Tacrolimus Elimination		Tacrolimus Control Arm
Arm/Group Description	Low dose tacrolimus (tacrolimus reduced) + everolimus + corticosteroids		Low dose tacrolimus (until Month 4, then tacrolimus eliminated) + everolimus + corticosteroids		Control dose tacrolimus + corticosteroids
All Cause Mortality
	Everolimus + Reduced Tacrolimus		Tacrolimus Elimination		Tacrolimus Control Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Everolimus + Reduced Tacrolimus		Tacrolimus Elimination		Tacrolimus Control Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	138/245 (56.3%)		152/229 (66.4%)		131/242 (54.1%)
Blood and lymphatic system disorders
Anaemia	4/245 (1.6%)		4/229 (1.7%)		5/242 (2.1%)
Anaemia megaloblastic	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Coagulopathy	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Febrile neutropenia	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Leukocytosis	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Neutropenia	2/245 (0.8%)		0/229 (0%)		0/242 (0%)
Pancytopenia	6/245 (2.4%)		0/229 (0%)		0/242 (0%)
Thrombocytopenia	3/245 (1.2%)		2/229 (0.9%)		1/242 (0.4%)
Thrombotic thrombocytopenic purpura	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Cardiac disorders
Acute coronary syndrome	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Acute myocardial infarction	1/245 (0.4%)		1/229 (0.4%)		2/242 (0.8%)
Angina pectoris	2/245 (0.8%)		0/229 (0%)		3/242 (1.2%)
Angina unstable	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Arteriosclerosis coronary artery	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Atrial fibrillation	2/245 (0.8%)		0/229 (0%)		1/242 (0.4%)
Atrioventricular block second degree	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Cardiac arrest	1/245 (0.4%)		1/229 (0.4%)		0/242 (0%)
Cardiac failure	2/245 (0.8%)		0/229 (0%)		2/242 (0.8%)
Cardiac failure congestive	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Cardio-respiratory arrest	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Congestive cardiomyopathy	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Coronary artery disease	3/245 (1.2%)		0/229 (0%)		3/242 (1.2%)
Myocardial infarction	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Myocardial ischaemia	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Palpitations	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Pericarditis	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Tachyarrhythmia	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Congenital, familial and genetic disorders
Hepato-lenticular degeneration	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Hydrocele	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Ear and labyrinth disorders
Acute vestibular syndrome	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Vertigo	0/245 (0%)		2/229 (0.9%)		0/242 (0%)
Eye disorders
Glaucoma	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Retinal detachment	2/245 (0.8%)		0/229 (0%)		0/242 (0%)
Gastrointestinal disorders
Abdominal hernia	5/245 (2%)		11/229 (4.8%)		5/242 (2.1%)
Abdominal pain	5/245 (2%)		7/229 (3.1%)		3/242 (1.2%)
Abdominal pain lower	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Abdominal pain upper	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Abdominal tenderness	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Ascites	4/245 (1.6%)		3/229 (1.3%)		2/242 (0.8%)
Colitis	0/245 (0%)		3/229 (1.3%)		0/242 (0%)
Colitis ulcerative	0/245 (0%)		1/229 (0.4%)		1/242 (0.4%)
Colonic polyp	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Constipation	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Crohn's disease	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Diarrhoea	4/245 (1.6%)		11/229 (4.8%)		4/242 (1.7%)
Diverticulum intestinal	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Dry mouth	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Duodenal perforation	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Duodenal ulcer	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Duodenal ulcer haemorrhage	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Duodenogastric reflux	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Femoral hernia	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Gastric ulcer	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Gastritis	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Gastrointestinal disorder	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Gastrointestinal haemorrhage	1/245 (0.4%)		2/229 (0.9%)		0/242 (0%)
Gastrointestinal inflammation	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Gastrointestinal obstruction	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Gingival erosion	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Haemorrhoidal haemorrhage	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Haemorrhoids	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Hernial eventration	2/245 (0.8%)		2/229 (0.9%)		0/242 (0%)
