Trial Outcomes & Findings for Everolimus in Combination With Cyclosporine Microemulsion in de Novo Renal Transplant Recipients (NCT NCT01276457)

Last Updated: 2011-05-20

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

223 participants

Primary outcome timeframe

Baseline to end of study (Month 24)

Results posted on

2011-05-20

Participant Flow

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.

Participant milestones

Participant milestones
Measure	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.	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.
Core Study STARTED	142	143
Core Study COMPLETED	129	123
Core Study NOT COMPLETED	13	20
Extension Study STARTED	111	112
Extension Study COMPLETED	105	110
Extension Study NOT COMPLETED	6	2

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Core Study Adverse Event	6	3
Core Study Lost to Follow-up	1	2
Core Study Administrative problems	1	1
Core Study Death	2	2
Core Study Lack of Efficacy	3	12
Extension Study Lost to Follow-up	3	0
Extension Study Death	0	1
Extension Study Lack of Efficacy	3	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Upper Everolimus Blood Target + Very Low Dose Cyclosporine n=111 Participants 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.	Standard Everolimus Blood Target + Low Dose Cyclosporine n=112 Participants 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 n=223 Participants Total of all reporting groups
Age Continuous	45.3 Years STANDARD_DEVIATION 12.2 • n=5 Participants	45.7 Years STANDARD_DEVIATION 10.2 • n=7 Participants	45.5 Years STANDARD_DEVIATION 11.2 • n=5 Participants
Sex: Female, Male Female	40 Participants n=5 Participants	37 Participants n=7 Participants	77 Participants n=5 Participants
Sex: Female, Male Male	71 Participants n=5 Participants	75 Participants n=7 Participants	146 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline to end of study (Month 24)

Population: 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.

Outcome measures

Outcome measures
Measure	Upper Everolimus Blood Target + Very Low Dose Cyclosporine n=142 Participants 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.	Standard Everolimus Blood Target + Low Dose Cyclosporine n=143 Participants 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.
Number of Participants With Biopsy-proven Acute Rejection	21 Participants	21 Participants

PRIMARY outcome

Timeframe: Month 12, Month 18, and Month 24

Population: 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.

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

Outcome measures

Outcome measures
Measure	Upper Everolimus Blood Target + Very Low Dose Cyclosporine n=111 Participants 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.	Standard Everolimus Blood Target + Low Dose Cyclosporine n=111 Participants 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.
Renal Function Assessed by Creatinine Clearance Month 12 (n=111, 111)	61.26 mL/min Standard Deviation 22.06	62.50 mL/min Standard Deviation 20.70
Renal Function Assessed by Creatinine Clearance Month 18 (n=108, 108)	60.90 mL/min Standard Deviation 22.85	62.80 mL/min Standard Deviation 21.18
Renal Function Assessed by Creatinine Clearance Month 24 (n=106, 110)	61.92 mL/min Standard Deviation 25.37	63.76 mL/min Standard Deviation 21.71

SECONDARY outcome

Timeframe: Baseline to end of study (Month 24)

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

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

Outcome measures

Outcome measures
Measure	Upper Everolimus Blood Target + Very Low Dose Cyclosporine n=142 Participants 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.	Standard Everolimus Blood Target + Low Dose Cyclosporine n=143 Participants 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.
Number of Participants Who Died, Number of Participants Who Lost Their Graft, and Number of Participants Who Died or Lost Their Graft Died	2 Participants	3 Participants
Number of Participants Who Died, Number of Participants Who Lost Their Graft, and Number of Participants Who Died or Lost Their Graft Lost graft	6 Participants	15 Participants
Number of Participants Who Died, Number of Participants Who Lost Their Graft, and Number of Participants Who Died or Lost Their Graft Died or lost graft	8 Participants	18 Participants

SECONDARY outcome

Timeframe: Baseline to end of study (Month 24)

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

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.

