Efficacy and Safety of Everolimus With Enteric-Coated Mycophenolate Sodium (EC-MPS) in a Cyclosporine Microemulsion-free Regimen Compared to Standard Therapy in de Novo Renal Transplant Patients - Study Results

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Open Label; Primary Purpose: Treatment
Condition:	Renal Transplantation
Interventions:	Drug: Everolimus Drug: Cyclosporine Drug: Enteric-coated mycophenolate sodium Drug: Corticosteroids

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study was an open-label, randomized, parallel-group, multi-center study with two treatment groups, cyclosporine continuation and cyclosporine withdrawal starting from Month 4.5 post-transplant. Study started in June 2005 and ended in September 2008.

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

Description

Everolimus + Mycophenolate Sodium

Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5 mg prednisolone or equivalent and had to be continued throughout the first year. Cyclosporine withdrawal started from Month 4.5 post-transplant.

Cyclosporine + Mycophenolate Sodium

Cyclosporine tablets orally twice a day to achieve protocol specific target levels and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.

Participant Flow: Overall Study

	Everolimus + Mycophenolate Sodium	Cyclosporine + Mycophenolate Sodium
STARTED	155 ^[1]	145
COMPLETED	118	117
NOT COMPLETED	37	28
Adverse Event	19	9
Lack of Efficacy	5	4
Protocol Violation	4	2
Withdrawal by Subject	9	3
Lost to Follow-up	0	8
Administrative problems	0	1
Death	0	1

[1]	"Started" indicates enrolled participants. Randomized participants for two arms are 154 and 146.

Baseline Characteristics

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Reporting Groups

	Description
Everolimus + Mycophenolate Sodium	Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5 mg prednisolone or equivalent and had to be continued throughout the first year. Cyclosporine withdrawal started from Month 4.5 post-transplant.
Cyclosporine + Mycophenolate Sodium	Cyclosporine tablets orally twice a day to achieve protocol specific target levels and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.
Total	Total of all reporting groups

Baseline Measures

	Everolimus + Mycophenolate Sodium	Cyclosporine + Mycophenolate Sodium	Total
Number of Participants [units: participants]	155	145	300
Age [units: Years] Mean ± Standard Deviation	46.9 ± 11.67	46.7 ± 11.85	46.8 ± 11.73
Gender [units: participants]
Female	53	59	112
Male	102	86	188

Outcome Measures

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1. Primary:

Renal Function (Nankivell Formula) at Month 12 Post Transplantation. [ Time Frame: at Month 12 post transplantation ]

Measure Type	Primary
Measure Title	Renal Function (Nankivell Formula) at Month 12 Post Transplantation.
Measure Description	Renal function at the end of the trial assessed as mean absolute values of the glomerular filtration rate (GFR) calculated by Nankivell formula 12 months after renal transplantation. The Nankivell formula: GFR = 6.7 / Scr + BW / 4 – Surea / 2-100 / (height)^2 + C ; where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kg, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients. The estimated GFR is expressed in mL/min per 1.73m^2.
Time Frame	at Month 12 post transplantation
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to Treat Population (randomized patients); Last Observation Carried Forward (LOCF). One patient in "cyclosporine" arm was not included in this analysis.

Reporting Groups

Description

Everolimus + Mycophenolate Sodium

Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5 mg prednisolone or equivalent and had to be continued throughout the first year. Cyclosporine withdrawal started from Month 4.5 post-transplant.

Cyclosporine + Mycophenolate Sodium

Cyclosporine tablets orally twice a day to achieve protocol specific target levels and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.

Measured Values

	Everolimus + Mycophenolate Sodium	Cyclosporine + Mycophenolate Sodium
Number of Participants Analyzed [units: participants]	154	145
Renal Function (Nankivell Formula) at Month 12 Post Transplantation. [units: mL/min /1.73m^2] Mean ± Standard Deviation	71.84 ± 18.53	61.24 ± 16.65

No statistical analysis provided for Renal Function (Nankivell Formula) at Month 12 Post Transplantation.

2. Secondary:

Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death [ Time Frame: Up to Month 12 ]

Measure Type	Secondary
Measure Title	Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death
Measure Description	The number of participants with occurrence of biopsy proven acute rejection (BPAR), graft loss, or death up to Month 12 during the randomized treatment period. BPAR was defined as a biopsy graded IA, IB, IIA, IIB or III according to Banff 97 classification. A graft core biopsy was performed prior to 24 hours following initiation of graft rejection therapy. The allograft is presumed to be lost on the day the patient starts dialysis and was not able to subsequently be removed from dialysis. If the patient underwent a graft nephrectomy, then the day of nephrectomy was the day of graft loss.
Time Frame	Up to Month 12
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intent to Treat Population (Randomized Patients)

Reporting Groups

Description

Everolimus + Mycophenolate Sodium

Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5 mg prednisolone or equivalent and had to be continued throughout the first year. Cyclosporine withdrawal started from Month 4.5 post-transplant.

Cyclosporine + Mycophenolate Sodium

Cyclosporine tablets orally twice a day to achieve protocol specific target levels and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.

