SCHEDULE - Scandinavian Heart Transplant Everolimus de Novo Study With Early Calcineurin Inhibitor (CNI) Avoidance

NCT01266148 | Completed Phase 4 Results

• 2 other identifiers: CRAD001ANO022009-013074-41
• Study Type: interventional
• Target: 115
• Locations: 3 countries
• Sites: 6

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

Conditions

Renal Function and Chronic Allograft Vasculopathy

Outcome Measures

Primary Outcomes (1)

• Measured Glomerular Filtration Rate (mGFR), 12 Months After Heart Transplantation

  Measured Glomerular Filtration Rate (mGFR) describes the flow rate of filtered fluid through the kidney. GFR is equal to the clearance rate when any solute is freely filtered and is neither reabsorbed nor secreted by the kidneys. The rate therefore measured is the quantity of the substance in the urine that originated from a calculable volume of blood. Participants' urine was used for this assessment at week 52 after heart transplant.

  Week 52

Secondary Outcomes (10)

• Progression of Chronic Allograft Vasculopathy (CAV) Based on Maximal Intimal Thickness (MIT) From Baseline to Week 52

  Baseline and week 52

• Progression of Chronic Allograft Vasculopathy (CAV) Based on Incidence of Chronic Allograft Vasculopathy (CAV) From Baseline to Week 52

  Baseline and week 52

• Change in Calculated Glomerular Filtration Rate From Pre-transplantation to Week 52

  Day 1, weeks 7 to 11(baseline) and of week 52

• Calculated Glomerular Filtration Rate From Pre-Transplantation to Week 52

  Day 1, weeks 7 to 11 and of week 52

• Number of Rejections Leading to Hemodynamic Compromise

  52 weeks

Study Arms (2)

Everolimus

EXPERIMENTAL

Participants started immunosuppressive regimen consisting of low dose CsA, everolimus, MMF and CS. After week 11, the participants regimen consisted of everolimus, MMF and CS.

Drug: Cyclosporine; Drug: Mycophenolate mofetil; Drug: Corticosteroids; Drug: Everolimus; Drug: Anti Thymocyte Globulin

Control

EXPERIMENTAL

Participants received an immunosuppressive regimen consisting of CsA, MMF and CS throughout the study.

Drug: Cyclosporine; Drug: Mycophenolate mofetil; Drug: Corticosteroids; Drug: Anti Thymocyte Globulin

Interventions

Cyclosporine DRUG

Cyclosporine (CsA) control group target blood level: 150-350 ng/mL (month 1-3); 100-250 ng/mL (month 4-6); 60-200 ng/mL (month 7-12); everolimus group target blood level: 75-175 ng/mL (month 1-3)

Control; Everolimus

Mycophenolate mofetil DRUG

Mycophenolate mofetil (MMF) target dose for control group: 2000-3000 mg/day everolimus group target dose: 1500-2000 mg/day and 75-175 ng/mL after week 11

Control; Everolimus

Corticosteroids DRUG

Corticosteroids (CS) initiated at 0.2-0.5 mg/kg/day. Tapered to no less than 0.1 mg/kg at Month 3 for control and everolimus groups.

Control; Everolimus

Everolimus DRUG

Everolimus 0.75 mg twice a day as starting dose up to a target blood level: 3-6 ng/mL (7-11 weeks) and 6-10 ng/mL for remaining of study

Everolimus

Anti Thymocyte Globulin DRUG

Induction therapy, Anti Thymocyte Globulin (ATG): 1-2 mg/kg/day during 3-5 days for control and everolimus groups after transplant surgery and prior to randomization.

Control; Everolimus

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (6)

Novartis Investigative Site

Århus N, DK-8200, Denmark

Location

Novartis Investigative Site

Copenhagen, DK-2100, Denmark

Location

Novartis Investigative Site

Oslo, 0424, Norway

Location

Novartis Investigative Site

Gothenburg, 413 45, Sweden

Location

Novartis Investigative Site

Linköping, 581 85, Sweden

Location

Novartis Investigative Site

Lund, 221 85, Sweden

Location

Related Publications (6)

• 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.

  PMID: 30354362 DERIVED

• 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.

  PMID: 30312541 DERIVED

• 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.

  PMID: 30211826 DERIVED

• 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.

  PMID: 28230646 DERIVED

• 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.

  PMID: 26820618 DERIVED

• 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.

  PMID: 25041227 DERIVED

MeSH Terms

Interventions

Cyclosporine; Mycophenolic Acid; Adrenal Cortex Hormones; Everolimus; Antilymphocyte Serum

Intervention Hierarchy (Ancestors)

Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Sirolimus; Macrolides; Lactones; Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures

Results Point of Contact

• Title: Study director
• Organization: Novartis Pharmaceuticals

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 9, 2010
• First Posted: December 24, 2010
• Study Start: November 1, 2009
• Primary Completion: December 1, 2012
• Study Completion: December 1, 2012
• Last Updated: June 10, 2015
• Results First Posted: May 13, 2014

Record last verified: 2015-05

Locations

SE (3); NO (1); DK (2)