A Factorial Randomized Controlled Trial of Correcting Anemia and Native Vitamin D Supplementation in Kidney Transplant Recipients
Trial Snapshot
- Phase
- Phase 4
- Status
- Terminated
- Sponsor
- Enrollment
- 161
- Locations
- 1
- Primary Endpoint
- Change in allograft kidney function
Study Overview
Brief Summary
The purpose of this study is to evaluate the effect of anemia correction and vitamin D supplementation in kidney transplant recipients.
Detailed Description
Sample size estimation:
The previous trial (the CAPRIT study) showed that 2.0 g/dL increase of hemoglobin (Hb) reduced 69% of 2-year decline in estimated glomerular filtration rate (eGFR) (Choukroun G, et al. J Am Soc Nephrol, 2012). Given that the annual eGFR decline in our patients with Hb level <10.5 g/dL was 1.66 (SD, 2.47) mL/min per 1.73 m2, the investigators hypothesized that the 2-year eGFR decline in the conservative anemia management group and the aggressive anemia correction group should be 3.32 (SD, 4.94) and 1.03 (SD, 4.94) mL/min per 1.73 m2, respectively. In order to compare the actual efficacy of the intervention with the assumptions above and to evaluate the need for an early termination of the trial, the investigators will perform one interim analysis using a Pocock type α-spending function when a total of 50-60% of the target sample size completed this study or dropped out. Assuming 20% of dropout or lost-to-follow, the planned sample size of 272 patients would yield a power of 90% for group comparison by using t-test with a type I error of 5%.
Regarding cholecalciferol supplementation, 1,000 IU/day would increase serum 25-hydroxyvitamin D level by 11.8 ng/mL in patients with BMI <30, as suggested by the previous trial (Gallagher JC, et al. Ann Intern Med, 2012). The investigators found in our prospective cohort study that the 98.2% of Japanese kidney transplant recipients had BMI <30, and that 10 ng/mL increase in 25-hydroxyvitamin D level was significantly associated with 0.75 mL/min/1.73 m2 less decrease in annual eGFR change independent of potential confounders (in submission). As with the anemia intervention arms above, the investigators will perform one interim analysis using a Pocock type α-spending function when a total of 50-60% of the target sample size completed this study or dropped out in order to compare the actual efficacy of the intervention with the assumptions above and to evaluate the need for an early termination of the trial. Therefore, the investigators expect 1.77 mL/min per 1.73 m2 in eGFR would be preserved by 1,000 IU/day of cholecalciferol supplementation for 2 years. Based on this assumption, this study size will provide a power of 70%.
Estimating kidney function:
In primary analyses, eGFR will be calculated by using the Japanese equation as in sample size calculation (Matsuo S, et al. Am J Kidney Dis, 2009). However, this formula has not yet been validated in kidney transplant recipients. Therefore, the investigators will use the creatinine-based CKD-EPI equation with Japanese coefficient (Stevens LA, et al. Nephrol Dial Transplant, 2010. Horio M, et al. Am J Kidney Dis, 2010) and an available formula if validated in Japanese kidney transplant recipients at the time of analysis.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Factorial
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 20 Years to 79 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •≥15 and <60 ml/min per 1.73 m2 of estimated glomerular filtration rate
- •Transplanted allograft kidney at least 1 year before
- •<10.5 g/dL of Hb without iron deficiency (serum ferritin level ≥50 ng/ml) or on erythropoiesis stimulating agents treatment regardless of iron status
- •With written informed consent
Exclusion Criteria
- •On anticancer treatment
- •History of ischemic stroke or transient ischemic attack
- •Corrected serum calcium ≥10.5 mg/dL
- •HIV virus infection
- •Anticipated refractory hypertension by using epoetin beta pegol
- •In pregnancy and lactation
- •Current use of native vitamin D supplement
- •Patients ineligible according to the investigator's judgement
Arms & Interventions
Low Hb target without cholecalciferol
Target Hemoglobin level: ≥9.5 and <10.5 g/dL
High Hb target without cholecalciferol
Target Hemoglobin level: ≥12.5 and <13.5 g/dL
Intervention: High Hb target (Other)
High Hb target with cholecalciferol
Target Hemoglobin level: ≥12.5 and <13.5 g/dL Cholecalciferol: 1,000 IU/day
Intervention: High Hb target (Other)
High Hb target with cholecalciferol
Target Hemoglobin level: ≥12.5 and <13.5 g/dL Cholecalciferol: 1,000 IU/day
Intervention: cholecalciferol (Dietary Supplement)
Low Hb target with cholecalciferol
Target Hemoglobin level: ≥9.5 and <10.5 g/dL Cholecalciferol: 1,000 IU/day
Intervention: cholecalciferol (Dietary Supplement)
Outcomes
Primary Outcomes
Change in allograft kidney function
Time Frame: 2 years
As allograft kidney function, GFR is estimated by the modified MDRD equation for Japanese patients with chronic kidney disease.
Secondary Outcomes
- Urine markers of kidney injury(6 months)
- Cardiac biomarkers(2 years)
- Bone-turnover markers(6 months)
- Time to the renal composite endpoint(2 years)
- Time to admission-required cardiovascular events(2 years)
- Time to all-cause death(2 years)
- Biopsy-proven acute cellular rejection(2 years)
- Time to Cancer development or recurrence(2 years)
- The dose of methoxy polyethylene glycol epoetin beta required to maintain the target hemoglobin level(1 year)
- Left ventricular mass index(2 years)
- Blood pressure(2 years)
- Bone mineral density of lumber spine and femoral neck.(2 years)
- Hypercalcemia(2 years)