Impaired gastric emptying	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Inguinal hernia	2/245 (0.8%)		1/229 (0.4%)		3/242 (1.2%)
Inguinal hernia strangulated	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Intestinal ischaemia	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Intestinal obstruction	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Intestinal perforation	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Large intestinal ulcer	0/245 (0%)		2/229 (0.9%)		0/242 (0%)
Localised intraabdominal fluid collection	2/245 (0.8%)		2/229 (0.9%)		2/242 (0.8%)
Lower gastrointestinal haemorrhage	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Melaena	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Mesenteric vein thrombosis	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Nausea	1/245 (0.4%)		3/229 (1.3%)		0/242 (0%)
Oesophagitis	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Pancreatic mass	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Pancreatitis	0/245 (0%)		1/229 (0.4%)		1/242 (0.4%)
Pancreatitis acute	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Peritoneal haemorrhage	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Rectal haemorrhage	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Spigelian hernia	0/245 (0%)		1/229 (0.4%)		1/242 (0.4%)
Tongue oedema	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Umbilical hernia	3/245 (1.2%)		3/229 (1.3%)		2/242 (0.8%)
Umbilical hernia, obstructive	2/245 (0.8%)		1/229 (0.4%)		1/242 (0.4%)
Upper gastrointestinal haemorrhage	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Varices oesophageal	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Vomiting	1/245 (0.4%)		6/229 (2.6%)		0/242 (0%)
General disorders
Asthenia	1/245 (0.4%)		3/229 (1.3%)		0/242 (0%)
Device dislocation	0/245 (0%)		1/229 (0.4%)		1/242 (0.4%)
Device occlusion	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Drug ineffective	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Feeling jittery	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
General physical health deterioration	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Generalised oedema	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Hernia obstructive	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Impaired healing	1/245 (0.4%)		1/229 (0.4%)		0/242 (0%)
Malaise	1/245 (0.4%)		1/229 (0.4%)		1/242 (0.4%)
Medical device complication	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Multi-organ failure	5/245 (2%)		1/229 (0.4%)		4/242 (1.7%)
Oedema peripheral	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Pyrexia	14/245 (5.7%)		20/229 (8.7%)		7/242 (2.9%)
Sensation of foreign body	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Spinal pain	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Sudden death	0/245 (0%)		1/229 (0.4%)		1/242 (0.4%)
Systemic inflammatory response syndrome	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Hepatobiliary disorders
Acute hepatic failure	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Bile duct obstruction	0/245 (0%)		1/229 (0.4%)		1/242 (0.4%)
Bile duct stenosis	3/245 (1.2%)		7/229 (3.1%)		6/242 (2.5%)
Bile duct stone	1/245 (0.4%)		3/229 (1.3%)		1/242 (0.4%)
Biliary cast syndrome	0/245 (0%)		0/229 (0%)		2/242 (0.8%)
Biliary cirrhosis	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Biliary cirrhosis primary	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Biliary dilatation	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Biliary ischaemia	2/245 (0.8%)		2/229 (0.9%)		3/242 (1.2%)
Biliary tract disorder	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Biloma	3/245 (1.2%)		1/229 (0.4%)		0/242 (0%)
Cholangitis	11/245 (4.5%)		11/229 (4.8%)		6/242 (2.5%)
Cholangitis acute	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Cholangitis chronic	0/245 (0%)		1/229 (0.4%)		1/242 (0.4%)
Cholelithiasis	0/245 (0%)		2/229 (0.9%)		1/242 (0.4%)
Cholelithiasis obstructive	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Cholestasis	6/245 (2.4%)		3/229 (1.3%)		5/242 (2.1%)
Chronic hepatic failure	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Cytolytic hepatitis	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Hepatic artery stenosis	0/245 (0%)		4/229 (1.7%)		2/242 (0.8%)
Hepatic artery thrombosis	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Hepatic failure	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Hepatic function abnormal	2/245 (0.8%)		1/229 (0.4%)		0/242 (0%)
Hepatic lesion	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Hepatic necrosis	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Hepatic steatosis	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Hepatic vein occlusion	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Hepatitis	0/245 (0%)		2/229 (0.9%)		1/242 (0.4%)
