EVEREST: Everolimus in Combination With Cyclosporine Microemulsion in de Novo Renal Transplant Recipients

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01276457
• Collaborator: (none)
• Enrollment: 223
• Arms: 2
• Duration (Months): 33.1

Study Details

Study Description

Brief Summary

The purpose of this study was to allow the continuation of everolimus treatment in patients who have completed the core study (NCT00170885) and to collect long-term safety, tolerability, and efficacy data in a group of patients treated with the upper everolimus target levels plus very low dose cyclosporin in comparison with the standard everolimus target levels plus low dose cyclosporin in patients with renal transplantation.

Condition or Disease	Intervention/Treatment	Phase
Transplantation Infection	Drug: Everolimus 0.25 and 0.75 mg tablets; Drug: Cyclosporine very low dose (150-300 ng/mL) microemulsion; Drug: Cyclosporine low dose (350-500 ng/mL) microemulsion	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 223 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An 18 Month Extension to the Multicenter, Randomized, Open-label Trial (NCT00170885) to Evaluate the Safety, Tolerability, and Efficacy of Two Regimens of Everolimus Plus Cyclosporine Microemulsion, Given According to Different Blood Target Levels, in de Novo Renal Transplant Recipients
• Study Start Date: May 1, 2006
• Actual Primary Completion Date: Feb 1, 2009
• Actual Study Completion Date: Feb 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Upper everolimus blood target + very low dose cyclosporine Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 8-12 ng/mL. Patients also received a very low dose of cyclosporine (150-300 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 200 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.	Drug: Everolimus 0.25 and 0.75 mg tablets; The dose of everolimus for each patient was adjusted to achieve the target everolimus blood level range. Everolimus blood trough level was measured 5 days after any dose adjustment to verify that the blood level was within the desired target level range.; Drug: Cyclosporine very low dose (150-300 ng/mL) microemulsion; The dose of cyclosporine for each patient was adjusted to achieve the target cyclosporine blood level. Cyclosporine dose adjustments were based on drug blood level determined from whole blood samples taken 2 hours (± 10 min) after the morning dose.; Other Names: Neoral
Active Comparator: Standard everolimus blood target + low dose cyclosporine Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 3-8 ng/mL. Patients also received a low dose of cyclosporine (350-500 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 400 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.	Drug: Everolimus 0.25 and 0.75 mg tablets; The dose of everolimus for each patient was adjusted to achieve the target everolimus blood level range. Everolimus blood trough level was measured 5 days after any dose adjustment to verify that the blood level was within the desired target level range.; Drug: Cyclosporine low dose (350-500 ng/mL) microemulsion; The dose of cyclosporine for each patient was adjusted to achieve the target cyclosporine blood level. Cyclosporine dose adjustments were based on drug blood level determined from whole blood samples taken 2 hours (± 10 min) after the morning dose.; Other Names: Neoral

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Biopsy-proven Acute Rejection [Baseline to end of study (Month 24)]

   A graft core biopsy was performed on all suspected acute rejection episodes within 48 hours. Biopsies were read by the local pathologist according to the 1997 Banff criteria. A biopsy-proven acute rejection was be defined as a biopsy graded IA, IB, IIA, IIB, or III.

2. Renal Function Assessed by Creatinine Clearance [Month 12, Month 18, and Month 24]

   Renal function was assessed by measuring serum creatinine and by computing creatinine clearance using the formula of Cockcroft-Gault.

Secondary Outcome Measures

1. Number of Participants Who Died, Number of Participants Who Lost Their Graft, and Number of Participants Who Died or Lost Their Graft [Baseline to end of study (Month 24)]

   A participant lost his graft if he/she started dialysis and was not able to subsequently be removed from dialysis or underwent graft nephrectomy.

2. Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths [Baseline to end of study (Month 24)]

   Safety was assessed using reports of adverse events of all participants in this study. Serious adverse events are those events that resulted in death, were life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly/birth defect.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients with functioning graft who had completed the 6-month treatment period of core study

• Patients who were receiving treatment with either everolimus and cyclosporin at the end of the core study

• Patients who signed the informed consent of the present study extension

Exclusion Criteria:

• Women who were pregnant, lactating or who wished to became pregnant.

