Study Evaluating of Calcineurin Inhibitor and Sirolimus (Rapamune) Treatment in Liver Transplant Recipients

• Sponsor: Wyeth is now a wholly owned subsidiary of Pfizer (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00086346
• Collaborator: (none)
• Enrollment: 607
• Locations: 42
• Arms: 2
• Duration (Months): 67
• Patients Per Site: 14.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the sirolimus conversion regimen as compared with the calcineurin inhibitor continuation regimen with regards to renal function in stable liver transplant subjects.

Condition or Disease	Intervention/Treatment	Phase
Liver Transplantation	Drug: Sirolimus (Rapamune); Drug: Cyclosporine or Tacrolimus	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 607 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-Label, Comparative Evaluation of Conversion From Calcineurin Inhibitor Treatment to Sirolimus Treatment Versus Continued Calcineurin Inhibitor Treatment in Liver Allograft Recipients Undergoing Maintenance Therapy
• Study Start Date: Dec 1, 2002
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Jul 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: A	Drug: Sirolimus (Rapamune)
Active Comparator: B	Drug: Cyclosporine or Tacrolimus

Outcome Measures

Primary Outcome Measures

1. Change From Baseline Adjusted Mean in Glomerular Filtration Rate (GFR) [Baseline and 12 months]

   GFR is an index of kidney function. GFR was calculated using Cockcroft-Gault method. A normal GFR is >90 mL/min, higher values indicate better function. Change=adjusted mean of 12 months minus baseline. Mean adjusted for baseline GFR, with antimetabolite therapy status and hepatitis C status as fixed effects.

2. Patient and Graft Survival [12 months]

   Endpoint was a composite assessment of patient and graft survival. Patients categorized as graft survival or graft loss. Graft loss defined as pure graft loss (requiring retransplant) or death (with a functioning graft), if the event occurred in the first 12 months after randomization. Patients with missing graft data were counted as graft losses.

Secondary Outcome Measures

1. Number of Patients With a Biopsy Confirmed Acute Rejection [12 months]

   Overall event rate is determined as yes or no.

2. Mean Serum Creatinine [12 months]

   Observed mean values for serum creatinine.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age greater than 13 years (age greater than 18 years as required by some local regulations).

• Receiving immunosuppressive therapy with calcineurin inhibitors (CI) +/- corticosteroids +/- antimetabolite.

• 6 to 144 months after orthotopic liver transplantation.

• Cockcroft-Gault GFR values ≥40 mL/min and ≤90mL/min at screening

Exclusion Criteria:

• History of nonhepatic transplantation

• Evidence of systemic infection (sepsis, bacteremia, pneumonia etc).

• Known or suspected malignancy < 5 years before random assignment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		San Francisco	California	United States	94143-0780
2		Tampa	Florida	United States	33606
3		New Orleans	Louisiana	United States	70121
4		Detroit	Michigan	United States	48202
5		Rochester	Minnesota	United States	55905
6		Omaha	Nebraska	United States	68198-3285
7		New York	New York	United States	10029
8		Rochester	New York	United States	14642-8410
9		Cleveland	Ohio	United States	44195
10		Philadelphia	Pennsylvania	United States	19104
11		Gent		Belgium	9000
12		Edmonton	Alberta	Canada	T6G 2B7
13		London	Ontario	Canada	N6A 5A5
14		Toronto	Ontario	Canada	M5G 2C4
15		Prague		Czech Republic	14021
16		Clichy		France	92118
17		Lyon		France	69437
18		Nice		France	06200
19		Paris		France	75679
20		Rennes		France	35033
21		Villejuif		France	94800
22		Berlin		Germany	13353
23		Hamburg		Germany	20251
24		München		Germany	81377
25		Bologna		Italy
26		Milano		Italy	20122
27		Padova		Italy	35128
28		Leiden		Netherlands	2300
29		Coimbra		Portugal	3049
30		Lisboa		Portugal	1069-166
31		Barcelona		Spain	08035
32		Barcelona		Spain	08036
33		Barcelona		Spain	08907
34		Madrid		Spain	28034
35		Pamplona		Spain	31008
36		Santiago de Compostela		Spain	15706
37		Valencia		Spain	46009
38		Bern		Switzerland	CH-3010
39		Zürich		Switzerland	CH-8091
40		Birmingham		United Kingdom	B15 2TH
41		Edinburgh		United Kingdom	EH16 4SA
42		Leeds		United Kingdom	LS9 7TF

