Introduction
Aims
Hypothesis
Materials and methods
Study design
Study settings
Recruitment
Study population
Inclusion criteria
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Male or female ≥18 years
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Living donor
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Low immunological risk:a.First (primary) transplantb.≤ 4 antigen mismatches (HLA A, B, DR, DQ matching scheme)c.Negative HLA Ab screening
Exclusion criteria
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High immunological risk as per KFSHRC protocol including (see attached protocol for more details Additional file 1)
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HLA identical or zero mismatched transplants
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Receiving cyclosporin as primary maintenance immunosuppressant
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Human immunodeficiency virus (HIV) co-infection
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Pregnant or nursing female
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Has received an investigational medication within the past 30 days
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Has a known contraindication to the administration of basiliximab
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Suspected or known to have a serious infection
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Multi-organ transplant
Randomization and blinding
Blinding
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A single pharmacist
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A single biostatistician
Pregnancy
Interim analysis
Duration of the study
Statistical methods
Treatment (interventions)
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Arm 1: Two doses of basiliximab, 20 mg intravenously, at 0 and 4 days post engraftment. The first dose to be given prior to reperfusion
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Arm 2: No induction (i.e., 100 ml of normal saline) will be administered intravenously, at 0 and 4 days post engraftment.
Labeling, handling, and storage
Medication dosage and administration
Concomitant medications
Study end points
Assessment of compliance
Efficacy assessments
Safety assessment
Maintenance protocol for low-risk patients
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Tacrolimus (FK-506)
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➢ Recipients for induction with basiliximab or no induction receive 0.1 mg/kg/day in two divided doses orally starting 2–4 doses prior to transplantation
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➢ Three divided doses (0600, 1400, 2200 h) are given to patients who require ≥15 mg/day to reach a therapeutic trough level.
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Mycophenolate Mofetil (MMF)
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Target dose: 1.5 g/day in two divided doses po:
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➢ All recipients receive at least two doses prior to transplant (the day before at 2100 h and the morning of transplant at 0600 h)
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➢ In case of side effects (leukopenia, thrombocytopenia), consider other potential culprits in addition to MMF (Valganciclovir, Ganciclovir, Septra®). Adjust or decrease doses accordingly (adjust mycophenolate mofetil dose first and if no response, proceed to adjustment of the doses of Septra® and/or Valcyte®). In case of gastrointestinal side effects (diarrhea, abdominal discomfort) related to mycophenolate mofetil, consider administering the dose with food, decreasing the dose or splitting the total dose into three divided doses.
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Corticosteroids (Solumedrol IV, prednisone po)
Corticosteroids’ maintenance protocol
Day/week/month | Dose |
Day 0 | Methylprednisolone 250 mg IV |
Day 1 | Methylprednisolone 80 mg IV |
Day 2 | Prednisone 60 mg po |
Day 3 | Prednisone 50 mg po |
Day 4 | Prednisone 40 mg po |
Day 5 | Prednisone 30 mg po |
Day 6 to day 14 | Prednisone 20 mg po daily |
3rd week | Prednisone 17.5 mg po daily |
4th week | Prednisone 15 mg po daily |
5th week | Prednisone 12.5 mg po daily |
6th week | Prednisone 10 mg po daily |
7th week | Prednisone 7.5 mg po daily |
8th week and on | Prednisone 5 mg po daily |
4th to 6th months | Prednisone may be tapered down to 2.5 mg every day or every other day |
Immediate-release tacrolimus (Prograf®) to LCPT long-acting tacrolimus (Envarsus®) conversion
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Dosing conversion from Prograf® (immediate-release) to once daily Envarsus® should be on a 1:0.7 (mg:mg) total daily dose basis and the Envarsus® maintenance dose should, therefore, be 25–30% less than the Prograf® dose, e.g., a patient who is receiving 1 mg BID tacrolimus (immediate release) should be converted to 1.5 mg tacrolimus LCPT (Envarsus) once daily.
Therapeutic drug monitoring
Therapeutic drug Levels
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➢ 0–30 days:
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◦ Target whole blood 12-h trough levels: 8–10 ng/ml
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➢ > 30 days:
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◦ Target whole blood 12-h trough levels: 6–8 ng/ml
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For newly transplanted patients, tacrolimus trough level will be ordered after the 4th dose.