Hepatitis acute	1/245 (0.4%)		1/229 (0.4%)		0/242 (0%)
Hepatitis cholestatic	2/245 (0.8%)		2/229 (0.9%)		1/242 (0.4%)
Hepatobiliary disease	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Hepatorenal syndrome	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Hepatotoxicity	2/245 (0.8%)		1/229 (0.4%)		0/242 (0%)
Jaundice	1/245 (0.4%)		0/229 (0%)		2/242 (0.8%)
Jaundice cholestatic	2/245 (0.8%)		1/229 (0.4%)		1/242 (0.4%)
Liver injury	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Portal hypertension	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Portal vein thrombosis	0/245 (0%)		0/229 (0%)		2/242 (0.8%)
Sphincter of Oddi dysfunction	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Immune system disorders
Drug hypersensitivity	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Liver transplant rejection	4/245 (1.6%)		24/229 (10.5%)		9/242 (3.7%)
Overlap syndrome	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Serum sickness	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Infections and infestations
Abdominal abscess	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Abdominal sepsis	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Abdominal wall abscess	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Abscess intestinal	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Acute sinusitis	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Anal abscess	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Appendicitis	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Bacterial infection	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Bacterial sepsis	0/245 (0%)		1/229 (0.4%)		1/242 (0.4%)
Biliary sepsis	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Bronchitis	1/245 (0.4%)		0/229 (0%)		2/242 (0.8%)
Bronchopneumonia	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Bronchopulmonary aspergillosis	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Cellulitis	4/245 (1.6%)		0/229 (0%)		3/242 (1.2%)
Cholangitis suppurative	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Clostridium difficile colitis	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Cytomegalovirus infection	3/245 (1.2%)		2/229 (0.9%)		1/242 (0.4%)
Device related infection	0/245 (0%)		1/229 (0.4%)		1/242 (0.4%)
Diarrhoea infectious	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Diverticulitis	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Enterobacter sepsis	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Enterococcal bacteraemia	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Enterococcal infection	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Enterococcal sepsis	1/245 (0.4%)		1/229 (0.4%)		2/242 (0.8%)
Erysipelas	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Escherichia bacteraemia	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Escherichia sepsis	2/245 (0.8%)		0/229 (0%)		1/242 (0.4%)
Febrile infection	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Gastroenteritis	3/245 (1.2%)		5/229 (2.2%)		1/242 (0.4%)
Gastroenteritis salmonella	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Gastrointestinal infection	3/245 (1.2%)		0/229 (0%)		0/242 (0%)
H1N1 influenza	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Hepatitis B	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Hepatitis C	10/245 (4.1%)		7/229 (3.1%)		7/242 (2.9%)
Herpes virus infection	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Herpes zoster	0/245 (0%)		2/229 (0.9%)		1/242 (0.4%)
Herpes zoster oticus	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Histoplasmosis	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Incision site infection	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Infected bites	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Infected cyst	1/245 (0.4%)		2/229 (0.9%)		0/242 (0%)
Infection	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Infectious peritonitis	1/245 (0.4%)		1/229 (0.4%)		0/242 (0%)
Influenza	0/245 (0%)		2/229 (0.9%)		0/242 (0%)
Intervertebral discitis	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Kidney infection	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Klebsiella infection	1/245 (0.4%)		1/229 (0.4%)		1/242 (0.4%)
Klebsiella sepsis	1/245 (0.4%)		1/229 (0.4%)		0/242 (0%)
Laryngitis	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Liver abscess	1/245 (0.4%)		1/229 (0.4%)		2/242 (0.8%)
Localised infection	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Lung abscess	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Lung infection	0/245 (0%)		3/229 (1.3%)		1/242 (0.4%)
Meningitis cryptococcal	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Neutropenic sepsis	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Oral candidiasis	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Osteomyelitis	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Otitis externa	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Peritoneal abscess	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Peritonitis	1/245 (0.4%)		1/229 (0.4%)		0/242 (0%)