Sponsors and Collaborators

• Wyeth is now a wholly owned subsidiary of Pfizer

Investigators

• Study Director: Medical Monitor, Wyeth is now a wholly owned subsidiary of Pfizer
• Principal Investigator: Trial Manager, For Italy, [e-mail]
• Principal Investigator: Trial Manager, For Germany, [e-mail]
• Principal Investigator: Trial Manager, For Belgium, [e-mail]
• Principal Investigator: Trial Manager, For Czech Republic, [e-mail]
• Principal Investigator: Trial Manager, For Netherlands, [e-mail]
• Principal Investigator: Trial Manager, For Switzerland, [e-mail]
• Principal Investigator: Trial Manager, For UK, [e-mail]

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00086346
• Other Study ID Numbers: 0468H1-313
• First Posted: Jul 2, 2004
• Last Update Posted: Apr 28, 2010
• Last Verified: Apr 1, 2010

• Keywords provided by , ,: Liver; Transplant
• Additional relevant MeSH terms: Cyclosporine; Sirolimus; Tacrolimus; Cyclosporins

Study Results

Participant Flow

Recruitment Details	Patients were recruited October 2002 to November 2006.
Pre-assignment Detail	Patients were screened up to 30 days.

Arm/Group Title	Sirolimus (SRL) Conversion	Calcineurin Inhibitors (CNI) Continuation
Arm/Group Description	Sirolimus was administered once daily. A loading dose of sirolimus, 10 to 15 mg, was administered in divided doses on day 1: the first dose was given after collection of the sirolimus trough level and a minimum of 4 hours following the last dose of CNI, and the second dose approximately 12 hours after the first dose. On days 2 through 6, sirolimus was administered in a dose of 3 to 5 mg/day. For the remaining study period, day 7 through month 72, appropriate daily doses of sirolimus were administered to attain the recommended trough concentrations of 8 to 16 ng/mL (using a chromatographic method) or 10 to 20 ng/mL (using an immunoassay).	Calcineurin Inhibitors administered per local practice to attain target trough levels of 3 to 10 ng/mL (tacrolimus) or 50 to 250 ng/mL (cyclosporin A), respectively.
Period Title: Randomization
STARTED	393	214
COMPLETED	389	210
NOT COMPLETED	4	4
Period Title: Randomization
STARTED	389	210
COMPLETED	249	187
NOT COMPLETED	140	23

Baseline Characteristics

Arm/Group Title	Sirolimus (SRL) Conversion	Calcineurin Inhibitors (CNI) Continuation	Total
Arm/Group Description	Sirolimus was administered once daily. A loading dose of sirolimus, 10 to 15 mg, was administered in divided doses on day 1: the first dose was given after collection of the sirolimus trough level and a minimum of 4 hours following the last dose of CNI, and the second dose approximately 12 hours after the first dose. On days 2 through 6, sirolimus was administered in a dose of 3 to 5 mg/day. For the remaining study period, day 7 through month 72, appropriate daily doses of sirolimus were administered to attain the recommended trough concentrations of 8 to 16 ng/mL (using a chromatographic method) or 10 to 20 ng/mL (using an immunoassay).	Calcineurin Inhibitors administered per local practice to attain target trough levels of 3 to 10 ng/mL (tacrolimus) or 50 to 250 ng/mL (cyclosporin A), respectively.	Total of all reporting groups
Overall Participants	393	214	607
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	57.0	56.5	57.0
Sex: Female, Male (Count of Participants)
Female	122 31%	64 29.9%	186.0 30.6%
Male	271 69%	150 70.1%	421.0 69.4%
Mean serum creatinine levels (μmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [μmol/L]	122.9 (32.3)	125.2 (31.9)	123.7 (32.2)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline Adjusted Mean in Glomerular Filtration Rate (GFR)
Description	GFR is an index of kidney function. GFR was calculated using Cockcroft-Gault method. A normal GFR is >90 mL/min, higher values indicate better function. Change=adjusted mean of 12 months minus baseline. Mean adjusted for baseline GFR, with antimetabolite therapy status and hepatitis C status as fixed effects.
Time Frame	Baseline and 12 months

Outcome Measure Data

Analysis Population Description

The intent to treat population was analyzed and consisted of all patients randomly assigned to treatment. Patients were stratified by hepatitis C status and whether or not they were receiving antimetabolite therapy at time of randomization.