Other protocol-defined inclusion/exclusion criteria applied to the study.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT01276457
• Other Study ID Numbers: CRAD001AIT02E1
• First Posted: Jan 13, 2011
• Last Update Posted: May 20, 2011
• Last Verified: May 1, 2011

• Keywords provided by , ,: immunosuppression; kidney transplantation; everolimus; safety
• Additional relevant MeSH terms: Cyclosporine; Everolimus; Cyclosporins

Study Results

Participant Flow

Recruitment Details	This study was an 18-month extension to the 6-month core study NCT01276457. All patients who were receiving treatment at the end of the core study and signed the informed consent of the extension study were included. Patients received the same treatment in the extension study that they received in the core study.

Arm/Group Title	Upper Everolimus Blood Target + Very Low Dose Cyclosporine	Standard Everolimus Blood Target + Low Dose Cyclosporine
Arm/Group Description	Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 8-12 ng/mL. Patients also received a very low dose of cyclosporine (150-300 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 200 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.	Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 3-8 ng/mL. Patients also received a low dose of cyclosporine (350-500 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 400 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.
Period Title: Core Study
STARTED	142	143
COMPLETED	129	123
NOT COMPLETED	13	20
Period Title: Core Study
STARTED	111	112
COMPLETED	105	110
NOT COMPLETED	6	2

Baseline Characteristics

Arm/Group Title	Upper Everolimus Blood Target + Very Low Dose Cyclosporine	Standard Everolimus Blood Target + Low Dose Cyclosporine	Total
Arm/Group Description	Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 8-12 ng/mL. Patients also received a very low dose of cyclosporine (150-300 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 200 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.	Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 3-8 ng/mL. Patients also received a low dose of cyclosporine (350-500 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 400 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.	Total of all reporting groups
Overall Participants	111	112	223
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	45.3 (12.2)	45.7 (10.2)	45.5 (11.2)
Sex: Female, Male (Count of Participants)
Female	40 36%	37 33%	77 34.5%
Male	71 64%	75 67%	146 65.5%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Biopsy-proven Acute Rejection
Description	A graft core biopsy was performed on all suspected acute rejection episodes within 48 hours. Biopsies were read by the local pathologist according to the 1997 Banff criteria. A biopsy-proven acute rejection was be defined as a biopsy graded IA, IB, IIA, IIB, or III.
Time Frame	Baseline to end of study (Month 24)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All randomized subjects for whom at least one valid post-baseline efficacy measurement was obtained and used for efficacy analyses.

Arm/Group Title	Upper Everolimus Blood Target + Very Low Dose Cyclosporine	Standard Everolimus Blood Target + Low Dose Cyclosporine
Arm/Group Description	Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 8-12 ng/mL. Patients also received a very low dose of cyclosporine (150-300 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 200 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.	Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 3-8 ng/mL. Patients also received a low dose of cyclosporine (350-500 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 400 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.
Measure Participants	142	143
Number [Participants]	21 18.9%	21 18.8%

2. Primary Outcome

Title	Renal Function Assessed by Creatinine Clearance
Description	Renal function was assessed by measuring serum creatinine and by computing creatinine clearance using the formula of Cockcroft-Gault.
Time Frame	Month 12, Month 18, and Month 24

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All randomized subjects for whom at least one valid post-baseline efficacy measurement was obtained and used for efficacy analyses.

Arm/Group Title	Upper Everolimus Blood Target + Very Low Dose Cyclosporine	Standard Everolimus Blood Target + Low Dose Cyclosporine
Arm/Group Description	Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 8-12 ng/mL. Patients also received a very low dose of cyclosporine (150-300 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 200 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.	Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 3-8 ng/mL. Patients also received a low dose of cyclosporine (350-500 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 400 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.
Measure Participants	111	111
Month 12 (n=111, 111)	61.26 (22.06)	62.50 (20.70)
Month 18 (n=108, 108)	60.90 (22.85)	62.80 (21.18)
Month 24 (n=106, 110)	61.92 (25.37)	63.76 (21.71)

3. Secondary Outcome

Title	Number of Participants Who Died, Number of Participants Who Lost Their Graft, and Number of Participants Who Died or Lost Their Graft
Description	A participant lost his graft if he/she started dialysis and was not able to subsequently be removed from dialysis or underwent graft nephrectomy.
Time Frame	Baseline to end of study (Month 24)

Outcome Measure Data

Analysis Population Description

Safety population: All randomized subjects who took at least one dose of study drug.