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Whole blood 24-h tacrolimus levels should be used for patients on once daily long acting tacrolimus following the same targets
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Antiviral prophylaxis
CMV prophylaxis (universal prophylaxis)
EBV prophylaxis
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EBV-negative kidney transplant recipients of EBV-positive kidneys receive valganciclovir 450 mg orally once daily (adjusted to renal function), for 6 months.
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Valganciclovir dose is adjusted according to renal function as follows:
Cr Cl (ml/min/)*
|
Dose
|
> 60 | No adjustment |
40–59 | 450 mg daily |
25–39 | 450 mg q 48 h |
10–24 | 450 mg twice/week |
< 10 | Not recommended, use gancilcovir IV 1.25 mg/kg |
Anti-bacterial prophylaxis
Trimethoprim-sulfamethoxazole (Septra®, Bactrim®)
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All recipients will receive one single strength trimethoprim-sulfamethoxazole tablet po every day (adjusted to renal function) for 6–9 months based on the burden of immunosuppression [23].
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Patients with recurrent urinary tract infections may continue Septra® or other antibiotic prophylaxis for the duration of the graft survival.
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Patients who are allergic to Sulfa or who have documented (glucose 6 phosphate dehydrogenase (G6PD) deficiency will receive pentamidine inhalation 300 mg every month or dapsone 100 mg daily for 6 months [23]. UTI prophylaxis (oral ciprofloxacin or cefuroxime) should be continued in these patients for 6 months at least [24].
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Dose of trimethoprim-sulfamethoxazole will be adjusted to single dose three times per week in patients with GFR ≤ 30 ml/min
Surgical prophylaxis
Tuberculosis prophylaxis
Antifungal prophylaxis
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This is aimed predominantly at mucocutaneous Candida infection during multiple high dose steroid therapy and/or prolonged courses of antimicrobial therapy. Patients at risk of mucocutaneous Candida infection receive Nystatin (Mycostatin®) 500,000 IU swish and swallow 3–4 times per day for adults or clotrimazole torches for the duration of high dose steroid or antimicrobial therapy (i.e., ≥ 20 mg prednisone or equivalent) [29, 30].
Data collection and management
Informed consent
Ethical consideration and patient confidentiality
Glossary of abbreviations and definition of terms (Tables 1 and 2)
Term | Definition |
---|---|
ALT
| Alanine aminotransferase |
AE
| Adverse event |
ANC
| Absolute neutrophil count |
ANOVA
| Analysis of variance |
AST
| Aspartate aminotransferase |
AZA
| Azathioprine |
BCAR
| Biopsy-proven acute rejection |
BMI
| Body mass index |
BP
| Blood pressure |
CI
| Confidence interval |
CMV
| Cytomegalovirus |
CNI
| Calcineurin inhibitor |
CSA
| Cyclosporine |
EBV
| Epstein-Barr virus |
eGFR
| Estimated glomerular filtration rate |
FK
| Tacrolimus |
HBV
| Hepatitis B virus |
HIV
| Human immunodeficiency virus |
IVIG
| Intravenous immune globulin |
MMF
| Mycophenolate |
PK
| Pharmacokinetic(S) |
PRA
| Panel reactive antibodies |
PTDM
| Post-transplant diabetes mellitus |
PTLD
| Post-transplant lymphoproliferative disorder |
SrCr
| Serum creatinine |
Patient variable | Definition | ||
---|---|---|---|
Adverse events
| An AE is any untoward medical occurrence in a clinical investigation subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs also include the following: Pre- or post-treatment complications that occur as a result of protocol mandated procedure (e.g., such as venipuncture, biopsy) during or after screening (before the administration of study investigational medicinal product). Any pre-existing condition that increases in severity, or changes in nature during or as a consequence of the study investigational medicinal product phase of a human clinical trial, will also be considered an AE. | ||
Acute rejection
| Acute rejection will be defined as a clinico-pathological event requiring clinical evidence and biopsy confirmation. Allograft biopsies will be evaluated for the presence and severity of acute rejection by a blinded central independent pathologist using Banff 97 working classification of kidney transplant pathology. In the analyses of acute rejection, the biopsy interpretation and grading by the central pathologist will supersede local interpretation. Biopsies performed for suspected acute rejection that do not fully meet the criteria but are interpreted by the central pathologist as acute rejection and result in treatment for acute rejection, will be counted as acute rejection. Subclinical rejection is defined as histological findings by the central pathologist consistent with acute rejection, but lacking its clinical correlate. Steroid-resistant acute rejection is defined as the use of lymphocyte-depletion therapy following treatment with corticosteroids. | ||