Outcome measures

Outcome measures
Measure	Upper Everolimus Blood Target + Very Low Dose Cyclosporine n=142 Participants 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.	Standard Everolimus Blood Target + Low Dose Cyclosporine n=143 Participants 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.
Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths AEs	142 Partcipants	143 Partcipants
Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths Infection	95 Partcipants	101 Partcipants
Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths Clinically significant AEs	58 Partcipants	53 Partcipants
Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths SAEs	85 Partcipants	90 Partcipants
Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths Died	2 Partcipants	3 Partcipants

Adverse Events

Upper Everolimus Blood Target + Very Low Dose Cyclosporine

Serious events: 85 serious events

Other events: 142 other events

Deaths: 0 deaths

Standard Everolimus Blood Target + Low Dose Cyclosporine

Serious events: 90 serious events

Other events: 142 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Study director

Novartis Pharmaceuticals

Phone: 862 778-8300

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Upper Everolimus Blood Target + Very Low Dose Cyclosporine n=142 participants at risk 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.	Standard Everolimus Blood Target + Low Dose Cyclosporine n=143 participants at risk 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.
Blood and lymphatic system disorders Anaemia	57.7% 82/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	51.0% 73/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Blood and lymphatic system disorders Leukopenia	9.2% 13/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	9.1% 13/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Blood and lymphatic system disorders Thrombocytopenia	5.6% 8/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	4.9% 7/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Cardiac disorders Tachycardia	6.3% 9/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	2.1% 3/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Gastrointestinal disorders Constipation	12.7% 18/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	7.7% 11/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Gastrointestinal disorders Diarrhoea	12.7% 18/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	12.6% 18/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
General disorders Oedema peripheral	26.1% 37/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	25.2% 36/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
General disorders Pyrexia	22.5% 32/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	28.0% 40/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Immune system disorders Kidney transplant rejection	2.1% 3/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	7.0% 10/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Infections and infestations Cytomegalovirus infection	3.5% 5/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	9.1% 13/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Infections and infestations Urinary tract infection	48.6% 69/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	56.6% 81/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Injury, poisoning and procedural complications Complications of transplanted kidney	16.2% 23/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	21.7% 31/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Investigations Blood creatinine increased	12.0% 17/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	8.4% 12/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Investigations Transaminases increased	8.5% 12/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	6.3% 9/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Investigations Weight increased	6.3% 9/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	6.3% 9/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Metabolism and nutrition disorders Acidosis	7.7% 11/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	4.9% 7/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Metabolism and nutrition disorders Diabetes mellitus	8.5% 12/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	4.9% 7/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Metabolism and nutrition disorders Dyslipidaemia	46.5% 66/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	38.5% 55/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Metabolism and nutrition disorders Fluid retention	9.2% 13/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	5.6% 8/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Metabolism and nutrition disorders Hypercholesterolaemia	16.2% 23/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	16.8% 24/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Metabolism and nutrition disorders Hyperglycaemia	10.6% 15/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	7.7% 11/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Metabolism and nutrition disorders Hyperkalaemia	4.9% 7/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	6.3% 9/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Metabolism and nutrition disorders Hyperlipidaemia	19.0% 27/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	18.2% 26/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Metabolism and nutrition disorders Hypertriglyceridaemia	14.8% 21/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	11.9% 17/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Metabolism and nutrition disorders Hyperuricaemia	21.1% 30/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	21.0% 30/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Metabolism and nutrition disorders Hypocalcaemia	23.2% 33/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	13.3% 19/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Metabolism and nutrition disorders Hypokalaemia	16.2% 23/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	21.7% 31/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Metabolism and nutrition disorders Iron deficiency	1.4% 2/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	5.6% 8/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Musculoskeletal and connective tissue disorders Arthralgia	8.5% 12/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	2.8% 4/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Psychiatric disorders Anxiety	3.5% 5/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	5.6% 8/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Renal and urinary disorders Proteinuria	12.7% 18/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	8.4% 12/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Renal and urinary disorders Renal tubular necrosis	8.5% 12/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	7.0% 10/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Reproductive system and breast disorders Ovarian cyst	6.3% 9/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	2.8% 4/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Vascular disorders Hypertension	22.5% 32/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	20.3% 29/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.
Vascular disorders Lymphocele	14.8% 21/142 • 24 months Population includes all the enrolled patients in the overall core and extension study.	13.3% 19/143 • 24 months Population includes all the enrolled patients in the overall core and extension study.