Arm/Group Title	Sirolimus (SRL) Conversion	Calcineurin Inhibitors (CNI) Continuation
Arm/Group Description	Sirolimus was administered once daily. A loading dose of sirolimus, 10 to 15 mg, was administered in divided doses on day 1: the first dose was given after collection of the sirolimus trough level and a minimum of 4 hours following the last dose of CNI, and the second dose approximately 12 hours after the first dose. On days 2 through 6, sirolimus was administered in a dose of 3 to 5 mg/day. For the remaining study period, day 7 through month 72, appropriate daily doses of sirolimus were administered to attain the recommended trough concentrations of 8 to 16 ng/mL (using a chromatographic method) or 10 to 20 ng/mL (using an immunoassay).	Calcineurin Inhibitors administered per local practice to attain target trough levels of 3 to 10 ng/mL (tacrolimus) or 50 to 250 ng/mL (cyclosporin A), respectively.
Measure Participants	393	214
Mean (Standard Error) [mL/min]	-4.45 (1.12)	-3.07 (1.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sirolimus (SRL) Conversion, Calcineurin Inhibitors (CNI) Continuation
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.342
	Comments
	Method	Rank ANCOVA
	Comments

2. Secondary Outcome

Title	Number of Patients With a Biopsy Confirmed Acute Rejection
Description	Overall event rate is determined as yes or no.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

The analysis population is the intent to treat. Any patient whose clinical rejection data was incomplete was designated as an acute rejection in the analysis.

Arm/Group Title	Sirolimus (SRL) Conversion	Calcineurin Inhibitors (CNI) Continuation
Arm/Group Description	Sirolimus was administered once daily. A loading dose of sirolimus, 10 to 15 mg, was administered in divided doses on day 1: the first dose was given after collection of the sirolimus trough level and a minimum of 4 hours following the last dose of CNI, and the second dose approximately 12 hours after the first dose. On days 2 through 6, sirolimus was administered in a dose of 3 to 5 mg/day. For the remaining study period, day 7 through month 72, appropriate daily doses of sirolimus were administered to attain the recommended trough concentrations of 8 to 16 ng/mL (using a chromatographic method) or 10 to 20 ng/mL (using an immunoassay).	Calcineurin Inhibitors administered per local practice to attain target trough levels of 3 to 10 ng/mL (tacrolimus) or 50 to 250 ng/mL (cyclosporin A), respectively.
Measure Participants	393	214
Yes	46	13
No	347	201

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sirolimus (SRL) Conversion, Calcineurin Inhibitors (CNI) Continuation
	Comments	Comparison between treatment groups of percentages of patients with biopsy-confirmed acute rejection.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

3. Secondary Outcome

Title	Mean Serum Creatinine
Description	Observed mean values for serum creatinine.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

On-therapy population; consisted of patients who were still receiving study medication at the defined endpoint.

Arm/Group Title	Sirolimus (SRL) Conversion	Calcineurin Inhibitors (CNI) Continuation
Arm/Group Description	Sirolimus was administered once daily. A loading dose of sirolimus, 10 to 15 mg, was administered in divided doses on day 1: the first dose was given after collection of the sirolimus trough level and a minimum of 4 hours following the last dose of CNI, and the second dose approximately 12 hours after the first dose. On days 2 through 6, sirolimus was administered in a dose of 3 to 5 mg/day. For the remaining study period, day 7 through month 72, appropriate daily doses of sirolimus were administered to attain the recommended trough concentrations of 8 to 16 ng/mL (using a chromatographic method) or 10 to 20 ng/mL (using an immunoassay).	Calcineurin Inhibitors administered per local practice to attain target trough levels of 3 to 10 ng/mL (tacrolimus) or 50 to 250 ng/mL (cyclosporin A), respectively.
Measure Participants	262	190
Mean (Standard Deviation) [µmol/L]	119.0 (38.9)	122.4 (31.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sirolimus (SRL) Conversion, Calcineurin Inhibitors (CNI) Continuation
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	1 way ANOVA, two sided
	Comments

4. Primary Outcome

Title	Patient and Graft Survival
Description	Endpoint was a composite assessment of patient and graft survival. Patients categorized as graft survival or graft loss. Graft loss defined as pure graft loss (requiring retransplant) or death (with a functioning graft), if the event occurred in the first 12 months after randomization. Patients with missing graft data were counted as graft losses.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Intent to treat analysis population with stratification by antimetabolite therapy and hepatitis C status.

