A Phase 4 interventional study of Everolimus and Tacrolimus in Liver Transplantation, sponsored by Novartis Pharmaceuticals. Completed at 15 sites in Germany. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2019-05-10.
Sponsored by Novartis Pharmaceuticals · Phase 4, Interventional, and Treatment
This trial evaluated the efficacy and safety of Everolimus in combination with tacrolimus versus a standard immunosuppressive regimen concerning kidney function in liver transplant recipients.
Novartis Pharmaceuticals is the lead sponsor of 2,673 studies on the registry; 228 are open to participants now.
Of its 576 completed or terminated interventional studies of FDA-regulated products, 431 (75%) have results posted.
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Male or female recipients of a full-size liver allograft, aged 18 to 65 years.
Exclusion criteria:
Patients with thrombocytopenia (platelets \<50,000/mm³), with an absolute neutrophil count of \<1,000/mm³ or leucopenia (leucocytes \<2000/mm³), with anemia with Hb \< 6g/dl at time of randomization
Patients with uncontrolled hypercholesterolemia (>350mg/dL; >9mmol/L) or hypertriglyceridemia (>750 mg/dL; >8.5 mmol/L) at time of randomization
History of malignancy of any organ system within the past 5 years whether or not there is evidence of local recurrence or metastases, other than non-metastatic basal or squamous cell carcinoma of the skin or HCC
Tacrolimus minimization arm. Everolimus (C0-h: 3-8 ng/mL) + tacrolimus (C0-h: \< 5 ng/mL)
Drug: Everolimus · Drug: Tacrolimus · Drug: Corticosteroids
Tacrolimus (C0-h: 6-10 ng/ml)
Drug: Tacrolimus · Drug: Corticosteroids
tablet containing 0.25mg, 0.5mg, 0.75mg or 1.0mg
Also known as: RAD001 / Certican
capsule containing 0.5, 1.0, or 5.0mg
Also known as: Tacrolimus Hexal
For patients in all groups, corticosteroids were initiated at or prior to the time of transplantation according to local practice. Corticosteroids may have been used for the duration of the study according to the investigator's discretion, but may not have been eliminated sooner than 6 months post-transplantation.
Estimated Glomerular Filtration Rate (GFR)
The estmated GFR was calculated using MDRD-4 formula (Modification of Diet in Renal Disease Study Group).
Time frame: month 12
Estimated GFR - PP Set
This was a sensitivity analysis for the primary outcome measure based on the per-protocol set of patients.
Time frame: month 12
Percentage of Participants With Treated Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death
Percentage of Participants with Treated Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death at Month 12
Time frame: 12 months
Number of Participants With HCV
Number of Participants with HCV (hepatitis C virus) assessed as treatment emergent adverse events of special interest
Time frame: 12 months
Incidence of HCV Related Fibrosis
Incidence of hepatitis C virus (HCV) related fibrosis assessed as treatment emergent adverse events of special interest
Time frame: 12 months
Incidence of de Novo HCC Malignancies
Incidence of de novo Hepatocellular Carcinoma (HCC) malignancies assessed as treatment emergent adverse events of special interest
Time frame: 12 months
Incidence and Severity of CMV Viral Infections.
Incidence and severity of cytomegalovirus (CMV) viral infections assessed as treatment emergent adverse events of special interest.
Time frame: 12 months
In total, 642 patients were screened for study eligibility at 15 study centers in Germany. 339 patients were randomized out of which 333 received study treatment and were included in the analyses.
| Milestone | Everolimus/Tacrolimus | Tacrolimus |
|---|---|---|
| Started | 171 | 168 |
| Full anylsis set (fas) | 169 | 164 |
| Safety set | 169 | 164 |
| Per protocol set (pp) | 110 | 101 |
| Completed | 166 | 148 |
| Not completed | 5 | 20 |
| Withdrew: Graft loss/retransplantation | 0 | 1 |
| Withdrew: Administrative problems | 1 | 2 |
| Withdrew: Lost to follow-up | 0 | 1 |
| Withdrew: Protocol violation | 0 | 1 |
| Withdrew: Withdrawal by subject | 0 | 7 |
| Withdrew: Death | 2 | 4 |
| Withdrew: Never received study treatment | 2 | 4 |
The estmated GFR was calculated using MDRD-4 formula (Modification of Diet in Renal Disease Study Group).
| mL/min | Everolimus/Tacrolimus | Tacrolimus |
|---|---|---|
| Estimated Glomerular Filtration Rate (GFR) | 73.46 ± 25.57 | 71.95 ± 27.17 |
This was a sensitivity analysis for the primary outcome measure based on the per-protocol set of patients.
