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| ID | Type | Description | Link |
|---|---|---|---|
| CRAD001ANO026YFU | Other Identifier | Novartis Pharmaceuticals | |
| 2016-000404-28 | EudraCT Number |
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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.
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)
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| EVEROLIMUS | Experimental | patients received everolimus (Certican), low-exposure CsA (Neoral), mycophenolate mofetil (MMF) and corticosteroids with CsA withdrawal after 7-11 weeks |
|
| Control | Active Comparator | patients received standard CsA, MMF and corticosteroids |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Everolimus | Drug | 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. |
| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Novartis Investigative Site | Århus N | DK-8200 | Denmark | |||
| Novartis Investigative Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26820618 | Background | 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. |
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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
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Two patients randomized to everolimus did not provide a month 12 measured GFR (mGFR) value and were excluded from the ITT population, which thus comprised 93 patients (46 everolimus, 47 controls).
In total, 95 patients (48 everolimus, 47 controls), attended the follow-up visit at 5-7 years post-transplant and were included in the safety population
The PP population (27 everolimus, 35 controls) excluded 7 patients in the everolimus group and 11 in the control group who discontinued study drug prematurely
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| ID | Title | Description |
|---|---|---|
| FG000 | Everolimus | patients received everolimus (Certican), low-exposure CsA (Neoral), mycophenolate mofetil (MMF) and corticosteroids with CsA withdrawal after 7-11 weeks |
| FG001 | Control | patients received standard CsA, MMF and corticosteroids |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
The Intention-to-Treat Set (ITT Set) consists of patients who:
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| ID | Title | Description |
|---|---|---|
| BG000 | Everolimus | patients received everolimus (Certican), low-exposure CsA (Neoral), mycophenolate mofetil (MMF) and corticosteroids with CsA withdrawal after 7-11 weeks |
| BG001 | Control |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | intent to treat. 1 patient was excluded from ITT due to missing mGFR. | Posted | Least Squares Mean | Standard Deviation | mL/min/1.73m2 | at the 5-7 year follow-up visit |
|
An average of 3 years (from the 3 year follow-up visit to the 5-7 year follow-up visit)
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Everolimus | All participants who were included in the initial core study SCHEDULE (CRAD001ANO02) who received an immunosuppressive regimen consisting of CsA, MMF and CS throughout the study. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Pneumonia | Respiratory, thoracic and mediastinal disorders | MedDRA (19.1) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
There is no investigational medicinal product (IMP). This study is a single follow-up visit. Hence patients' first and last visit dates are the same.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Disclosure Office | Novartis Pharmaceuticals | (862) 778-8300 | Novartis.email@novartis.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| SAP | No | Yes | No | Statistical Analysis Plan | Sep 1, 2017 | Sep 25, 2018 | SAP_000.pdf |
| Prot | Yes | No | No | Study Protocol | Jul 7, 2016 | Sep 25, 2018 | Prot_001.pdf |
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| ID | Term |
|---|---|
| D006086 | Graft vs Host Disease |
| ID | Term |
|---|---|
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D000068338 | Everolimus |
| D016572 | Cyclosporine |
| D009173 | Mycophenolic Acid |
| D000305 | Adrenal Cortex Hormones |
| ID | Term |
|---|---|
| D020123 | Sirolimus |
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D003524 |
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| 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) |
|
| 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 |
|
| 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. |
|
| 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 |
| Copenhagen |
| DK-2100 |
| Denmark |
| Novartis Investigative Site | Oslo | 0372 | Norway |
| Novartis Investigative Site | Gothenburg | 413 45 | Sweden |
| Novartis Investigative Site | Linköping | 581 85 | Sweden |
| Novartis Investigative Site | Lund | 221 85 | Sweden |
patients received standard CsA, MMF and corticosteroids
| BG002 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Safety Set | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
|
|
|
| Secondary | 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. | Intent to Treat. | Posted | Mean | Standard Deviation | mm | within 5-7 years |
|
|
|
|
| Secondary | 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. | Intent to Treat | Posted | Number | percent of participants | at the 5-7 year follow-up |
|
|
|
| Secondary | Myocardial Structure and Function | Myocardial structure and function by echocardiography assessment measured by ventricular end systolic diameter. | intent to treat | Posted | Mean | Standard Deviation | cm | within 5-7 years |
|
|
|