Measured Values

	Everolimus + Mycophenolate Sodium	Cyclosporine + Mycophenolate Sodium
Number of Participants Analyzed [units: participants]	154	146
Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death [units: Participants]
BPAR: Yes	15	5
BPAR: No	139	141
Graft Loss: Yes	0	0
Graft Loss: No	154	146
Death: Yes	0	1
Death: No	154	145

No statistical analysis provided for Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death

3. Secondary:

Number of Participants With Occurrence of Treatment Failures [ Time Frame: up to or at Month 12 ]

Measure Type	Secondary
Measure Title	Number of Participants With Occurrence of Treatment Failures
Measure Description	Treatment failures defined as a composite endpoint of biopsy proven acute rejection, graft loss, death, loss to follow up and discontinuations due to lack of efficacy or toxicity, or conversion to another regimen (at least one condition must be present).
Time Frame	up to or at Month 12
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Intention to treat (ITT) population (Randomized Patients).

Reporting Groups

Description

Everolimus + Mycophenolate Sodium

Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5 mg prednisolone or equivalent and had to be continued throughout the first year. Cyclosporine withdrawal started from Month 4.5 post-transplant.

Cyclosporine + Mycophenolate Sodium

Cyclosporine tablets orally twice a day to achieve protocol specific target levels and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.

Measured Values

	Everolimus + Mycophenolate Sodium	Cyclosporine + Mycophenolate Sodium
Number of Participants Analyzed [units: participants]	154	146
Number of Participants With Occurrence of Treatment Failures [units: Participants]
Treatment failure: Yes	29	23
Treatment failure: No	125	123

No statistical analysis provided for Number of Participants With Occurrence of Treatment Failures

4. Secondary:

Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12 [ Time Frame: Month 4.5 and Month 12 ]

Measure Type	Secondary
Measure Title	Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12
Measure Description	An updated 1991 Framingham coronary prediction algorithm was used to estimate the total risk of developing coronary heart diseases (CHD) over the course of 10 years. Risk was calculated separately for male and females. To calculate risk, points were assigned for each of the following risk factors: age, levels of LDL cholesterol, HDL cholesterol, blood pressure, cigarette smoking, and diabetes mellitus. The sum of the individual risk factor points gives a total point score, which ranges from -5 to 18 for men and -16 to 24 for women. Higher points indicate a higher risk for CHD.
Time Frame	Month 4.5 and Month 12
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population for whom data was available at Month 4.5 and end of treatment.

Reporting Groups

Description

Everolimus + Mycophenolate Sodium

Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5 mg prednisolone or equivalent and had to be continued throughout the first year. Cyclosporine withdrawal started from Month 4.5 post-transplant.

Cyclosporine + Mycophenolate Sodium

Cyclosporine tablets orally twice a day to achieve protocol specific target levels and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.

Measured Values

	Everolimus + Mycophenolate Sodium	Cyclosporine + Mycophenolate Sodium
Number of Participants Analyzed [units: participants]	155	145
Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12 [units: Points] Mean ± Standard Deviation
Male (n= 55, 37)	0.5 ± 1.87	0.1 ± 1.86
Female (n= 22, 35)	0.0 ± 2.01	0.8 ± 2.70
Total Population (n= 77, 72)	0.4 ± 1.91	0.4 ± 2.32

No statistical analysis provided for Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12

5. Secondary:

Number of Participants Who Experienced an Adverse Event or Serious Adverse Event [ Time Frame: Up to 12 months ]

Measure Type	Secondary
Measure Title	Number of Participants Who Experienced an Adverse Event or Serious Adverse Event
Measure Description	Additional information about the number of participants who experienced Adverse Events (greater than 5%) or Serious Adverse Events can be found in the Adverse Event section.
Time Frame	Up to 12 months
Safety Issue	Yes

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Safety Population consisted of all participants in whom transplantation was performed and who were treated with at least one dose of any immunosuppressive medication.

Reporting Groups

Description

Everolimus + Mycophenolate Sodium

Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5 mg prednisolone or equivalent and had to be continued throughout the first year. Cyclosporine withdrawal started from Month 4.5 post-transplant.

Cyclosporine + Mycophenolate Sodium

Cyclosporine tablets orally twice a day to achieve protocol specific target levels and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.

Measured Values

	Everolimus + Mycophenolate Sodium	Cyclosporine + Mycophenolate Sodium
Number of Participants Analyzed [units: participants]	155	145
Number of Participants Who Experienced an Adverse Event or Serious Adverse Event [units: Participants]
Adverse Events	155	145
Serious Adverse Events	95	86

No statistical analysis provided for Number of Participants Who Experienced an Adverse Event or Serious Adverse Event

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: 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.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Study Director
Organization: Novartis Pharmaceuticals
phone: 862-778-8300

No publications provided by Novartis

Publications automatically indexed to this study:

Budde K, Becker T, Arns W, Sommerer C, Reinke P, Eisenberger U, Kramer S, Fischer W, Gschaidmeier H, Pietruck F; ZEUS Study Investigators. Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet. 2011 Mar 5;377(9768):837-47. Epub 2011 Feb 19.

Responsible Party:	novartis
ClinicalTrials.gov Identifier:	NCT00154310 History of Changes
Other Study ID Numbers:	CRAD001A2418
Study First Received:	September 8, 2005
Results First Received:	January 11, 2011
Last Updated:	June 24, 2011
Health Authority:	Germany: Federal Institute for Drugs and Medical Devices