Arm/Group Title	Upper Everolimus Blood Target + Very Low Dose Cyclosporine	Standard Everolimus Blood Target + Low Dose Cyclosporine
Arm/Group Description	Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 8-12 ng/mL. Patients also received a very low dose of cyclosporine (150-300 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 200 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.	Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 3-8 ng/mL. Patients also received a low dose of cyclosporine (350-500 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 400 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.
Measure Participants	142	143
Died	2 1.8%	3 2.7%
Lost graft	6 5.4%	15 13.4%
Died or lost graft	8 7.2%	18 16.1%

4. Secondary Outcome

Title	Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths
Description	Safety was assessed using reports of adverse events of all participants in this study. Serious adverse events are those events that resulted in death, were life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly/birth defect.
Time Frame	Baseline to end of study (Month 24)

Outcome Measure Data

Analysis Population Description

Safety population: All randomized subjects who took at least one dose of study drug.

Arm/Group Title	Upper Everolimus Blood Target + Very Low Dose Cyclosporine	Standard Everolimus Blood Target + Low Dose Cyclosporine
Arm/Group Description	Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 8-12 ng/mL. Patients also received a very low dose of cyclosporine (150-300 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 200 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.	Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 3-8 ng/mL. Patients also received a low dose of cyclosporine (350-500 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 400 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.
Measure Participants	142	143
AEs	142	143
Infection	95	101
Clinically significant AEs	58	53
SAEs	85	90
Died	2	3