Peritonitis bacterial	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Pharyngitis	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Pneumocystis jiroveci pneumonia	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Pneumonia	6/245 (2.4%)		9/229 (3.9%)		4/242 (1.7%)
Pneumonia fungal	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Pneumonia herpes viral	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Postoperative wound infection	0/245 (0%)		1/229 (0.4%)		1/242 (0.4%)
Pseudomembranous colitis	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Pseudomonal bacteraemia	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Pseudomonal sepsis	0/245 (0%)		0/229 (0%)		2/242 (0.8%)
Pyelonephritis	1/245 (0.4%)		1/229 (0.4%)		0/242 (0%)
Respiratory tract infection	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Respiratory tract infection viral	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Sepsis	1/245 (0.4%)		1/229 (0.4%)		2/242 (0.8%)
Septic shock	3/245 (1.2%)		3/229 (1.3%)		0/242 (0%)
Sinusitis	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Sinusitis aspergillus	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Skin infection	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Splenic abscess	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Staphylococcal sepsis	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Streptococcal sepsis	1/245 (0.4%)		1/229 (0.4%)		0/242 (0%)
Tooth abscess	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Upper respiratory tract infection	2/245 (0.8%)		0/229 (0%)		0/242 (0%)
Urinary tract infection	2/245 (0.8%)		3/229 (1.3%)		2/242 (0.8%)
Urosepsis	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Wound abscess	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Wound infection	2/245 (0.8%)		0/229 (0%)		1/242 (0.4%)
Injury, poisoning and procedural complications
Abdominal wound dehiscence	1/245 (0.4%)		1/229 (0.4%)		0/242 (0%)
Anastomotic stenosis	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Biliary anastomosis complication	3/245 (1.2%)		3/229 (1.3%)		6/242 (2.5%)
Cervical vertebral fracture	1/245 (0.4%)		1/229 (0.4%)		0/242 (0%)
Chemical peritonitis	2/245 (0.8%)		2/229 (0.9%)		1/242 (0.4%)
Complications of transplanted heart	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Complications of transplanted liver	1/245 (0.4%)		4/229 (1.7%)		0/242 (0%)
Contusion	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Craniocerebral injury	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Fall	0/245 (0%)		0/229 (0%)		2/242 (0.8%)
Femoral neck fracture	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Foot fracture	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Foreign body	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Graft dysfunction	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Graft loss	1/245 (0.4%)		2/229 (0.9%)		2/242 (0.8%)
Hepatic haematoma	1/245 (0.4%)		1/229 (0.4%)		1/242 (0.4%)
Hip fracture	2/245 (0.8%)		0/229 (0%)		0/242 (0%)
Humerus fracture	0/245 (0%)		0/229 (0%)		2/242 (0.8%)
Hypoinsulinaemia postoperative	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Incisional hernia	9/245 (3.7%)		7/229 (3.1%)		5/242 (2.1%)
Joint dislocation	2/245 (0.8%)		0/229 (0%)		0/242 (0%)
Liver graft loss	2/245 (0.8%)		0/229 (0%)		1/242 (0.4%)
Lumbar vertebral fracture	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Overdose	0/245 (0%)		2/229 (0.9%)		0/242 (0%)
Pelvic fracture	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Post procedural bile leak	2/245 (0.8%)		2/229 (0.9%)		1/242 (0.4%)
Post procedural complication	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Post procedural haemorrhage	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Post-traumatic pain	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Postoperative hernia	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Procedural pain	0/245 (0%)		1/229 (0.4%)		1/242 (0.4%)
Pubis fracture	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Radius fracture	0/245 (0%)		1/229 (0.4%)		1/242 (0.4%)
Rib fracture	0/245 (0%)		0/229 (0%)		2/242 (0.8%)
Road traffic accident	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Spinal compression fracture	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Spinal fracture	1/245 (0.4%)		1/229 (0.4%)		0/242 (0%)
Splenic rupture	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Toxicity to various agents	2/245 (0.8%)		2/229 (0.9%)		0/242 (0%)
Vascular pseudoaneurysm	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Wound dehiscence	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Investigations