Bone profile
| Serum calcium, albumin, phosphorus, and magnesium | ||
Chemistry
| Glucose, potassium, sodium, chloride | ||
Chronic allograft nephropathy (CAN)
| Biopsy-proven CAN will be determined by a central histopathologist using the Banff working classification of kidney transplant pathology. | ||
Coagulation
| INR, prothrombin time (PT), activated partial thromboplastin time (APTT) | ||
Creatinine clearance
| Creatinine clearance is calculated by the Cockcroft-Gault equation using ideal body weight (IBW). Male: CLcr (mL/min) = [140 − age (years)] × BW (kg)/72 × Scr Female: CLcr (mL/min) = [140 − age (years)] × BW (kg) × 0.85/72 × Scr | ||
Criteria for performing an allograft biopsy to assess for acute rejection
| 1. An unexplained rise of serum creatinine ≥25% from baseline creatinine 2. An unexplained decreased urine output 3. A serum creatinine that remains elevated within 14 days post-transplantation and clinical suspicion of acute rejection exists | ||
delayed graft function (DGF)
| A subject will be determined to have DGF if the subject is treated with dialysis within the first week (days 1–7) post transplantation. | ||
Graft Loss
| Graft loss is defined as either functional loss or physical loss. Functional loss will be defined as a sustained level of SCr ≥ 6.0 mg/dL (530 μmol/L) as determined by the central laboratory for ≥4 weeks or ≥ 56 consecutive days of dialysis, or impairment of renal function to such a degree that the subject undergoes re-transplant | ||
Hematology
| Hematocrit, hemoglobin (Hb), platelet count, red blood cell count (RBC), white blood cell count (WBC) with differential (absolute and percentage) including lymphocytes, monocytes, neutrophils, eosinophils, basophils, reticulocyte count, and mean corpuscular volume (MCV). | ||
Hypertension
| Hypertension will be as defined in this study according to the Eighth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [34, 35] for subjects with chronic kidney disease. This definition is based upon systolic blood pressure (SBP) ≥ 130 mmHg or diastolic blood pressure (DBP) ≥ 80 mmHg. In addition, all subjects who have a SBP < 130 mmHg and a DBP < 80 mmHg who are receiving an antihypertensive medication(s) for the indication of hypertension or with a medical history of hypertension are included in this definition. | ||
Immediate graft function (IGF)
| A subject will be determined to have IGF if SCr at Day 5 < 3.0 mg/dL (i.e., 260 μmol/L) and if the subject did not have DGF. | ||
Liver enzymes
| Alanine aminotransferase (ALT/SGPT), aspartate aminotransferase (AST/SGOT), albumin, alkaline phosphatase, direct bilirubin (screening only), total bilirubin, lipase | ||
Measures of acute rejection
| Acute rejection will be defined as a clinico-pathological event requiring clinical evidence and biopsy confirmation. Allograft biopsies will be evaluated for the presence and severity of acute rejection by a central independent pathologist using the most recent Banff working classification of kidney transplant pathology. | ||
Post-transplant diabetes mellitus (PTDM)
| PTDM will be defined according to the definition set forth by a recent international consensus guideline [36‐40]. These criteria are summarized as: • Symptoms of diabetes plus casual plasma glucose (PG) concentration ≥ 200 mg/dL (11.1 mmol/L) OR • fasting plasma glucose (FPG) ≥ 126 mg/dL (7.0 mmol/L) OR • 2-h Plasma Glucose ≥ 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (GTT) AND • A confirmatory laboratory test based on measurements of venous PG must be done on another day in the absence of unequivocal hyperglycemia accompanied by acute metabolic decompensation. | ||
Stages of chronic kidney disease
| The stages of chronic kidney disease are defined as set forth in the NKF-K/DOQI guidelines. | ||
Stage
|
Description
|
GFR (mL/min/1.73 m
2
)
| |
1
| Kidney damage with normal or ↑ eGFR | ≥ 90 | |
2
| Kidney damage with mild ↓ GFR | 60–89 | |
3
| Moderate ↓ GFR | 30–59 | |
4
| Severe ↓ GFR | 15–29 | |
5
| Kidney failure | < 15 (or dialysis) | |
Slow graft function (SGF)
| A subject will be determined to have SGF if SCr at day 5 ≥ 3.0 mg/dL (i.e., 260 μmol/L) and if the subject did not have DGF. |