NCT01150097

Extension Study to Evaluate the Long-term Efficacy and Safety of Everolimus in Liver Transplant Recipients

Completed Phase 3 Results posted Last updated 7 November 2018

What this trial tests

Phase 3 trial testing Tacrolimus (reduced tacrolimus) in Liver Transplant Recipient in 284 participants. Completed in 3 May 2013.

Timeline

31 March 2010

Primary endpoint
3 May 2013

3 May 2013

Quick facts

Lead sponsor	Novartis Pharmaceuticals
Phase	Phase 3
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	284
Start date	31 March 2010
Primary completion	3 May 2013
Estimated completion	3 May 2013
Sites	57 locations across France, Colombia, Italy, Netherlands, Russia, Belgium, Sweden, Ireland

Drugs / interventions tested

• Tacrolimus (reduced tacrolimus) — full drug profile →
• Everolimus (reduced tacrolimus) — full drug profile →
• Tacrolimus (tacrolimus elimination) — full drug profile →
• Everolimus (tacrolimus elimination)
• Tacrolimus (tacrolimus control) — full drug profile →
• Corticosteroids (corticosteroids) — full drug profile →

Conditions studied

• Liver Transplant Recipient — all drugs for Liver Transplant Recipient →

Sponsor

Novartis Pharmaceuticals — full company profile →

Who can join

Adults 20 to 75, any sex, with Liver Transplant Recipient. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death Primary · from months 24 to 36

The number of participants who experienced composite efficacy failure was analyzed. Composite efficacy failure was defined as treated biopsy proven acute rejection (tBPAR), graft loss, or death. A BPAR was defined as an acute rejection confirmed by biopsy with a Rejection Activity Index (RAI) score ≥ 3. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, and venous endothelial inflammation) each scored on a scale of 0 (absent)

Group	Value	95% CI
Everolimus + Reduced Tacrolimus	2
Tacrolimus Elimination	1
Tacrolimus Control	3

Incidence Rate of Composite Efficacy Failure Defined as Treated Biopsy Proven Acute Rejection (tBPAR ), Graft Loss or Death Primary · from months 36 to 48

The number of participants who experienced composite efficacy failure was analyzed. Composite efficacy failure was defined as treated biopsy proven acute rejection (tBPAR), graft loss, or death. A BPAR was defined as an acute rejection confirmed by biopsy with a Rejection Activity Index (RAI) score ≥ 3. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, and venous endothelial inflammation) each scored on a scale of 0 (absent)

Group	Value	95% CI
Everolimus + Reduced Tacrolimus	1
Tacrolimus Elimination	0

Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death Primary · from months 24 to 36

The number of participants who experienced graft loss or death was analyzed. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.

Group	Value	95% CI
Everolimus + Reduced Tacrolimus	2
Tacrolimus Elimination	0
Tacrolimus Control	1

Incidence Rate of Composite Efficacy Failure Defined as Graft Loss or Death Primary · from months 36 - 48

The number of participants who experienced graft loss or death was analyzed. The graft was presumed to be lost on the day the patient was newly listed for a liver graft, received a graft re-transplant, or died.

Group	Value	95% CI
Everolimus + Reduced Tacrolimus	0
Tacrolimus Elimination	0

Incidence Rate of tBPAR Secondary · from months 24 - 36

The number of participants who had a tBPAR was analyzed. tBPAR was defined as a BPAR which was treated with anti-rejection therapy. The RAI is used to score liver biopsies with acute rejection and is composed of 3 categories (portal inflammation, bile duct inflammation damage, and venous endothelial inflammation) each scored on a scale of 0 (absent) to 3 (severe) by a trained pathologist. The total RAI score = the sum of the scores of the 3 categories and ranges from 0 to 9, with a higher score indicating greater rejection.

Group	Value	95% CI
Everolimus + Reduced Tacrolimus	0
Tacrolimus Elimination	1
Tacrolimus Control	2

Change in Renal Function Primary · from months 24 to 36

Change in renal function was assessed by the estimated Glomerular Filtration Rate (eGFR) using the abbreviated (4 variables) Modification of Diet in Renal Disease (MDRD-4) formula which was developed by the MDRD Study Group and has been validated in patients with chronic kidney disease. The MDRD-4 formula used for the eGFR calculation is: eGFR (mL/min/1.73m\^2) = 186.3\*(C\^-1.154)\*(A\^-0.203)\*G\*R, where C is the serum concentration of creatinine (mg/dL), A is age (years), G=0.742 when gender is female, otherwise G=1, R=1.21 when race is black, otherwise R=1.

