Clinical trial NCT01266148: SCHEDULE - Scandinavian Heart Transplant Everolimus de Novo Study With Early Calcineurin Inhibitor (CNI) Avoidance
Official title: SCHEDULE - Scandinavian Heart Transplant Everolimus de Novo Study With Early CNI Avoidance
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Renal Function and Chronic Allograft Vasculopathy
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2010-12-24
Enrollment: 115
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: A controlled, randomized, open-label, multicenter study evaluating if early initiation of everolimus and early elimination of cyclosporine in de novo heart transplant recipients can improve long-term renal function and slow down the progression of chronic allograft vasculopathy

Detailed description: This was a prospective, multi-center, randomized, controlled, parallel group, open label study in de novo heart transplant recipients. Patients eligibility for randomization was assessed 5 days after heart transplant.. Patients fulfilling the inclusion and exclusion criteria were randomized to one of two treatment groups: either conventional treatment with Cyclosporine A (CsA), Mycophenolate mofetil (MMF), and corticosteroids (Group A), or low-dose CsA and everolimus, reduced dose MMF, and corticosteroids (Group B). After 7 to 11 weeks, CsA was discontinued in Group B, while the standard triple-drug immunosuppressive regimen was maintained in Group A.

Eligibility criteria: De novo heart transplant recipients who had received induction therapy with antithomocyte globulin (ATG) were eligible for inclusion.

Recipients of multi-organ transplants or a previous transplant were excluded, as were those with a donor aged \> 70 years, cold ischemia time \>6 hours, patients with severe systemic infection, recipients of ABO incompatible transplants, patients with severe hypercholesterolemia (\>350mg/dL) or hypertriglyceridemia (\>750 mg/dL), patients with past (\<5 years). In order to continue in the study after week 7-11 (period 1), patients had to complete first 7-11 weeks on randomized immunosuppression and none of the following criteria should be present: Ongoing rejection treatment or experience of one grade 3R rejection or two or more grade 2R rejections during first 7-11 weeks.

Primary outcomes:
measure: Measured Glomerular Filtration Rate (mGFR), 12 Months After Heart Transplantation
timeFrame: Week 52
Secondary outcomes:
measure: Progression of Chronic Allograft Vasculopathy (CAV) Based on Maximal Intimal Thickness (MIT) From Baseline to Week 52
timeFrame: Baseline and week 52
measure: Progression of Chronic Allograft Vasculopathy (CAV) Based on Incidence of Chronic Allograft Vasculopathy (CAV) From Baseline to Week 52
timeFrame: Baseline and week 52
measure: Change in Calculated Glomerular Filtration Rate From Pre-transplantation to Week 52
timeFrame: Day 1, weeks 7 to 11(baseline) and of week 52
measure: Calculated Glomerular Filtration Rate From Pre-Transplantation to Week 52
timeFrame: Day 1, weeks 7 to 11 and of week 52
measure: Number of Rejections Leading to Hemodynamic Compromise
timeFrame: 52 weeks
measure: Occurrence of Treatment Failures up to 12 Months After Transplant
timeFrame: 52 weeks
measure: Average Level of Protenuria at Week 52
timeFrame: 52 weeks
measure: Lipid Profile at 12 Months
timeFrame: 52 weeks
measure: Change in Quality of Life Assessed by SF-36 (Minnesota Living With Heart Failure Questionnaire ([MLHF)]) From Pre-transplant to Week 52 of Treatment
timeFrame: Pre transplant and 52 weeks
measure: Change in Quality of Life - Euro Quality of Life 5D (EQ-5D)
timeFrame: Pre transplant and 52 weeks
Other outcomes:
Locations:
city: Copenhagen
country: Denmark
facility: Novartis Investigative Site
city: Århus N
country: Denmark
facility: Novartis Investigative Site
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Göteborg
country: Sweden
facility: Novartis Investigative Site
city: Linkoping
country: Sweden
facility: Novartis Investigative Site
city: Lund
country: Sweden
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Arora S, Andreassen AK, Karason K, Gustafsson F, Eiskjaer H, Botker HE, Radegran G, Gude E, Ioanes D, Solbu D, Dellgren G, Ueland T, Aukrust P, Gullestad L; SCHEDULE (Scandinavian Heart Transplant Everolimus De Novo Study With Early Calcineurin Inhibitors Avoidance) Investigators. Effect of Everolimus Initiation and Calcineurin Inhibitor Elimination on Cardiac Allograft Vasculopathy in De Novo Heart Transplant Recipients. Circ Heart Fail. 2018 Sep;11(9):e004050. doi: 10.1161/CIRCHEARTFAILURE.117.004050.
citation: Norum HM, Michelsen AE, Lekva T, Arora S, Otterdal K, Olsen MB, Kong XY, Gude E, Andreassen AK, Solbu D, Karason K, Dellgren G, Gullestad L, Aukrust P, Ueland T. Circulating delta-like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus-based immunosuppression. Am J Transplant. 2019 Apr;19(4):1050-1060. doi: 10.1111/ajt.15141. Epub 2018 Nov 5.
citation: Andreassen AK, Broch K, Eiskjaer H, Karason K, Gude E, Molbak D, Stueflotten W, Gullestad L; SCHEDULE (SCandinavian HEart transplant everolimus De-novo stUdy with earLy calcineurin inhibitors avoidancE) Investigators. Blood Pressure in De Novo Heart Transplant Recipients Treated With Everolimus Compared With a Cyclosporine-based Regimen: Results From the Randomized SCHEDULE Trial. Transplantation. 2019 Apr;103(4):781-788. doi: 10.1097/TP.0000000000002445.
citation: Nelson LM, Andreassen AK, Andersson B, Gude E, Eiskjaer H, Radegran G, Dellgren G, Gullestad L, Gustafsson F. Effect of Calcineurin Inhibitor-Free, Everolimus-Based Immunosuppressive Regimen on Albuminuria and Glomerular Filtration Rate After Heart Transplantation. Transplantation. 2017 Nov;101(11):2793-2800. doi: 10.1097/TP.0000000000001706.
citation: Andreassen AK, Andersson B, Gustafsson F, Eiskjaer H, Radegran G, Gude E, Jansson K, Solbu D, Karason K, Arora S, Dellgren G, Gullestad L; SCHEDULE investigators. Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Three-Year Results From the Randomized SCHEDULE Study. Am J Transplant. 2016 Apr;16(4):1238-47. doi: 10.1111/ajt.13588. Epub 2016 Jan 28.
citation: Andreassen AK, Andersson B, Gustafsson F, Eiskjaer H, Radegran G, Gude E, Jansson K, Solbu D, Sigurdardottir V, Arora S, Dellgren G, Gullestad L; SCHEDULE Investigators. Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: a randomized trial. Am J Transplant. 2014 Aug;14(8):1828-38. doi: 10.1111/ajt.12809.