Arm/Group Title	Sirolimus (SRL) Conversion	Calcineurin Inhibitors (CNI) Continuation
Arm/Group Description	Sirolimus was administered once daily. A loading dose of sirolimus, 10 to 15 mg, was administered in divided doses on day 1: the first dose was given after collection of the sirolimus trough level and a minimum of 4 hours following the last dose of CNI, and the second dose approximately 12 hours after the first dose. On days 2 through 6, sirolimus was administered in a dose of 3 to 5 mg/day. For the remaining study period, day 7 through month 72, appropriate daily doses of sirolimus were administered to attain the recommended trough concentrations of 8 to 16 ng/mL (using a chromatographic method) or 10 to 20 ng/mL (using an immunoassay).	Calcineurin Inhibitors administered per local practice to attain target trough levels of 3 to 10 ng/mL (tacrolimus) or 50 to 250 ng/mL (cyclosporin A), respectively.
Measure Participants	393	214
Graft survival	367	202
Graft loss (total)	26	12
Graft loss: Pure (with retransplant)	0	0
Graft loss: Death	13	3
Graft loss: Incomplete data	13	9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sirolimus (SRL) Conversion, Calcineurin Inhibitors (CNI) Continuation
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	The a priori criterion for declaring non-inferiority was a lower bound of the 95% confidence interval (CI) having a ≥ 5% difference in graft loss. -5.2 is < 5 % difference.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.2
	Confidence Interval	() 95%; -5.2 to 2.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Weighted difference in percentage of graft loss: (CNI% minus SRL%); negative values are favorable to CNI group

