Why carry out this study?
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A calcineurin inhibitor (CNI) is considered essential after lung transplantation (LTx) but few randomized controlled trials (RCT) exploring the differences between cyclosporine and tacrolimus exist in LTx. |
Therefore, we wanted to test whether chronic lung allograft dysfunction (CLAD) would be more prevalent with cyclosporine or tacrolimus in a RCT.
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The ScanCLAD study is an investigator initiated, pragmatic, controlled, randomized, open-label, multi-center study evaluating if an immunosuppressive protocol based on ATG-induction, once daily tacrolimus-dose, mycophenolate mofetil and corticosteroid reduces the incidence of CLAD after LTx, compared to a cyclosporine-based protocol with all other immunosuppressive and prophylactic drugs being identical between groups.
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What was learned from the study?
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The ScanCLAD study is enrolling and investigates which CNI is to be preferred from a CLAD perspective after LTx. |
The ScanCLAD study is designed with more than 10 sub-studies addressing other important and unresolved issues in LTx. |
Introduction
Methods
Study Aim
Study Design
Study Objectives and Endpoints
To compare the efficacy between treatment regimes by assessing the difference in |
Renal function evaluated by mGFR at 3 months after LTx |
The composite measure of freedom from allograft rejection, CLAD, graft survival, and patient survival at 12, 24, and 36 months after transplantation |
The cumulative incidence of PGD at 72 h |
Patient survival at 1 and 3 years |
The cumulative incidence of acute allograft rejection and CLAD at 6 months, 1 year, and 3 years |
The cumulative incidence of BOS and RAS at 6 months, 1 year, and 3 years |
Development of DSA at 12, 24, and 36 months |
Renal function evaluated by mGFR, by iohexol or Cr-EDTA clearance, at 12, 24, and 36 months |
Renal function evaluated by cGFR, by three different formulas, at 3, 12, 24, and 36 months |
The cumulative incidence of PTDM at 6, 12, 24, and 36 months after transplantation |
Use of antidiabetic medication at 6, 12, 24, and 36 months |
Incidence and number of antihypertensive and lipid-lowering drugs at 12, 24, and 36 months |
Development and magnitude of proteinuria at 12, 24, and 36 months |
Lipid profile at 12, 24, and 36 months |
Incidence of CMV that required treatment (CMV infection or CMV syndrome) |
Cumulative incidence of malignancy stratified by PTLD and all other cancers, at 36 months |
Safety and tolerability |
Quality of life, assessed by EQ 5D3L and SGRQ, both self-administered, pre-transplant and at 12, 24, and 36 months |
Define the pharmacokinetics of tacrolimus in patients without CF (n = 12) and all included patients with CF (n = 15–20) undergoing primary lung transplantation treated with Advagraf®-based immunosuppression |
Immunological equipotency of tacrolimus and cyclosporine in vivo and in vitro |
Occurrence of treatment failures up to or at 36 months; defined as a composite endpoint of graft loss, death, loss to follow-up or discontinuation due to lack of efficacy or toxicity (at least one condition must be present) |
Recovery of right heart function irrespective of diagnosis in patients with PAH (categories 1–5 according to WHO 1–5) |
Study Population
Inclusion criteria |
Male or female lung recipients 18–70 years of age undergoing primary double (including size reduction) lung transplantation |
Patient willing and capable of giving written informed consent for study participation and anticipated to be able to participate in the study for 36 months |
Exclusion criteria |
Recipients of multiorgan transplant, and/or previously transplanted with any organ, including previous lung transplantation |