Blood alkaline phosphatase increased	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Blood lactic acid increased	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
C-reactive protein increased	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Chest X-ray abnormal	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Gamma-glutamyltransferase increased	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Hepatic enzyme abnormal	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Hepatic enzyme increased	4/245 (1.6%)		4/229 (1.7%)		5/242 (2.1%)
Immunosuppressant drug level increased	1/245 (0.4%)		1/229 (0.4%)		0/242 (0%)
Liver function test abnormal	3/245 (1.2%)		4/229 (1.7%)		2/242 (0.8%)
Platelet count decreased	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Renal function test abnormal	0/245 (0%)		1/229 (0.4%)		1/242 (0.4%)
Transaminases increased	4/245 (1.6%)		1/229 (0.4%)		3/242 (1.2%)
Urine output decreased	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Metabolism and nutrition disorders
Cachexia	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Decreased appetite	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Dehydration	2/245 (0.8%)		1/229 (0.4%)		1/242 (0.4%)
Diabetes mellitus	2/245 (0.8%)		2/229 (0.9%)		2/242 (0.8%)
Diabetes mellitus malnutrition-related	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Diabetic ketoacidosis	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Fluid overload	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Gout	2/245 (0.8%)		0/229 (0%)		0/242 (0%)
Hyperglycaemia	4/245 (1.6%)		1/229 (0.4%)		3/242 (1.2%)
Hyperkalaemia	0/245 (0%)		1/229 (0.4%)		2/242 (0.8%)
Hypoglycaemia	3/245 (1.2%)		1/229 (0.4%)		0/242 (0%)
Hypomagnesaemia	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Ketoacidosis	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Malnutrition	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Obesity	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Type 2 diabetes mellitus	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/245 (0.4%)		1/229 (0.4%)		0/242 (0%)
Arthritis	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Back pain	0/245 (0%)		2/229 (0.9%)		0/242 (0%)
Costochondritis	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Intervertebral disc protrusion	1/245 (0.4%)		0/229 (0%)		2/242 (0.8%)
Joint swelling	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Musculoskeletal pain	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Osteoporosis	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Pain in extremity	0/245 (0%)		2/229 (0.9%)		0/242 (0%)
Pathological fracture	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Rhabdomyolysis	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Tendonitis	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Anogenital warts	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Benign duodenal neoplasm	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Benign pancreatic neoplasm	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Castleman's disease	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Colorectal cancer metastatic	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Endometrial cancer	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Gastric sarcoma	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Glioblastoma	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Hepatic cancer metastatic	0/245 (0%)		1/229 (0.4%)		1/242 (0.4%)
Hepatic neoplasm malignant	3/245 (1.2%)		1/229 (0.4%)		1/242 (0.4%)
Hepatic neoplasm malignant recurrent	0/245 (0%)		2/229 (0.9%)		1/242 (0.4%)
Histiocytosis haematophagic	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Kaposi's sarcoma	0/245 (0%)		1/229 (0.4%)		2/242 (0.8%)
Laryngeal cancer	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Lung neoplasm	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Lung neoplasm malignant	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Lymphoma	2/245 (0.8%)		1/229 (0.4%)		0/242 (0%)
Malignant melanoma	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Metastases to adrenals	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Metastases to bone	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Metastases to spine	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Metastatic malignant melanoma	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Metastatic neoplasm	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Oropharyngeal cancer stage unspecified	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Plasmacytoma	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Post transplant lymphoproliferative disorder	2/245 (0.8%)		1/229 (0.4%)		0/242 (0%)
Prostate cancer	2/245 (0.8%)		0/229 (0%)		0/242 (0%)
Rectal cancer	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Retroperitoneal cancer	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Squamous cell carcinoma	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Squamous cell carcinoma of skin	0/245 (0%)		0/229 (0%)		2/242 (0.8%)