| mL/min | Everolimus/Tacrolimus | Tacrolimus |
|---|---|---|
| Estimated GFR - PP Set | 74.83 ± 25.19 | 70.65 ± 24.91 |
Percentage of Participants with Treated Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death at Month 12
| Percent of Patients | Everolimus/Tacrolimus | Tacrolimus |
|---|---|---|
| Percentage of Participants With Treated Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | 9.5 | 7.9 |
Number of Participants with HCV (hepatitis C virus) assessed as treatment emergent adverse events of special interest
| Participants | Everolimus/Tacrolimus | Tacrolimus |
|---|---|---|
| Number of Participants With HCV | 6 | 12 |
Incidence of hepatitis C virus (HCV) related fibrosis assessed as treatment emergent adverse events of special interest
| Participants | Everolimus/Tacrolimus | Tacrolimus |
|---|---|---|
| Incidence of HCV Related Fibrosis | 1 | 0 |
Incidence of de novo Hepatocellular Carcinoma (HCC) malignancies assessed as treatment emergent adverse events of special interest
| Participants | Everolimus/Tacrolimus | Tacrolimus |
|---|---|---|
| Incidence of de Novo HCC Malignancies | 0 | 2 |
Incidence and severity of cytomegalovirus (CMV) viral infections assessed as treatment emergent adverse events of special interest.
| Participants | Everolimus/Tacrolimus | Tacrolimus |
|---|---|---|
| No CMV viral infection | 136 | 129 |
| Asymptomatic | 0 | 5 |
| Mild | 16 | 20 |
| Moderate | 13 | 9 |
| Severe | 4 | 1 |
Collected over Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit up to approximately 12 months. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Everolimus/Tacrolimus | 3/169 (1.8%) | 111/169 (65.7%) | 164/169 (97%) |
| Tacrolimus | 4/164 (2.4%) | 101/164 (61.6%) | 153/164 (93.3%) |
| Event | Everolimus/Tacrolimus | Tacrolimus |
|---|---|---|
| BILIARY ANASTOMOSIS COMPLICATIONInjury, poisoning and procedural complications | 8/169 | 13/164 |
| CHOLANGITISHepatobiliary disorders | 13/169 | 7/164 |
| LIVER TRANSPLANT REJECTIONImmune system disorders | 12/169 | 9/164 |
| INCISIONAL HERNIAInjury, poisoning and procedural complications | 11/169 | 4/164 |
| PNEUMONIAInfections and infestations | 10/169 | 7/164 |
| ACUTE KIDNEY INJURYRenal and urinary disorders | 10/169 | 8/164 |
| HEPATIC ENZYME INCREASEDInvestigations | 6/169 | 7/164 |
| BILE DUCT STENOSISHepatobiliary disorders | 5/169 | 6/164 |
| TRANSAMINASES INCREASEDInvestigations | 2/169 | 6/164 |
| CHOLANGITIS INFECTIVEInfections and infestations | 6/169 | 1/164 |
| Event | Everolimus/Tacrolimus | Tacrolimus |
|---|---|---|
| HEADACHENervous system disorders | 48/169 | 22/164 |
| LEUKOPENIABlood and lymphatic system disorders | 45/169 | 12/164 |
| DIARRHOEAGastrointestinal disorders | 43/169 | 39/164 |
| VIRAL UPPER RESPIRATORY TRACT INFECTIONInfections and infestations | 41/169 | 29/164 |
| OEDEMA PERIPHERALGeneral disorders | 38/169 | 15/164 |
| INCISIONAL HERNIAInjury, poisoning and procedural complications | 35/169 | 10/164 |
| URINARY TRACT INFECTIONInfections and infestations | 30/169 | 24/164 |
| HYPERCHOLESTEROLAEMIAMetabolism and nutrition disorders | 30/169 | 9/164 |
| CYTOMEGALOVIRUS INFECTIONInfections and infestations | 24/169 | 28/164 |
| HYPERTENSIONVascular disorders | 28/169 | 24/164 |
| Age, Continuous(Years) | Everolimus/Tacrolimus | Tacrolimus | Total |
|---|---|---|---|
| Mean | 53.68 ± 9.38 | 53.46 ± 9.64 | 53.57 ± 9.49 |
| Sex: Female, Male(Participants) | Everolimus/Tacrolimus | Tacrolimus | Total |
|---|---|---|---|
| Female | 36 | 43 | 79 |
| Male | 133 | 121 | 254 |
| Race/Ethnicity, Customized(Participants) | Everolimus/Tacrolimus | Tacrolimus | Total |
|---|---|---|---|
| Caucasian | 168 | 157 | 325 |
| Black | 1 | 1 | 2 |
| Asian | 0 | 3 | 3 |
| Other | 0 | 3 | 3 |
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Novartis Pharmaceuticals