Adverse Events

Arm/Group Title	Sirolimus (SRL) Conversion		Calcineurin Inhibitors (CNI) Continuation
Arm/Group Description	Sirolimus was administered once daily. A loading dose of sirolimus, 10 to 15 mg, was administered in divided doses on day 1: the first dose was given after collection of the sirolimus trough level and a minimum of 4 hours following the last dose of CNI, and the second dose approximately 12 hours after the first dose. On days 2 through 6, sirolimus was administered in a dose of 3 to 5 mg/day. For the remaining study period, day 7 through month 72, appropriate daily doses of sirolimus were administered to attain the recommended trough concentrations of 8 to 16 ng/mL (using a chromatographic method) or 10 to 20 ng/mL (using an immunoassay).		Calcineurin Inhibitors administered per local practice to attain target trough levels of 3 to 10 ng/mL (tacrolimus) or 50 to 250 ng/mL (cyclosporin A), respectively.
All Cause Mortality
	Sirolimus (SRL) Conversion		Calcineurin Inhibitors (CNI) Continuation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sirolimus (SRL) Conversion		Calcineurin Inhibitors (CNI) Continuation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	193/ (NaN)		79/ (NaN)
Blood and lymphatic system disorders
Anemia	12/389 (3.1%)		4/210 (1.9%)
Aplastic anema	0/389 (0%)		1/210 (0.5%)
Coagulation disorder	0/389 (0%)		1/210 (0.5%)
International normalized ratio increased	1/389 (0.3%)		0/210 (0%)
Leukopenia	1/389 (0.3%)		0/210 (0%)
Lymphadenopathy	2/389 (0.5%)		0/210 (0%)
Lymphagitis	1/389 (0.3%)		0/210 (0%)
Microcytic anemia	1/389 (0.3%)		0/210 (0%)
Pancytopenia	1/389 (0.3%)		1/210 (0.5%)
Cardiac disorders
Angina pectoris	3/389 (0.8%)		1/210 (0.5%)
Arterial anomaly	1/389 (0.3%)		1/210 (0.5%)
Atrial fibrillation	1/389 (0.3%)		1/210 (0.5%)
Atrial flutter	1/389 (0.3%)		0/210 (0%)
AV block	1/389 (0.3%)		0/210 (0%)
AV block complete	1/389 (0.3%)		1/210 (0.5%)
Cardiomegaly	0/389 (0%)		1/210 (0.5%)
Cardiomyopathy	1/389 (0.3%)		0/210 (0%)
Cardiovascular disorder	3/389 (0.8%)		0/210 (0%)
Cerebral ischemia	0/389 (0%)		1/210 (0.5%)
Coronary occlusion	1/389 (0.3%)		1/210 (0.5%)
Heart failure	4/389 (1%)		1/210 (0.5%)
Left heart failure	1/389 (0.3%)		0/210 (0%)
Myocardial infarct	0/389 (0%)		1/210 (0.5%)
Myocardial ischemia	2/389 (0.5%)		0/210 (0%)
Pericardial effusion	1/389 (0.3%)		0/210 (0%)
Pericarditis	1/389 (0.3%)		1/210 (0.5%)
Shock	1/389 (0.3%)		0/210 (0%)
Sick sinus syndrome	1/389 (0.3%)		0/210 (0%)
Supraventricular tachycardia	0/389 (0%)		1/210 (0.5%)
Syncope	3/389 (0.8%)		1/210 (0.5%)
Tachycardia	0/389 (0%)		1/210 (0.5%)
Endocrine disorders
Diabetes mellitus	3/389 (0.8%)		2/210 (1%)
Thyroid disorder	0/389 (0%)		1/210 (0.5%)
Eye disorders
Cataract specified	1/389 (0.3%)		1/210 (0.5%)
Eye hemorrhage	1/389 (0.3%)		0/210 (0%)
Glaucoma	1/389 (0.3%)		0/210 (0%)
Retinal detachment	1/389 (0.3%)		0/210 (0%)
Retinal disorder	1/389 (0.3%)		0/210 (0%)
Gastrointestinal disorders
Carcinoma of the mouth	0/389 (0%)		1/210 (0.5%)
Cholangitis	5/389 (1.3%)		2/210 (1%)
Cholelithiasis	2/389 (0.5%)		0/210 (0%)
Colitis	2/389 (0.5%)		1/210 (0.5%)
Constipation	1/389 (0.3%)		0/210 (0%)
Diarrhea	16/389 (4.1%)		5/210 (2.4%)
Enteritis	0/389 (0%)		1/210 (0.5%)
Esophageal stenosis	1/389 (0.3%)		0/210 (0%)
Gamma glutamyl transpeptidase increased	3/389 (0.8%)		0/210 (0%)
Gastroenteritis	9/389 (2.3%)		4/210 (1.9%)
Gastrointestinal carcinoma	4/389 (1%)		4/210 (1.9%)
Gastrointestinal disorder	8/389 (2.1%)		1/210 (0.5%)
Gastrointestinal hemorrhage	4/389 (1%)		2/210 (1%)
Hepatic neoplasia	3/389 (0.8%)		2/210 (1%)