Nervous system disorders
Aphasia	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Cerebral haemorrhage	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Cerebral infarction	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Cerebrovascular accident	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Cluster headache	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Convulsion	1/245 (0.4%)		1/229 (0.4%)		1/242 (0.4%)
Critical illness polyneuropathy	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Dizziness	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Dyskinesia	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Encephalitis	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Epilepsy	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Headache	3/245 (1.2%)		0/229 (0%)		3/242 (1.2%)
Ischaemic stroke	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Lethargy	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Migraine	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Monoparesis	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Post herpetic neuralgia	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Psychomotor hyperactivity	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Radiculitis brachial	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Transient ischaemic attack	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Tremor	2/245 (0.8%)		0/229 (0%)		1/242 (0.4%)
VIIth nerve paralysis	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Pregnancy	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Psychiatric disorders
Adjustment disorder	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Agitation	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Alcoholism	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Anxiety	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Bipolar I disorder	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Confusional state	1/245 (0.4%)		1/229 (0.4%)		0/242 (0%)
Delirium	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Depression	2/245 (0.8%)		2/229 (0.9%)		0/242 (0%)
Drug abuse	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Hallucination, visual	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Insomnia	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Major depression	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Mental status changes	0/245 (0%)		0/229 (0%)		2/242 (0.8%)
Nervousness	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Psychotic disorder	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Suicide attempt	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Renal and urinary disorders
Acute prerenal failure	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Calculus urinary	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Nephrolithiasis	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Nephropathy	0/245 (0%)		0/229 (0%)		2/242 (0.8%)
Nephropathy toxic	1/245 (0.4%)		1/229 (0.4%)		1/242 (0.4%)
Nephrosclerosis	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Nephrotic syndrome	1/245 (0.4%)		1/229 (0.4%)		0/242 (0%)
Proteinuria	2/245 (0.8%)		0/229 (0%)		0/242 (0%)
Renal failure	9/245 (3.7%)		4/229 (1.7%)		7/242 (2.9%)
Renal failure acute	11/245 (4.5%)		3/229 (1.3%)		5/242 (2.1%)
Renal failure chronic	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Renal impairment	0/245 (0%)		3/229 (1.3%)		0/242 (0%)
Ureteric fistula	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Reproductive system and breast disorders
Endometrial dysplasia	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/245 (0.4%)		1/229 (0.4%)		0/242 (0%)
Cough	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Dyspnoea	4/245 (1.6%)		1/229 (0.4%)		1/242 (0.4%)
Dyspnoea exertional	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Haemothorax	0/245 (0%)		2/229 (0.9%)		2/242 (0.8%)
Hydropneumothorax	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Hydrothorax	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Hypoxia	0/245 (0%)		2/229 (0.9%)		0/242 (0%)
Interstitial lung disease	0/245 (0%)		1/229 (0.4%)		1/242 (0.4%)
Lung disorder	2/245 (0.8%)		1/229 (0.4%)		0/242 (0%)
Pleural effusion	3/245 (1.2%)		1/229 (0.4%)		3/242 (1.2%)
Pulmonary embolism	2/245 (0.8%)		2/229 (0.9%)		0/242 (0%)
Pulmonary fibrosis	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Pulmonary hypertension	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Pulmonary oedema	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Respiratory acidosis	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Respiratory failure	4/245 (1.6%)		0/229 (0%)		0/242 (0%)
Sinus disorder	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Skin and subcutaneous tissue disorders