Patients with hypersensitivity to or other reasons to not be able to take the immunosuppressive drugs used in the study |
Donor lung cold ischemic time > 12 h |
Patients who previously have been treated with anti-thymocyte globulin preparations (e.g., ATG-Fresenius®, Thymoglobulin®) |
Patients who are recipients of ABO-incompatible transplants |
Patients with platelet count < 50,000/mm3 at the evaluation before transplantation |
Patients who are unlikely to comply with the study requirements |
Patients, and/or those receiving organs from donors, who are positive for HIV, hepatitis B surface antigen, or hepatitis C virus |
Patients with donor older than 75 years |
Patient who have received an unlicensed drug or therapy within 1 month prior to study entry or if such therapy is to be instituted post-transplantation |
Patient unable to participate in the study for the full 36-month period |
Patients with any past (within the past 3 years (low-risk malignancy) to 5 years (high-risk malignancy)) or present malignancy (other than excised basal cell carcinoma) |
Women capable of becoming pregnant must have a negative pregnancy test prior to randomization |
Substudies
Donor-specific antibodies in chronic lung allograft dysfunction |
PTDM in lung transplantation |
Equipotency of tacrolimus and cyclosporine in vivo and in vitro |
Quality of life after lung transplantation in Scandinavia |
Cytomegalovirus as a risk factor for CLAD and its subtypes BOS and RAS |
Imaging in primary graft dysfunction |
Clinical pharmacokinetics of once-daily prolonged release tacrolimus in cystic fibrosis compared to non-cystic fibrosis lung transplant recipients |
Recovery of RV failure in PAH after lung transplantation |
Lung donor characteristics as risk factors for PGD and CLAD |
Molecular biomarkers as potential targets for therapeutic strategies after lung transplantation |
Correlation of the incidence of acute rejection with the non-invasive blood transcriptional assay (SORT) |
Weight-to-height ratio as a predictor for CLAD and overall survival after lung transplantation |
Cytokines and inflammatory variables in lung-transplanted recipients |
AMR in lung transplantation: treatment and risk factors |
CLAD subtypes, BOS and RAS, defined by computed tomography volumetry |
Clinical Assessment
Period | Period 1 | Period 2 | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
Visit | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
Week/month | Pre-LTx | LTx | W1 | W4 | M3 | M6 | M9 | M12 | M24 | M36 |
Informed consent | x | |||||||||
Inclusion/exclusion | x | x | ||||||||
Randomization | x | |||||||||
Demography | x | |||||||||
General medical history | x | |||||||||
Transplantation information | x | |||||||||
Background donor | x | |||||||||
Protocol biopsy | x | x | x | |||||||
HLA typing | x | |||||||||
HLAab/DSA (stored) | x | x | x | x | x | x | x | |||
Vital signs | x | x | x | x | x | x | x | x | x | x |
Lung function test Spiro, DLCO, VOL | x | x | x | x | x | x | x | x | ||
6 min walk test | x | x | x | x | ||||||
Quality of life | x | x | x | x | ||||||
Laboratory test | ||||||||||
Hematology/biochemistry | x | x | x | x | x | x | x | x | x | x |
Lipid profile | x | x | x | x | x | |||||
Viral serology and PCR | x | x | x | x | x | x | x | x | ||
Flow cytometry (T cell activation) & ImmunKnow® assay | x | x | x | x | x | |||||
Pregnancy test | x | |||||||||
Urinalysis | x | x | x | x | x | x | x | |||
cGFR | x | x | x | x | x | x | x | |||
mGFR | x | x | x | x | x | |||||
HR-CT scan | x | x | x | x | x | x | ||||
Drug concentration | ||||||||||
Cya/Tac blood conc level | x | x | x | x | x | x | x | x | ||
MPA blood conc level | x | x | ||||||||
Echocardiography in PAH | x | x | x | x | x | x | ||||
DNA/RNA isolation | X | x | x | x | x | x | ||||
Tac pharmacokinetics | x | x | ||||||||
OGTT | x | x | x | x | x | |||||
SORT analysis | x | x | x | x | x | x | x | x | x | |
Weight-to-height ratio | x | x | x | x | x | x | x | x | ||