Hepatitis	2/389 (0.5%)		1/210 (0.5%)
Ileitis	0/389 (0%)		1/210 (0.5%)
Ileus	3/389 (0.8%)		1/210 (0.5%)
Intestinal obstruction	2/389 (0.5%)		1/210 (0.5%)
Jaundice	0/389 (0%)		1/210 (0.5%)
Liver damage	1/389 (0.3%)		1/210 (0.5%)
Liver fatty deposit	1/389 (0.3%)		0/210 (0%)
Liver function tests abnormal	15/389 (3.9%)		3/210 (1.4%)
Melena	0/389 (0%)		1/210 (0.5%)
Nausea	6/389 (1.5%)		1/210 (0.5%)
Nausea and vomiting	0/389 (0%)		1/210 (0.5%)
Pancreatitis	2/389 (0.5%)		0/210 (0%)
Peridontal abcess	1/389 (0.3%)		0/210 (0%)
Rectal disorder	1/389 (0.3%)		2/210 (1%)
Rectal hemorrhage	0/389 (0%)		1/210 (0.5%)
Sclerosing cholangitis	1/389 (0.3%)		0/210 (0%)
Stomatitis	1/389 (0.3%)		0/210 (0%)
Stools abnormal	1/389 (0.3%)		0/210 (0%)
Ulcerative colitis	1/389 (0.3%)		2/210 (1%)
Vomiting	10/389 (2.6%)		2/210 (1%)
General disorders
Abdominal pain	10/389 (2.6%)		4/210 (1.9%)
Abdominal syndrome acute	1/389 (0.3%)		1/210 (0.5%)
Abscess	5/389 (1.3%)		0/210 (0%)
Accidental injury	6/389 (1.5%)		3/210 (1.4%)
Accidental overdose	3/389 (0.8%)		0/210 (0%)
Adenoma	1/389 (0.3%)		0/210 (0%)
Allergic reaction	1/389 (0.3%)		0/210 (0%)
Ascites	1/389 (0.3%)		0/210 (0%)
Asthenia	2/389 (0.5%)		2/210 (1%)
Back pain	3/389 (0.8%)		0/210 (0%)
Carcinoma	2/389 (0.5%)		0/210 (0%)
Cellulitis	6/389 (1.5%)		3/210 (1.4%)
Chest pain	4/389 (1%)		3/210 (1.4%)
Chills	2/389 (0.5%)		3/210 (1.4%)
Death	1/389 (0.3%)		0/210 (0%)
Diarrhea infectious	1/389 (0.3%)		0/210 (0%)
Face edema	1/389 (0.3%)		0/210 (0%)
Fever	16/389 (4.1%)		8/210 (3.8%)
Flu syndrome	1/389 (0.3%)		0/210 (0%)
Headache	2/389 (0.5%)		0/210 (0%)
Hernia	11/389 (2.8%)		3/210 (1.4%)
Infection	10/389 (2.6%)		2/210 (1%)
Medication error	1/389 (0.3%)		0/210 (0%)
Neck pain	1/389 (0.3%)		0/210 (0%)
Neoplasm	3/389 (0.8%)		0/210 (0%)
Overdose	3/389 (0.8%)		0/210 (0%)
Pain	4/389 (1%)		0/210 (0%)
Sepsis	9/389 (2.3%)		3/210 (1.4%)
Septic shock	1/389 (0.3%)		0/210 (0%)
Transplant rejection	1/389 (0.3%)		1/210 (0.5%)
Device malfunction	1/389 (0.3%)		1/210 (0.5%)
Local reaction to procedure	13/389 (3.3%)		3/210 (1.4%)
Surgical procedure	1/389 (0.3%)		0/210 (0%)
Metabolism and nutrition disorders
Acidosis	1/389 (0.3%)		0/210 (0%)
Alkaline phosphotase increased	7/389 (1.8%)		0/210 (0%)
Bilirubinemia	0/389 (0%)		1/210 (0.5%)
BUN increased	2/389 (0.5%)		0/210 (0%)
Creatinine increased	5/389 (1.3%)		2/210 (1%)
Dehydration	4/389 (1%)		3/210 (1.4%)
Diabetic ketoacidosis	1/389 (0.3%)		0/210 (0%)
Electrolyte abnormality	1/389 (0.3%)		0/210 (0%)
Gout	0/389 (0%)		1/210 (0.5%)
Healing abnormal	5/389 (1.3%)		2/210 (1%)
Hyperglycemia	2/389 (0.5%)		1/210 (0.5%)
Hyperkalemia	0/389 (0%)		1/210 (0.5%)
Hyperlipemia	1/389 (0.3%)		0/210 (0%)
Hypocalcemia	1/389 (0.3%)		0/210 (0%)
Hypoglycemia	2/389 (0.5%)		0/210 (0%)
Hypokalemia	3/389 (0.8%)		0/210 (0%)
Hyponatremia	0/389 (0%)		1/210 (0.5%)
Peripheral edema	4/389 (1%)		0/210 (0%)
SGOT increased	6/389 (1.5%)		2/210 (1%)
SGPT increased	5/389 (1.3%)		2/210 (1%)
Weight gain	0/389 (0%)		1/210 (0.5%)
Weight loss	1/389 (0.3%)		1/210 (0.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/389 (0.8%)		2/210 (1%)
Arthritis	2/389 (0.5%)		0/210 (0%)
Arthrosis	2/389 (0.5%)		2/210 (1%)
Bone necrosis	1/389 (0.3%)		0/210 (0%)
Bursitis	1/389 (0.3%)		0/210 (0%)
Musculoskeletal anomaly	1/389 (0.3%)		0/210 (0%)
Osteomyelitis	0/389 (0%)		1/210 (0.5%)
Nervous system disorders
Alcoholism	1/389 (0.3%)		0/210 (0%)
Aphasia	0/389 (0%)		1/210 (0.5%)
CNS neoplasia	0/389 (0%)		1/210 (0.5%)
Convulsion	2/389 (0.5%)		1/210 (0.5%)
Depression	1/389 (0.3%)		1/210 (0.5%)
Dizziness	1/389 (0.3%)		1/210 (0.5%)