Actinic keratosis	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Alopecia	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Cholestatic pruritus	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Decubitus ulcer	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Erythema nodosum	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Pruritus	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Scar	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Skin ulcer	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Stevens-Johnson syndrome	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Surgical and medical procedures
Colostomy closure	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Vascular disorders
Aortic aneurysm	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Circulatory collapse	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Deep vein thrombosis	2/245 (0.8%)		1/229 (0.4%)		0/242 (0%)
Haematoma	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Hyperaemia	1/245 (0.4%)		0/229 (0%)		0/242 (0%)
Hypertension	1/245 (0.4%)		0/229 (0%)		3/242 (1.2%)
Hypertensive crisis	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Hypotension	1/245 (0.4%)		0/229 (0%)		1/242 (0.4%)
Hypovolaemic shock	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Lymphocele	0/245 (0%)		0/229 (0%)		1/242 (0.4%)
Peripheral arterial occlusive disease	0/245 (0%)		1/229 (0.4%)		0/242 (0%)
Other (Not Including Serious) Adverse Events
	Everolimus + Reduced Tacrolimus		Tacrolimus Elimination		Tacrolimus Control Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	218/245 (89%)		194/229 (84.7%)		205/242 (84.7%)
Blood and lymphatic system disorders
Anaemia	22/245 (9%)		26/229 (11.4%)		20/242 (8.3%)
Leukopenia	31/245 (12.7%)		23/229 (10%)		12/242 (5%)
Thrombocytopenia	16/245 (6.5%)		17/229 (7.4%)		5/242 (2.1%)
Gastrointestinal disorders
Abdominal pain	35/245 (14.3%)		29/229 (12.7%)		28/242 (11.6%)
Abdominal pain upper	13/245 (5.3%)		10/229 (4.4%)		16/242 (6.6%)
Constipation	18/245 (7.3%)		16/229 (7%)		20/242 (8.3%)
Diarrhoea	56/245 (22.9%)		55/229 (24%)		58/242 (24%)
Nausea	36/245 (14.7%)		23/229 (10%)		33/242 (13.6%)
Vomiting	20/245 (8.2%)		17/229 (7.4%)		21/242 (8.7%)
General disorders
Fatigue	27/245 (11%)		22/229 (9.6%)		28/242 (11.6%)
Oedema peripheral	49/245 (20%)		43/229 (18.8%)		31/242 (12.8%)
Pyrexia	37/245 (15.1%)		39/229 (17%)		23/242 (9.5%)
Hepatobiliary disorders
Cholestasis	15/245 (6.1%)		7/229 (3.1%)		7/242 (2.9%)
Infections and infestations
Hepatitis C	25/245 (10.2%)		17/229 (7.4%)		21/242 (8.7%)
Nasopharyngitis	24/245 (9.8%)		24/229 (10.5%)		26/242 (10.7%)
Urinary tract infection	21/245 (8.6%)		16/229 (7%)		11/242 (4.5%)
Injury, poisoning and procedural complications
Incisional hernia	19/245 (7.8%)		9/229 (3.9%)		15/242 (6.2%)
Investigations
Blood creatinine increased	5/245 (2%)		6/229 (2.6%)		18/242 (7.4%)
Hepatic enzyme increased	13/245 (5.3%)		19/229 (8.3%)		14/242 (5.8%)
Liver function test abnormal	16/245 (6.5%)		25/229 (10.9%)		23/242 (9.5%)
Transaminases increased	14/245 (5.7%)		9/229 (3.9%)		9/242 (3.7%)
Metabolism and nutrition disorders
Decreased appetite	16/245 (6.5%)		6/229 (2.6%)		16/242 (6.6%)
Diabetes mellitus	17/245 (6.9%)		8/229 (3.5%)		12/242 (5%)
Hypercholesterolaemia	27/245 (11%)		21/229 (9.2%)		9/242 (3.7%)
Hyperkalaemia	12/245 (4.9%)		8/229 (3.5%)		24/242 (9.9%)
Hyperlipidaemia	21/245 (8.6%)		24/229 (10.5%)		5/242 (2.1%)
Hypertriglyceridaemia	20/245 (8.2%)		9/229 (3.9%)		4/242 (1.7%)
Hypokalaemia	13/245 (5.3%)		9/229 (3.9%)		9/242 (3.7%)
Hypomagnesaemia	19/245 (7.8%)		6/229 (2.6%)		17/242 (7%)
Musculoskeletal and connective tissue disorders
Arthralgia	21/245 (8.6%)		12/229 (5.2%)		23/242 (9.5%)
Back pain	20/245 (8.2%)		13/229 (5.7%)		29/242 (12%)
Muscle spasms	14/245 (5.7%)		9/229 (3.9%)		23/242 (9.5%)
Musculoskeletal pain	5/245 (2%)		1/229 (0.4%)		15/242 (6.2%)
Pain in extremity	10/245 (4.1%)		14/229 (6.1%)		16/242 (6.6%)
Nervous system disorders
Headache	51/245 (20.8%)		40/229 (17.5%)		53/242 (21.9%)
Tremor	23/245 (9.4%)		17/229 (7.4%)		36/242 (14.9%)
Psychiatric disorders
Depression	16/245 (6.5%)		9/229 (3.9%)		14/242 (5.8%)
Insomnia	16/245 (6.5%)		18/229 (7.9%)		24/242 (9.9%)
Renal and urinary disorders
Renal failure	18/245 (7.3%)		12/229 (5.2%)		22/242 (9.1%)
Renal impairment	8/245 (3.3%)		7/229 (3.1%)		16/242 (6.6%)
Respiratory, thoracic and mediastinal disorders
Cough	21/245 (8.6%)		14/229 (6.1%)		20/242 (8.3%)
Dyspnoea	17/245 (6.9%)		5/229 (2.2%)		13/242 (5.4%)
Oropharyngeal pain	16/245 (6.5%)		6/229 (2.6%)		4/242 (1.7%)
Pleural effusion	13/245 (5.3%)		6/229 (2.6%)		11/242 (4.5%)
Skin and subcutaneous tissue disorders
Pruritus	13/245 (5.3%)		11/229 (4.8%)		6/242 (2.5%)
Pruritus generalised	13/245 (5.3%)		14/229 (6.1%)		17/242 (7%)
Vascular disorders
Hypertension	51/245 (20.8%)		35/229 (15.3%)		42/242 (17.4%)

Limitations/Caveats

[Not Specified]

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.