Adverse Events

Time Frame	24 months
Adverse Event Reporting Description	Population includes all the enrolled patients in the overall core and extension study.
Arm/Group Title	Upper Everolimus Blood Target + Very Low Dose Cyclosporine		Standard Everolimus Blood Target + Low Dose Cyclosporine
Arm/Group Description	Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 8-12 ng/mL. Patients also received a very low dose of cyclosporine (150-300 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 200 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.		Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 3-8 ng/mL. Patients also received a low dose of cyclosporine (350-500 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 400 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study.
All Cause Mortality
	Upper Everolimus Blood Target + Very Low Dose Cyclosporine		Standard Everolimus Blood Target + Low Dose Cyclosporine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Upper Everolimus Blood Target + Very Low Dose Cyclosporine		Standard Everolimus Blood Target + Low Dose Cyclosporine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	85/142 (59.9%)		90/143 (62.9%)
Blood and lymphatic system disorders
Anaemia	3/142 (2.1%)		5/143 (3.5%)
Bone marrow toxicity	1/142 (0.7%)		0/143 (0%)
Haemolytic uraemic syndrome	0/142 (0%)		1/143 (0.7%)
Leukopenia	1/142 (0.7%)		2/143 (1.4%)
Cardiac disorders
Acute myocardial infarction	0/142 (0%)		2/143 (1.4%)
Arrhythmia	1/142 (0.7%)		0/143 (0%)
Atrial fibrillation	0/142 (0%)		1/143 (0.7%)
Atrioventricular block	0/142 (0%)		1/143 (0.7%)
Cardiac arrest	2/142 (1.4%)		0/143 (0%)
Cardiac failure congestive	1/142 (0.7%)		0/143 (0%)
Cardiomyopathy	0/142 (0%)		1/143 (0.7%)
Cardiovascular disorder	1/142 (0.7%)		0/143 (0%)
Coronary artery stenosis	0/142 (0%)		1/143 (0.7%)
Myocardial infarction	1/142 (0.7%)		1/143 (0.7%)
Ventricular tachycardia	1/142 (0.7%)		0/143 (0%)
Congenital, familial and genetic disorders
Hydrocele	0/142 (0%)		1/143 (0.7%)
Pulmonary arteriovenous fistula	0/142 (0%)		1/143 (0.7%)
Eye disorders
Orbital oedema	0/142 (0%)		1/143 (0.7%)
Gastrointestinal disorders
Abdominal compartment syndrome	0/142 (0%)		1/143 (0.7%)
Abdominal hernia	4/142 (2.8%)		2/143 (1.4%)
Abdominal pain	0/142 (0%)		3/143 (2.1%)
Aphthous stomatitis	1/142 (0.7%)		0/143 (0%)
Ascites	0/142 (0%)		2/143 (1.4%)
Diarrhoea	1/142 (0.7%)		2/143 (1.4%)
Enterovesical fistula	1/142 (0.7%)		0/143 (0%)
Gastrointestinal disorder	1/142 (0.7%)		0/143 (0%)
Inguinal hernia	2/142 (1.4%)		0/143 (0%)
Intestinal obstruction	1/142 (0.7%)		2/143 (1.4%)
Intestinal perforation	0/142 (0%)		2/143 (1.4%)
Malabsorption	1/142 (0.7%)		0/143 (0%)
Pancreatitis	2/142 (1.4%)		0/143 (0%)
Rectal haemorrhage	1/142 (0.7%)		0/143 (0%)
Stomatitis	1/142 (0.7%)		0/143 (0%)
Subileus	0/142 (0%)		1/143 (0.7%)
Umbilical hernia	1/142 (0.7%)		0/143 (0%)
Vomiting	0/142 (0%)		1/143 (0.7%)
General disorders
Implant site effusion	1/142 (0.7%)		0/143 (0%)
Inflammation	0/142 (0%)		1/143 (0.7%)
Mucosal inflammation	1/142 (0.7%)		0/143 (0%)
Oedema peripheral	0/142 (0%)		2/143 (1.4%)
Pain	0/142 (0%)		1/143 (0.7%)
Pyrexia	13/142 (9.2%)		17/143 (11.9%)
Sudden death	0/142 (0%)		1/143 (0.7%)
Hepatobiliary disorders
Cholecystitis	1/142 (0.7%)		0/143 (0%)
Portal hypertension	0/142 (0%)		1/143 (0.7%)
Immune system disorders
Kidney transplant rejection	11/142 (7.7%)		9/143 (6.3%)
Transplant rejection	7/142 (4.9%)		12/143 (8.4%)
Infections and infestations
Abdominal abscess	1/142 (0.7%)		0/143 (0%)
Bronchitis acute	1/142 (0.7%)		1/143 (0.7%)
Bronchopneumonia	1/142 (0.7%)		1/143 (0.7%)