Dysarthria	0/389 (0%)		1/210 (0.5%)
Hemiplegia	0/389 (0%)		1/210 (0.5%)
Hypesthesia	1/389 (0.3%)		0/210 (0%)
Subdural hematoma	1/389 (0.3%)		0/210 (0%)
Renal and urinary disorders
Acute kidney failure	7/389 (1.8%)		2/210 (1%)
Albuminuria	1/389 (0.3%)		0/210 (0%)
Dysuria	1/389 (0.3%)		1/210 (0.5%)
Hematuria	0/389 (0%)		1/210 (0.5%)
Hydronephrosis	1/389 (0.3%)		1/210 (0.5%)
Kidney calculus	3/389 (0.8%)		1/210 (0.5%)
Kidney failure	7/389 (1.8%)		1/210 (0.5%)
Kidney function abnormal	6/389 (1.5%)		1/210 (0.5%)
Nephritis	1/389 (0.3%)		0/210 (0%)
Nephrosclerosis	2/389 (0.5%)		0/210 (0%)
Nephrosis	1/389 (0.3%)		0/210 (0%)
Polyuria	1/389 (0.3%)		0/210 (0%)
Pyelonephritis	1/389 (0.3%)		0/210 (0%)
Uremia	2/389 (0.5%)		1/210 (0.5%)
Urinary tract disorder	0/389 (0%)		1/210 (0.5%)
Urinary tract infection	7/389 (1.8%)		3/210 (1.4%)
Urine abnormality	1/389 (0.3%)		0/210 (0%)
Urolithiasis	1/389 (0.3%)		0/210 (0%)
Reproductive system and breast disorders
Breast neoplasm	0/389 (0%)		1/210 (0.5%)
Fallopian tube disorder	1/389 (0.3%)		0/210 (0%)
Ovarian cyst	3/389 (0.8%)		0/210 (0%)
Ovarian disorder	0/389 (0%)		1/210 (0.5%)
Prostatic carcinoma	3/389 (0.8%)		0/210 (0%)
Prostatic disorder	0/389 (0%)		1/210 (0.5%)
Unintended pregnancy	0/389 (0%)		1/210 (0.5%)
Respiratory, thoracic and mediastinal disorders
Bronchitis	0/389 (0%)		2/210 (1%)
Carcinoma of lung	3/389 (0.8%)		2/210 (1%)
Cough increased	3/389 (0.8%)		1/210 (0.5%)
Dyspnea	7/389 (1.8%)		1/210 (0.5%)
Hemoptysis	1/389 (0.3%)		1/210 (0.5%)
Hemothorax	1/389 (0.3%)		0/210 (0%)
Interstitial pneumonia	1/389 (0.3%)		0/210 (0%)
Laryngitis	1/389 (0.3%)		0/210 (0%)
Lung disorder	2/389 (0.5%)		0/210 (0%)
Lung edema	1/389 (0.3%)		0/210 (0%)
Lung hemorrhage	1/389 (0.3%)		0/210 (0%)
Lung infiltration nos	1/389 (0.3%)		0/210 (0%)
Pharyngitis	2/389 (0.5%)		0/210 (0%)
Pleural effusion	2/389 (0.5%)		0/210 (0%)
Pneumonia	17/389 (4.4%)		4/210 (1.9%)
Pneumonitis	2/389 (0.5%)		0/210 (0%)
Pneumothorax	1/389 (0.3%)		0/210 (0%)
Sinusitis	1/389 (0.3%)		0/210 (0%)
Upper respiratory infection	5/389 (1.3%)		1/210 (0.5%)
Skin and subcutaneous tissue disorders
Herpes simplex	1/389 (0.3%)		0/210 (0%)
Herpes zoster	1/389 (0.3%)		1/210 (0.5%)
Maculopapular rash	1/389 (0.3%)		0/210 (0%)
Purpuric rash	0/389 (0%)		1/210 (0.5%)
Rash	3/389 (0.8%)		1/210 (0.5%)
Skin carcinoma	14/389 (3.6%)		19/210 (9%)
Skin hypertrophy	1/389 (0.3%)		0/210 (0%)
Skin melanoma	1/389 (0.3%)		3/210 (1.4%)
Skin ulcer	1/389 (0.3%)		0/210 (0%)
Vascular disorders
Aortic stenosis	1/389 (0.3%)		0/210 (0%)
Arterial thrombosis	2/389 (0.5%)		0/210 (0%)
Cerebrovascular accident	1/389 (0.3%)		6/210 (2.9%)
Deep vein thrombosis	0/389 (0%)		1/210 (0.5%)
Hemorrhage	3/389 (0.8%)		1/210 (0.5%)
Hypertension	2/389 (0.5%)		1/210 (0.5%)
Hypotension	1/389 (0.3%)		0/210 (0%)
Mesenteric venous occlusion	1/389 (0.3%)		0/210 (0%)
Peripheral vascular disorder	1/389 (0.3%)		0/210 (0%)
Postural hypotension	1/389 (0.3%)		0/210 (0%)
Pulmonary embolus	0/389 (0%)		2/210 (1%)
Pulmonary hypertension	1/389 (0.3%)		0/210 (0%)
Vascular disorder	0/389 (0%)		1/210 (0.5%)
Other (Not Including Serious) Adverse Events
	Sirolimus (SRL) Conversion		Calcineurin Inhibitors (CNI) Continuation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	386/389 (99.2%)		201/210 (95.7%)
Blood and lymphatic system disorders
Anemia	94/389 (24.2%)		19/210 (9%)
Leukopenia	55/389 (14.1%)		10/210 (4.8%)
Thrombocytopenia	58/389 (14.9%)		8/210 (3.8%)
Cardiac disorders
Hypertension	65/389 (16.7%)		40/210 (19%)
Endocrine disorders
Diabetes mellitus	25/389 (6.4%)		9/210 (4.3%)