Group	Value	95% CI
Everolimus + Reduced Tacrolimus	-0.9	± 16.13
Tacrolimus Elimination	2.5	± 12.40
Tacrolimus Control	-3.3	± 11.84

Adverse events — posted to ClinicalTrials.gov

Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Reduced TAC, Month 36

Serious: 32/106 (30%)

Deaths: —

TAC Elimination, Month 36

Serious: 16/51 (31%)

Deaths: —

TAC Control, Month 36

Serious: 28/125 (22%)

Deaths: —

Reduced RAD + TAC, Month 48

Serious: 34/106 (32%)

Deaths: —

TAC Elimination, Month 48

Serious: 24/51 (47%)

Deaths: —

Serious adverse events (121 terms)

Reaction	System	Reduced TAC, Month 36	TAC Elimination, Month 36	TAC Control, Month 36	Reduced RAD + TAC, Month 48	TAC Elimination, Month 48
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—
Incisional hernia	Injury, poisoning and procedural complications	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—
Hernial eventration	Gastrointestinal disorders	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—
Impaired healing	General disorders	—	—	—	—	—
Cellulitis	Infections and infestations	—	—	—	—	—
Gastroenteritis	Infections and infestations	—	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—
Ankle fracture	Injury, poisoning and procedural complications	—	—	—	—	—
Basal cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—
Squamous cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—
Squamous cell carcinoma of skin	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—
Haemolytic uraemic syndrome	Blood and lymphatic system disorders	—	—	—	—	—
Lymphadenopathy	Blood and lymphatic system disorders	—	—	—	—	—
Splenomegaly	Blood and lymphatic system disorders	—	—	—	—	—
Acute myocardial infarction	Cardiac disorders	—	—	—	—	—
Cardiac failure	Cardiac disorders	—	—	—	—	—
Coronary artery stenosis	Cardiac disorders	—	—	—	—	—
Myocardial infarction	Cardiac disorders	—	—	—	—	—
Tachycardia	Cardiac disorders	—	—	—	—	—
Abdominal adhesions	Gastrointestinal disorders	—	—	—	—	—

Other adverse events (17 terms — click to expand)

Reaction	System	Reduced TAC, Month 36	TAC Elimination, Month 36	TAC Control, Month 36	Reduced RAD + TAC, Month 48	TAC Elimination, Month 48
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—
Renal failure	Renal and urinary disorders	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—	—
Incisional hernia	Injury, poisoning and procedural complications	—	—	—	—	—
Hypercholesterolaemia	Metabolism and nutrition disorders	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—
Hepatitis C	Infections and infestations	—	—	—	—	—
Influenza	Infections and infestations	—	—	—	—	—
Osteoporosis	Musculoskeletal and connective tissue disorders	—	—	—	—	—

Most-reported serious reactions: Diarrhoea, Pyrexia, Incisional hernia, Pneumonia, Hernial eventration, Vomiting, Impaired healing, Cellulitis.

Data from ClinicalTrials.gov NCT01150097 adverse events section.

Sponsor's own description

The reason for this extension is to evaluate the long-term safety and efficacy of two concentration-controlled everolimus regimen in de novo liver transplant recipients. The most important long-term safety assessments include evaluation of renal function, progression of HCV related allograft fibrosis, and other treatment related effects at Month 36 post-transplantation compared to extension baseline (Months 24 post-transplantation).

Publications & conference data

2 peer-reviewed publications reference this trial (live from Europe PMC):

1. The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence.
   Klintmalm GB, Nashan B. · · 2014 · cited 51× · PMID 24719752 · DOI 10.1155/2014/845438
2. The role of everolimus in liver transplantation.
   Ganschow R, Pollok JM, Jankofsky M, Junge G. · · 2014 · cited 27× · PMID 25214801 · DOI 10.2147/ceg.s41780