Cytokines and inflammatory variables | x | x | x | x | x | x |
Group A: cyclosporine A, MMF, and corticosteroids |
Induction therapy: Thymoglobulin® (1.5 mg/kg given immediately postoperatively). Antihistamine (Tavegyl®) or similar at a dose of 2 mg iv before induction therapy is initiated |
Cyclosporine A: given orally pretransplant at a dose of 2–3 mg/kg |
Continued postop day 1 (24 h postoperatively) at a dose of 3 mg/kg2, according to local practice and blood concentration: 0–3 months, 250–300; 3–6 months, 200–250; 6–12 months, 150–200; > 12 months 100–150 ng/ml. Cyclosporine A will be administered twice daily |
MMF target dose 2000 mg/day (1 g × 2) |
Controlled by a single area under the curve (AUC) measurement on day 90 with a target AUC between 40 and 60 mg h/L and corrected accordingly |
Corticosteroids |
Day 0 (day of lung transplantation); 500 + 500 mg methylprednisolone iv before reperfusion, i.e., restoration of blood flow into the transplanted allograft |
From day 1: Initiated at 0.2 mg/kg/day; tapered to 0.1 mg/kg/day 1–6 months; less than 0.1 mg/kg/day > 3–6 months |
Group B: tacrolimus (Advagraf®), MMF, and corticosteroids |
Induction therapy: Thymoglobulin® (1.5 mg/kg given immediately postoperatively). Antihistamine (Tavegyl®) or similar should be started at a dose of 2 mg iv before induction therapy is initiated |
Tacrolimus (Advagraf®) |
Tacrolimus should be given orally pretransplant at a dose of 0.05–0.1 mg/kg |
Continued postop day 1 (24 h postoperatively) at a dose of 0.1–0.2 mg/kg/24 h. To allow tacrolimus blood concentrations to stabilize, Adport® (or any tacrolimus galenic form) should be ordered BiD for the first 3–7 days, or prolonged if long ICU stay is required, and patient should be switched to the investigational drug Advagraf® OD at the ward or just prior to being discharged from ICU, and subsequently managed according to blood concentration levels: 0–3 months, 10–14, 3–6 months, 8–12; 6–12 months, 8–10; > 12 months, 6–8 ng/ml |
MMF target dose 2000 mg/day (1 g × 2) |
Controlled by a single AUC measurement day 90 with a target AUC between 40 and 60 mg h/L and corrected accordingly |
Corticosteroids |
Day 0; 500 + 500 mg methylprednisolone iv before reperfusion, i.e., restoration of blood flow into the transplanted allograft |
From day 1: initiated at 0.2 mg/kg/day; tapered to 0.1 mg/kg/day 1–6 months; less than 0.1 mg/kg/day > 3–6 months |
Efficacy Measurements
- Lung function testing: Experienced and skilled technicians in a specialized respiratory laboratory will perform the pulmonary function tests. The quality control and performance of spirometry, measurements of lung volumes, and carbon monoxide uptake (CO uptake), i.e., transfer factor or diffusing capacity (DLCO), are in accordance with the European recommendations [8‐10]. Spirometry is performed on a rolling seal spirometer. The forced expiratory vital capacity (FVC) and forced expiratory volume in first second (FEV1) are taken as the highest of repeated recordings. Lung volumes, i.e., total lung capacity (TLC), functional residual capacity (FRC), and residual volume (RV), are obtained in a body plethysmograph. CO uptake is obtained by the single-breath method using standard equipment. Volume and gas concentration calibrations are checked daily. At visits 4 and 7 only spirometry will be performed without volumes or DLCO. The baseline value is defined as the mean of the two best FEV1 values post LTx, from which CLAD will be determined (and FVC will be used to discriminate between BOS and RAS) according to the most updated recommendations [7].
- Measured glomerular filtration rate (mGFR): The mGFR is the best clinical estimate of renal function in health and disease, and correlates well with the clinical severity of renal function disturbances also after transplantation [11]. GFR will be measured using Cr-EDTA clearance or iohexol clearance. The same method should be used throughout the study for a given patient.