Gastrointestinal disorders
Anorexia	25/389 (6.4%)		5/210 (2.4%)
Aphthous stomatitis	34/389 (8.7%)		2/210 (1%)
Constipation	36/389 (9.3%)		20/210 (9.5%)
Diarrhea	136/389 (35%)		38/210 (18.1%)
Dyspepsia	17/389 (4.4%)		11/210 (5.2%)
Gastrointestinal disorder	26/389 (6.7%)		10/210 (4.8%)
Liver function tests abnormal	59/389 (15.2%)		25/210 (11.9%)
Mouth ulceration	44/389 (11.3%)		2/210 (1%)
Nausea	51/389 (13.1%)		19/210 (9%)
Stomatitis	103/389 (26.5%)		4/210 (1.9%)
Vomiting	35/389 (9%)		17/210 (8.1%)
Gastroenteritis	19/389 (4.9%)		12/210 (5.7%)
General disorders
Abdominal pain	70/389 (18%)		30/210 (14.3%)
Accidental injury	67/389 (17.2%)		32/210 (15.2%)
Asthenia	79/389 (20.3%)		28/210 (13.3%)
Back pain	42/389 (10.8%)		27/210 (12.9%)
Chest pain	31/389 (8%)		18/210 (8.6%)
Face edema	22/389 (5.7%)		4/210 (1.9%)
Fever	79/389 (20.3%)		26/210 (12.4%)
Flu syndrome	22/389 (5.7%)		7/210 (3.3%)
Headache	84/389 (21.6%)		23/210 (11%)
Hernia	25/389 (6.4%)		10/210 (4.8%)
Pain	71/389 (18.3%)		39/210 (18.6%)
Cellulitis	20/389 (5.1%)		7/210 (3.3%)
Flu Syndrome	16/389 (4.1%)		15/210 (7.1%)
Infection	97/389 (24.9%)		43/210 (20.5%)
Injury, poisoning and procedural complications
Local reaction to procedure	36/389 (9.3%)		16/210 (7.6%)
Metabolism and nutrition disorders
Alkaline phosphatase increased	32/389 (8.2%)		10/210 (4.8%)
BUN increased	12/389 (3.1%)		13/210 (6.2%)
Creatinine increased	24/389 (6.2%)		26/210 (12.4%)
Hypercholesteremia	110/389 (28.3%)		9/210 (4.3%)
Hyperglycemia	39/389 (10%)		22/210 (10.5%)
Hyperkalemia	11/389 (2.8%)		17/210 (8.1%)
Hyperlipemia	159/389 (40.9%)		20/210 (9.5%)
Hyperuricemia	10/389 (2.6%)		16/210 (7.6%)
Hypokalemia	23/389 (5.9%)		5/210 (2.4%)
Lactic dehydrogenase increased	20/389 (5.1%)		3/210 (1.4%)
Peripheral edema	127/389 (32.6%)		29/210 (13.8%)
SGOT increased	37/389 (9.5%)		12/210 (5.7%)
SGPT increased	40/389 (10.3%)		9/210 (4.3%)
Weight loss	26/389 (6.7%)		6/210 (2.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	57/389 (14.7%)		35/210 (16.7%)
Leg cramps	5/389 (1.3%)		12/210 (5.7%)
Nervous system disorders
Depression	16/389 (4.1%)		13/210 (6.2%)
Dizziness	36/389 (9.3%)		15/210 (7.1%)
Insomnia	27/389 (6.9%)		11/210 (5.2%)
Paresthesia	20/389 (5.1%)		4/210 (1.9%)
Renal and urinary disorders
Albuminuria	25/389 (6.4%)		5/210 (2.4%)
Kidney function abnormal	24/389 (6.2%)		22/210 (10.5%)
Urinary Tract Infection	36/389 (9.3%)		21/210 (10%)
Respiratory, thoracic and mediastinal disorders
Cough increased	66/389 (17%)		28/210 (13.3%)
Dyspnea	36/389 (9.3%)		13/210 (6.2%)
Pharyngitis	40/389 (10.3%)		14/210 (6.7%)
Rhinitis	35/389 (9%)		11/210 (5.2%)
Erythema	24/389 (6.2%)		3/210 (1.4%)
Pruritus	50/389 (12.9%)		14/210 (6.7%)
Bronchitis	25/389 (6.4%)		14/210 (6.7%)
Pneumonia	30/389 (7.7%)		9/210 (4.3%)
Sinusitis	27/389 (6.9%)		15/210 (7.1%)
Upper Respiratory Infection	54/389 (13.9%)		36/210 (17.1%)
Skin and subcutaneous tissue disorders
Acne	52/389 (13.4%)		4/210 (1.9%)
Dry skin	32/389 (8.2%)		3/210 (1.4%)
Rash	111/389 (28.5%)		16/210 (7.6%)
Skin disorder	28/389 (7.2%)		13/210 (6.2%)
Skin hypertrophy	8/389 (2.1%)		12/210 (5.7%)
Herpes Simplex	33/389 (8.5%)		3/210 (1.4%)
Skin Carcinoma	14/389 (3.6%)		19/210 (9%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

The PIs agreed to allow the sponsor 60 days to review and require changes to presentations or publications but only to protect confidential information and intellectual property, and for the sponsor to file a patent application, as applicable. The PIs also agreed for data to be presented first as a joint, multi-center publication.