SCHEDULE Follow Up Visit 5-7 yr (CRAD001ANO05)

5, 6 or 7 Year Follow-up Control After the SCHEDULE Study (SCANDINAVIAN HEART TRANSPLANT EVEROLIMUS DE NOVO STUDY WITH EARLY CNI AVOIDANCE)

The major aim of this extension study was to evaluate the long-term effect (i.e. 5 to 7 years) of early initiation of everolimus and early elimination of CsA compared to standard immunosuppressive regimen including CsA on primary and secondary endpoints investigated in the SCHEDULE (NCT01266148) main study.

Study Overview

• Status: Completed
• Conditions: Heart Transplantation
• Intervention / Treatment: Drug: Everolimus; Drug: Cyclosporine; Drug: Mycophenolate mofetil; Drug: Corticosteroids

Detailed Description

This protocol was written to describe the procedures for a single 5, 6 or 7 year follow-up control visit of patients who participated in the 12-month SCHEDULE (NCT01266148) study and the following 3-year follow-up examination/visit. The aim of this 5 to 7-year follow-up visit was to examine the effect of long term treatment, i.e. 5, 6 or 7 years, with early initiation of everolimus (Certican®) and early elimination of cyclosporine (CsA), compared to standard immunosuppressive regimen including CsA, on renal and heart function. During the time period of this follow-up examinations, this visit was performed as part of a routine annual visit 5, 6 or 7 years since transplantation (and inclusion in the original SCHEDULE study).

Study code of SCHEDULE, the core study: CRAD001ANO02 (EudraCT No.: 2009-013074-41)

• Study Type: Interventional
• Enrollment (Actual): 95
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, DK-2100
    • Novartis Investigative Site
  • Århus N, Denmark, DK-8200
    • Novartis Investigative Site
• Norway
  • Oslo, Norway, 0372
    • Novartis Investigative Site
• Sweden
  • Göteborg, Sweden, 413 45
    • Novartis Investigative Site
  • Linkoping, Sweden, 581 85
    • Novartis Investigative Site
  • Lund, Sweden, 221 85
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients who participated in the SCHEDULE 12-month main study, and who completed the 3 year follow-up visit
• Patients who are coming for a regular annual clinic visit 5 to 7 years after randomization in the main study
• Obtaining of a separate signed patient informed consent will be required for participation in this follow-up examination.

Exclusion Criteria:

• Patients with a retransplanted heart since the original SCHEDULE study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: EVEROLIMUS; patients received everolimus (Certican), low-exposure CsA (Neoral), mycophenolate mofetil (MMF) and corticosteroids with CsA withdrawal after 7-11 weeks	Drug: Everolimus; All patients, independent of their initial randomization in the core study, were followed up as in one single group Commercially available everolimus (Certican®), oral route, was used.
Active Comparator: Control; patients received standard CsA, MMF and corticosteroids	Drug: Cyclosporine; 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); Drug: Mycophenolate mofetil; 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; Drug: Corticosteroids; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measured Glomerular Filtration Rate (mGFR)	Renal function as assessed by measured Glomerular Filtration Rate (mGFR) (Cr-EDTA or iohexol clearance). Baseline Visit 1 and Patient 4252 excluded from the intent treat analysis set.	at the 5-7 year follow-up visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression of Cardiac Allograft Vasculopathy (CAV) Recorded by Intravascular Ultrasound (IVUS)	Cardiac Allograft Vasculopathy (CAV) was defined as mean maximal intimal thickness (MIT) ≥0.5 mm, measured for the entire matched pullback recording by intravascular ultrasound (IVUS). The incidence of CAV at 5-7 years was compared between groups using the Cochran-Mantel-Haenszel test with stratification according to baseline distribution of CAV incidence.	within 5-7 years
Percent of Participants With Incidence of Coronary Allograft Vasculopathy (CAV)	Cardiac Allograft Vasculopathy (CAV) was defined as mean maximal intimal thickness (MIT) ≥0.5 mm, measured for the entire matched pullback recording by intravascular ultrasound (IVUS). The incidence of CAV at 5-7 years was compared between groups using the Cochran-Mantel-Haenszel test with stratification according to baseline distribution of CAV incidence.	at the 5-7 year follow-up
Myocardial Structure and Function	Myocardial structure and function by echocardiography assessment measured by ventricular end systolic diameter.	within 5-7 years
Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up	This Quality of life Short Form Survey with 36 items (Minnesota Living with Heart Failure Questionnaire)was administered to patients pre-transplantation and after transplantation at the 5-7 year visit. This data represents the change. The survey consist of scores on a scale. Each form is scaled from 0 t 100. 0 = maximum disability and 100 equals no disability.	at the 5-7 year visit
Change From Baseline in the Euro Quality of Life 5D	Change from baseline in Euro Quality of Life-5D from 3 Year Follow-Up to 5 to 7 Year Follow-Up Baseline Visit 1 (ITT Set) Euro Quality of Life 5D (EQ-5D): is a descriptive system of healthrelated quality of life states consisting of five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) each of which can be assessed as one of three levels of severity (no problems/some or moderate problems/extreme problems). A Visual Analogue Scale (VAS)-scale is also included in the EQ-5D questionnaire. The EQ-5D index is calculated based on the United Kingdom Time Trade-Off (TTO) N3 value set which converts the five dimensions scores into a single measure with a possible range from -0.163 (worst possible health state) to +1 (perfect health). A positive change from baseline indicates an improvement in Quality of Life.	Baseline, 5-7 year visit
Change From Baseline in Visual Analog Scale (VAS)	Change in visual analog scale (VAS) from baseline to the 5 to 7 Year follow up visit. 0 is no pain; and 10 is the worst possible pain	baseline, at the 5-7 year visit
Number of Participants With Beck Depression Inventory (BDI)	Beck Depression Inventory (BDI) Score has the following categories of depression. Normal, Mild, Moderate Severe and Missing.	at the 5-7 year visit

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2016
• Primary Completion (Actual): September 25, 2017
• Study Completion (Actual): September 25, 2017

Study Registration Dates

• First Submitted: June 1, 2016
• First Submitted That Met QC Criteria: August 9, 2016
• First Posted (Estimate): August 12, 2016

Study Record Updates

• Last Update Posted (Actual): October 3, 2019
• Last Update Submitted That Met QC Criteria: October 2, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: transplant; allograft rejection; xenograft rejection; host vs graft disease
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Mycophenolic Acid; Everolimus; Cyclosporine; Cyclosporins
• Other Study ID Numbers: CRAD001ANO05; CRAD001ANO026YFU (Other Identifier: Novartis Pharmaceuticals); 2016-000404-28 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No