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

Study Overview
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Brief Summary
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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
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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.

Official Title
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SCHEDULE - Scandinavian Heart Transplant Everolimus de Novo Study With Early CNI Avoidance

Conditions
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Renal Function and Chronic Allograft Vasculopathy

Intervention / Treatment
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* Drug: Cyclosporine
* Drug: Mycophenolate mofetil
* Drug: Corticosteroids
* Drug: Everolimus
* Drug: Anti Thymocyte Globulin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Everolimus<br>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<br>* 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)<br>Drug: Mycophenolate mofetil<br>* 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<br>Drug: Corticosteroids<br>* 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.<br>Drug: Everolimus<br>* 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<br>Drug: Anti Thymocyte Globulin<br>* 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.<br>|
| Experimental: Control<br>Participants received an immunosuppressive regimen consisting of CsA, MMF and CS throughout the study. | Drug: Cyclosporine<br>* 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)<br>Drug: Mycophenolate mofetil<br>* 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<br>Drug: Corticosteroids<br>* 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.<br>Drug: Anti Thymocyte Globulin<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression of Chronic Allograft Vasculopathy (CAV) Based on Maximal Intimal Thickness (MIT) From Baseline to Week 52 | The progression of chronic allograft vasculopathy (CAV) was assessed by intravascular ultrasound (IVUS) examinations and measured Maximal Intimal Thickness (MIT)(in mm). A major coronary epicardial artery (preferentially the left-anterior descending coronary artery) was imaged, and the MIT parameters were recorded at baseline and at 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 | the progression of chronic allograft vasculopathy (CAV) assessed by intravascular ultrasound (IVUS) examinations, measured the incidence of CAV (in percent of patients) at baseline and at week 52. Incidence of CAV represents percent of patients having a MIT (maximal intima thickness) > 0.5 mm. | Baseline and week 52 | 
| Change in Calculated Glomerular Filtration Rate From Pre-transplantation to Week 52 | Change in calculated glomerular filtration rate from pre-transplantation to week 52 was calculated according to the Modification of Diet in Renal Disease (MDRD) method. Measurements were taken prior to transplant (day 1), between weeks 7 to 11 and end week 52. | Day 1, weeks 7 to 11(baseline) and of week 52 | 
| Calculated Glomerular Filtration Rate From Pre-Transplantation to Week 52 | Calculated Glomerular Filtration Rate from pre-transplantation to week 52 was calculated according to the Modification of Diet in Renal Disease (MDRD) method. Measurements were taken prior to transplant (day 1), between weeks 7 to 11 and end of week 52. | Day 1, weeks 7 to 11 and of week 52 | 
| Number of Rejections Leading to Hemodynamic Compromise | Number of all rejections were recorded through the duration of the study with the intent to identify rejections leading to hemodynamic compromise. | 52 weeks | 
| Occurrence of Treatment Failures up to 12 Months After Transplant | Treatment failure was defined as the number of participants who died or lost their graft at any timepoint througout the duration of the study. | 52 weeks | 
| Average Level of Protenuria at Week 52 | Proteinuria is measured as the ratio of albumin/creatinine mg/mmol. Measurements were taken from participants urine samples. | 52 weeks | 
| Lipid Profile at 12 Months | Total Cholesterol, LDL-Chol, HDL-Chol and TG at week 52. Measurements were taken via participants blood samples. | 52 weeks | 
| Change in Quality of Life Assessed by SF-36 (Minnesota Living With Heart Failure Questionnaire ([MLHF)]) From Pre-transplant to Week 52 of Treatment | Change in Quality of Life was assessed via the SF-36 (Minnesota Living with Heart Failure questionnaire ([MLHF)]) before transplant surgery and at week 52 of treatment. The SF-36 is a validated, self-administered questionnaire. The questionnaire, which includes 36 questions measures 8 dimensions of health: physical function, role-physical, bodily pain, general health, vitality, social function, role-emotional, and mental health. Scores can be summarized in 2 summary components assessing physical and mental health. Items in each dimension are coded, aggregated, summed, and transformed into a scale ranging from 0 (worse health) to 100 (best health). | Pre transplant and 52 weeks | 
| Change in Quality of Life - Euro Quality of Life 5D (EQ-5D) | Change in Quality of Life was assessed via the EQ-5D questionnaire which consists of: EQ-5D-5L descriptive system and EQ Visual Analogue scale (EQ VAS). The EQ-5D-5L comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression). Each dimension has 5 levels (no problems, slight problems, moderate problems, severe problems, and extreme problems). The patient indicates his/her health state by checking the most appropriate statement. This decision results in a 1-digit number expressing the level selected for that dimension. The digits for 5 dimensions are combined in a 5-digit number describing the respondent's health state. The possible score is 1 to 5 where a lower number indicates improvement. The EQ VAS records the patient's self-rated health on a 20 cm vertical, visual analogue scale with endpoints labelled 'the best health you can imagine' and 'the worst health you can imagine'. The score is 0 to 100 where a higher score represents improvement. | Pre transplant and 52 weeks |