Bronchopulmonary aspergillosis	0/142 (0%)		1/143 (0.7%)
Cytomegalovirus infection	3/142 (2.1%)		3/143 (2.1%)
Ear infection	1/142 (0.7%)		0/143 (0%)
Gastroenteritis	1/142 (0.7%)		2/143 (1.4%)
Gastroenteritis bacterial	0/142 (0%)		1/143 (0.7%)
Herpes zoster	1/142 (0.7%)		0/143 (0%)
Infected lymphocele	1/142 (0.7%)		1/143 (0.7%)
Omphalitis	1/142 (0.7%)		0/143 (0%)
Pneumocystis jiroveci pneumonia	1/142 (0.7%)		0/143 (0%)
Pneumonia	3/142 (2.1%)		4/143 (2.8%)
Pulmonary tuberculosis	1/142 (0.7%)		0/143 (0%)
Pyelonephritis	0/142 (0%)		1/143 (0.7%)
Pyelonephritis acute	2/142 (1.4%)		1/143 (0.7%)
Relapsing fever	0/142 (0%)		1/143 (0.7%)
Respiratory tract infection	0/142 (0%)		1/143 (0.7%)
Sepsis	1/142 (0.7%)		0/143 (0%)
Subcutaneous abscess	0/142 (0%)		1/143 (0.7%)
Tonsillitis	0/142 (0%)		1/143 (0.7%)
Urinary tract infection	7/142 (4.9%)		4/143 (2.8%)
Urosepsis	2/142 (1.4%)		0/143 (0%)
Viral infection	0/142 (0%)		2/143 (1.4%)
Wound infection	1/142 (0.7%)		0/143 (0%)
Injury, poisoning and procedural complications
Arterial injury	1/142 (0.7%)		0/143 (0%)
Chronic allograft nephropathy	3/142 (2.1%)		0/143 (0%)
Complications of transplanted kidney	0/142 (0%)		5/143 (3.5%)
Drug toxicity	2/142 (1.4%)		1/143 (0.7%)
Graft dysfunction	0/142 (0%)		2/143 (1.4%)
Injury	1/142 (0.7%)		0/143 (0%)
Kidney rupture	2/142 (1.4%)		1/143 (0.7%)
Perinephric collection	1/142 (0.7%)		0/143 (0%)
Perirenal haematoma	0/142 (0%)		1/143 (0.7%)
Therapeutic agent toxicity	1/142 (0.7%)		2/143 (1.4%)
Investigations
Arterial bruit	1/142 (0.7%)		0/143 (0%)
Biopsy endometrium	0/142 (0%)		1/143 (0.7%)
Blood creatine increased	2/142 (1.4%)		0/143 (0%)
Blood creatinine increased	13/142 (9.2%)		7/143 (4.9%)
Blood culture positive	1/142 (0.7%)		0/143 (0%)
Blood pressure decreased	1/142 (0.7%)		0/143 (0%)
Blood urea increased	0/142 (0%)		1/143 (0.7%)
Creatine urine increased	1/142 (0.7%)		0/143 (0%)
Cytomegalovirus test	0/142 (0%)		1/143 (0.7%)
Legionella serology	0/142 (0%)		1/143 (0.7%)
Transaminases increased	1/142 (0.7%)		0/143 (0%)
Metabolism and nutrition disorders
Dehydration	1/142 (0.7%)		1/143 (0.7%)
Diabetes mellitus	2/142 (1.4%)		0/143 (0%)
Hyperglycaemia	1/142 (0.7%)		0/143 (0%)
Hyperlipidaemia	1/142 (0.7%)		0/143 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/142 (0.7%)		0/143 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/142 (0.7%)		0/143 (0%)
Epithelioma	0/142 (0%)		1/143 (0.7%)
Liposarcoma	1/142 (0.7%)		0/143 (0%)
Psychiatric disorders
Depression	0/142 (0%)		1/143 (0.7%)
Mental disorder	1/142 (0.7%)		0/143 (0%)
Renal and urinary disorders
Anuria	2/142 (1.4%)		1/143 (0.7%)
Calculus bladder	0/142 (0%)		1/143 (0.7%)
Diffuse mesangial sclerosis	1/142 (0.7%)		0/143 (0%)
Dysuria	0/142 (0%)		1/143 (0.7%)
Focal glomerulosclerosis	1/142 (0.7%)		1/143 (0.7%)
Haematuria	2/142 (1.4%)		2/143 (1.4%)
Hydronephrosis	1/142 (0.7%)		2/143 (1.4%)
Nephritis interstitial	1/142 (0.7%)		0/143 (0%)
Nephropathy	1/142 (0.7%)		0/143 (0%)
Nephropathy toxic	1/142 (0.7%)		2/143 (1.4%)
Proteinuria	2/142 (1.4%)		2/143 (1.4%)
Renal artery stenosis	1/142 (0.7%)		4/143 (2.8%)
Renal failure acute	4/142 (2.8%)		1/143 (0.7%)
Renal impairment	3/142 (2.1%)		6/143 (4.2%)
Renal tubular necrosis	1/142 (0.7%)		1/143 (0.7%)
Ureteral disorder	0/142 (0%)		1/143 (0.7%)
Ureteric stenosis	2/142 (1.4%)		3/143 (2.1%)
Urinary retention	1/142 (0.7%)		0/143 (0%)
Urinary tract disorder	0/142 (0%)		1/143 (0.7%)
Urogenital fistula	1/142 (0.7%)		0/143 (0%)
Vesicoureteric reflux	1/142 (0.7%)		0/143 (0%)
Reproductive system and breast disorders
Metrorrhagia	2/142 (1.4%)		1/143 (0.7%)
Ovarian cyst	1/142 (0.7%)		2/143 (1.4%)