- Rejection episodes and graft loss: All suspected rejection episodes will be recorded in the adverse event (AE) module in the eCRF, whether a biopsy was performed, whether follow-up biopsies were performed, whether anti-rejection therapy was administered, whether the acute rejection was confirmed or with final clinical diagnosis specified, and final clinical outcome.Biopsy-Proven Acute Rejection
- In all suspected rejection episodes, a transbronchial biopsy will be done according to local practice prior to or at the latest within 24 h after the initiation of anti-rejection therapy. Biopsies will be read and interpreted by local pathologists. A biopsy-proven acute rejection will be defined as a biopsy graded A1–A4 or antibody-mediated rejection according to International Society of Heart and Lung Transplantation (ISHLT) classification [14].
Graft Loss- Graft loss is considered a serious adverse event (SAE) and should be reported in the SAE module, and the reason for graft loss should be recorded thoroughly.
- Primary graft dysfunction: Primary graft dysfunction (PGD) is defined according to ISHLT definition as pulmonary infiltrates and hypoxemia occurring in the first 72 h after transplantation [15]. Because chest x-ray has a low sensitivity to detect interstitial changes in transplanted lungs, follow-up will include high-resolution computed tomography (HR-CT) on day 3 at definition of PGD and subsequent follow-up at months 3 and 12 where bronchoscopy with transbronchial biopsy (TBB) is available for correlation study. A validated scoring system, which has been used in a previous prospective study of PGD, will be applied [16, 17].
- Measurements of inflammatory variables: Cytokines and other inflammatory variable will be analyzed in plasma/serum enzyme immunoassays or Luminex multiplex assay. Serum and plasma samples will be taken before transplantation, at 1, 4, and 12 weeks, and at 6 and 12 months post-transplant and cryopreserved at − 80 °C for later analyses. All analyses will be performed at a central laboratory in Oslo, Norway. Standard inflammatory cytokines/chemokines and complement activation will be measured as previously described [18].
- Measurements of donor-specific antibodies: The human leukocyte antigen (HLA) antibody status and the presence of donor-specific HLA antibodies (DSA) before transplantation and produced de novo at 4 weeks, 3 and 12 months, and 2 and 3 years post-transplantation will be analyzed using standard methodology already in use in the tissue typing lab at Sahlgrenska University Hospital. All tests will be performed in one laboratory to avoid interlaboratory variation. Collected samples will be stored at − 80 °C for additional analyses if new tests for other antigens appear on the market.
- Functional assessments: A 6-minute walk test (6MWT) is a functional test that may be performed in the hallway or on the treadmill in a standardized manner.
- Quality of life assessments: Two standardized questionnaires, EQ5D3L and The St. George’s Respiratory Questionnaire (SGRQ), will be used. Measurements will be done prior to LTx and 1, 2, and 3 years after lung transplantation.
- NODAT/PTDM: New-onset diabetes after transplantation (NODAT) or post-transplantation diabetes mellitus (PTDM) [19] will be assessed by oral glucose tolerance test (OGTT) pre-Tx and at 6, 12, 24, and 36 months after transplantation.
Results
Safety Assessment
Sample Size and Power Calculation
Statistical Analyses
Populations for Analysis
- The per protocol transplanted (PPtrans) population will consist of all patients in whom transplantation was performed and who were randomized and treated with at least one dose of randomized treatment. The PPtrans population is also the safety population (SAF).
- The per protocol CLAD (PPCLAD) population (or full-analysis set population, FAS) will consist of all randomized patients who received at least one dose of any immunosuppressive therapy, underwent transplantation, and had at least one post-baseline assessment of the primary efficacy variable (CLAD). Randomized patients without data on the primary outcome variable will be excluded from this population.
- The per protocol drug (PPdrug) population will consist of all ITT patients who did not show major deviations from the protocol procedures that may have an impact on the study outcome, remained on randomized study drug, and who have completed the treatment phase at 36 months according to protocol.