| Secondary | 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. | intent to treat | Posted | Mean | Standard Deviation | scores on a scale | at the 5-7 year visit |
|
|
|
| Secondary | 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. | intent to treat | Posted | Mean | Standard Deviation | scores on the scale | Baseline, 5-7 year visit |
|
|
|
| Secondary | 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 | Intent to treat | Posted | Mean | Standard Deviation | mm | baseline, at the 5-7 year visit |
|
|
|
| Secondary | 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. | ITT | Posted | Count of Participants | Participants | at the 5-7 year visit |
|
|
|
| 0 |
| 48 |
| 26 |
| 48 |
| 15 |
| 48 |
| EG001 | Control | patients received standard CsA, MMF and corticosteroids | 0 | 47 | 18 | 47 | 4 | 47 |
| Acute myocardial infarction | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
|
| Arrhythmia | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
|
| Atrial fibrillation | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
|
| Atrioventricular block | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
|
| Cardiac arrest | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
|
| Cardiac failure | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
|
| Stress cardiomyopathy | Cardiac disorders | MedDRA (19.1) | Systematic Assessment |
|
| Retinal detachment | Eye disorders | MedDRA (19.1) | Systematic Assessment |
|
| Abdominal discomfort | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Anal fissure | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Food poisoning | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Large intestinal stenosis | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Proctalgia | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Small intestinal perforation | Gastrointestinal disorders | MedDRA (19.1) | Systematic Assessment |
|
| Hernia | General disorders | MedDRA (19.1) | Systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA (19.1) | Systematic Assessment |
|
| Cholelithiasis | Hepatobiliary disorders | MedDRA (19.1) | Systematic Assessment |
|
| Heart transplant rejection | Immune system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Diverticulitis | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Escherichia sepsis | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Gastroenteritis | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Herpes zoster | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Meningitis | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Viral infection | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Femoral neck fracture | Injury, poisoning and procedural complications | MedDRA (19.1) | Systematic Assessment |
|
| Femur fracture | Injury, poisoning and procedural complications | MedDRA (19.1) | Systematic Assessment |
|
| Pelvic fracture | Injury, poisoning and procedural complications | MedDRA (19.1) | Systematic Assessment |
|
| Upper limb fracture | Injury, poisoning and procedural complications | MedDRA (19.1) | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (19.1) | Systematic Assessment |
|
| Intervertebral disc protrusion | Musculoskeletal and connective tissue disorders | MedDRA (19.1) | Systematic Assessment |
|
| Pseudarthrosis | Musculoskeletal and connective tissue disorders | MedDRA (19.1) | Systematic Assessment |
|
| Spinal column stenosis | Musculoskeletal and connective tissue disorders | MedDRA (19.1) | Systematic Assessment |
|
| Basal cell carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (19.1) | Systematic Assessment |
|
| Squamous cell carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (19.1) | Systematic Assessment |
|
| Uterine cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (19.1) | Systematic Assessment |
|
| Cerebrovascular accident | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA (19.1) | Systematic Assessment |
|
| Depression | Psychiatric disorders | MedDRA (19.1) | Systematic Assessment |
|
| Aortic aneurysm | Vascular disorders | MedDRA (19.1) | Systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA (19.1) | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA (19.1) | Systematic Assessment |
|
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
| Cyclosporins |
| D010456 | Peptides, Cyclic |
| D047028 | Macrocyclic Compounds |
| D011083 | Polycyclic Compounds |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D002208 | Caproates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D005227 | Fatty Acids |
| D008055 | Lipids |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| LVEDD (left ventricular end diastolic diameter) |
|
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| Mental Health Summary |
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| Physical Functioning |
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| Role Physical |
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| Bodily Pain |
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| General Health |
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| Vitality |
|
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| Social Functioning |
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| Role Emotional |
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| Mental Health |
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| Moderate |
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| Severe |
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| Missing |
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