Ovarian cyst torsion	0/142 (0%)		1/143 (0.7%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/142 (0.7%)		0/143 (0%)
Haemoptysis	0/142 (0%)		1/143 (0.7%)
Interstitial lung disease	0/142 (0%)		3/143 (2.1%)
Pneumonitis	2/142 (1.4%)		5/143 (3.5%)
Pulmonary oedema	1/142 (0.7%)		1/143 (0.7%)
Respiratory failure	0/142 (0%)		1/143 (0.7%)
Surgical and medical procedures
Cholecystectomy	0/142 (0%)		1/143 (0.7%)
Inguinal hernia repair	1/142 (0.7%)		0/143 (0%)
Lymphocele marsupialisation	0/142 (0%)		1/143 (0.7%)
Nephrectomy	0/142 (0%)		1/143 (0.7%)
Nephrostomy	0/142 (0%)		1/143 (0.7%)
Parathyroidectomy	1/142 (0.7%)		0/143 (0%)
Removal of ambulatory peritoneal catheter	0/142 (0%)		1/143 (0.7%)
Stent removal	0/142 (0%)		1/143 (0.7%)
Ureteric repair	0/142 (0%)		1/143 (0.7%)
Vascular disorders
Aneurysm	0/142 (0%)		4/143 (2.8%)
Arteriovenous fistula	0/142 (0%)		1/143 (0.7%)
Deep vein thrombosis	4/142 (2.8%)		3/143 (2.1%)
Haemorrhage	0/142 (0%)		1/143 (0.7%)
Hypertensive crisis	2/142 (1.4%)		2/143 (1.4%)
Hypotension	1/142 (0.7%)		1/143 (0.7%)
Lymphocele	12/142 (8.5%)		5/143 (3.5%)
Lymphorrhoea	1/142 (0.7%)		0/143 (0%)
Thrombosis	1/142 (0.7%)		0/143 (0%)
Venous thrombosis limb	1/142 (0.7%)		0/143 (0%)
Other (Not Including Serious) Adverse Events
	Upper Everolimus Blood Target + Very Low Dose Cyclosporine		Standard Everolimus Blood Target + Low Dose Cyclosporine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	142/142 (100%)		142/143 (99.3%)
Blood and lymphatic system disorders
Anaemia	82/142 (57.7%)		73/143 (51%)
Leukopenia	13/142 (9.2%)		13/143 (9.1%)
Thrombocytopenia	8/142 (5.6%)		7/143 (4.9%)
Cardiac disorders
Tachycardia	9/142 (6.3%)		3/143 (2.1%)
Gastrointestinal disorders
Constipation	18/142 (12.7%)		11/143 (7.7%)
Diarrhoea	18/142 (12.7%)		18/143 (12.6%)
General disorders
Oedema peripheral	37/142 (26.1%)		36/143 (25.2%)
Pyrexia	32/142 (22.5%)		40/143 (28%)
Immune system disorders
Kidney transplant rejection	3/142 (2.1%)		10/143 (7%)
Infections and infestations
Cytomegalovirus infection	5/142 (3.5%)		13/143 (9.1%)
Urinary tract infection	69/142 (48.6%)		81/143 (56.6%)
Injury, poisoning and procedural complications
Complications of transplanted kidney	23/142 (16.2%)		31/143 (21.7%)
Investigations
Blood creatinine increased	17/142 (12%)		12/143 (8.4%)
Transaminases increased	12/142 (8.5%)		9/143 (6.3%)
Weight increased	9/142 (6.3%)		9/143 (6.3%)
Metabolism and nutrition disorders
Acidosis	11/142 (7.7%)		7/143 (4.9%)
Diabetes mellitus	12/142 (8.5%)		7/143 (4.9%)
Dyslipidaemia	66/142 (46.5%)		55/143 (38.5%)
Fluid retention	13/142 (9.2%)		8/143 (5.6%)
Hypercholesterolaemia	23/142 (16.2%)		24/143 (16.8%)
Hyperglycaemia	15/142 (10.6%)		11/143 (7.7%)
Hyperkalaemia	7/142 (4.9%)		9/143 (6.3%)
Hyperlipidaemia	27/142 (19%)		26/143 (18.2%)
Hypertriglyceridaemia	21/142 (14.8%)		17/143 (11.9%)
Hyperuricaemia	30/142 (21.1%)		30/143 (21%)
Hypocalcaemia	33/142 (23.2%)		19/143 (13.3%)
Hypokalaemia	23/142 (16.2%)		31/143 (21.7%)
Iron deficiency	2/142 (1.4%)		8/143 (5.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	12/142 (8.5%)		4/143 (2.8%)
Psychiatric disorders
Anxiety	5/142 (3.5%)		8/143 (5.6%)
Renal and urinary disorders
Proteinuria	18/142 (12.7%)		12/143 (8.4%)
Renal tubular necrosis	12/142 (8.5%)		10/143 (7%)
Reproductive system and breast disorders
Ovarian cyst	9/142 (6.3%)		4/143 (2.8%)
Vascular disorders
Hypertension	32/142 (22.5%)		29/143 (20.3%)
Lymphocele	21/142 (14.8%)		19/143 (13.3%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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 (i.e., data from all sites) in the clinical trial.