CANDLE-KIT: Correcting Anemia and Native Vitamin D Supplementation in Kidney Transplant Recipients

Sponsor

CANDLE-KIT Trial Study Group (Other)

Overall Status

Terminated

CT.gov ID

NCT01817699

Collaborator

Chugai Pharmaceutical (Industry), Japanese Society for the Promotion of Science (Other), The Japan Kidney Foundation (Other), Roche Diagnostics (Industry)

161

Enrollment

Location

Arms

Actual Duration (Months)

2.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effect of anemia correction and vitamin D supplementation in kidney transplant recipients.

Condition or Disease	Intervention/Treatment	Phase
Kidney Transplantation Anemia Vitamin D Deficiency Renal Insufficiency, Chronic	Other: High Hb target Dietary Supplement: cholecalciferol	Phase 4

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.

Statistical analyses:

For group comparison in a primary analysis, the investigators will use t-test or Wilcoxon rank sum test according to the distribution of eGFR change. In the further analyses, to analyze the time course of eGFR with respect to treatment assignment, changes in eGFR over time will be analyzed with a linear mixed model for repeated measures with both fixed and random intercept and slope. The multivariate model will contain time-varying eGFR as dependent variable and treatment group as well as the number of measurements (time) as independent variables. The study hypothesis will be tested by adding appropriate interaction terms between the exposures and time. For secondary endpoints, the investigators will use t-test, Wilcoxon rank sum test, or log-rank test for group comparison, and generalized linear models or Cox proportional hazards models to estimate each effect of the interventions, appropriately. The investigators will also adjust for baseline levels or past history of each outcome. Other potential confounders, such as age, sex, time since transplantation, blood pressure, urinary protein level, and diabetes, will be adjusted in sensitivity analyses.

The interaction will be checked between anemia management and cholecalciferol supplementation as well as between each intervention and baseline levels of urinary protein, eGFR, Hb, 25-hydroxyvitamin D, the use of active vitamin D compounds, and the length of time since transplantation. Additionally, stratified analyses will be conducted according to 0.2 g/g･creatinine of urinary protein and the date of transplantation (November 1999, the release date of mycophenolate mofetil in Japan). However, the study size is not large enough to statistically evaluate these interactions. The results from these analyses should be interpreted with caution and regarded as exploratory and hypothesis generating.

Missing values:

Missing values will not be imputed in primary analyses. In sensitivity analyses, the investigators will use multiple imputation method and last-observation-carried-forward method.

Note:

The interim analysis plan was added to the protocol with an increase in the sample size from 246 to 272, which has been approved by the local ethics committee on August 27, 2018.

Study Design

Study Type:

Interventional

Actual Enrollment :

161 participants

Allocation:

Randomized

Intervention Model:

Factorial Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Factorial Randomized Controlled Trial of Correcting Anemia and Native Vitamin D Supplementation in Kidney Transplant Recipients

Actual Study Start Date :

Apr 1, 2013

Actual Primary Completion Date :

Dec 1, 2018

Actual Study Completion Date :

Dec 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Low Hb target without cholecalciferol Target Hemoglobin level: ≥9.5 and <10.5 g/dL
Active Comparator: Low Hb target with cholecalciferol Target Hemoglobin level: ≥9.5 and <10.5 g/dL Cholecalciferol: 1,000 IU/day	Dietary Supplement: cholecalciferol 1,000 IU (1 tablet)/day, orally. Tablets are repacked into blister package. Other Names: Super vitamin D (Nature Made®)
Active Comparator: High Hb target without cholecalciferol Target Hemoglobin level: ≥12.5 and <13.5 g/dL	Other: High Hb target 25 to 250 μg of methoxy polyethylene glycol epoetin beta (Mircera®, Chugai pharmaceutical Co. Ltd.) will be administered subcutaneously at 2- to 6-week interval. Dose and interval will be adjusted according to hemoglobin level and its target.
Experimental: High Hb target with cholecalciferol Target Hemoglobin level: ≥12.5 and <13.5 g/dL Cholecalciferol: 1,000 IU/day	Other: High Hb target 25 to 250 μg of methoxy polyethylene glycol epoetin beta (Mircera®, Chugai pharmaceutical Co. Ltd.) will be administered subcutaneously at 2- to 6-week interval. Dose and interval will be adjusted according to hemoglobin level and its target. Dietary Supplement: cholecalciferol 1,000 IU (1 tablet)/day, orally. Tablets are repacked into blister package. Other Names: Super vitamin D (Nature Made®)

Outcome Measures

Primary Outcome Measures

Change in allograft kidney function [2 years]
As allograft kidney function, GFR is estimated by the modified MDRD equation for Japanese patients with chronic kidney disease.

Secondary Outcome Measures

Urine markers of kidney injury [6 months]
protein-creatinine ratio liver type fatty acid binding protein (L-FABP) neutrophil gelatinase-associated lipocalin (NGAL) transforming growth factor (TGF)-β.
The dose of methoxy polyethylene glycol epoetin beta required to maintain the target hemoglobin level [1 year]
For vitamin D supplementation study only.
Blood pressure [2 years]
Cardiac biomarkers [2 years]
brain natriuretic peptide (BNP) cardiac troponin-T (cTnT).
Left ventricular mass index [2 years]
Biopsy-proven acute cellular rejection [2 years]
Bone-turnover markers [6 months]
intact parathyroid hormone (1-84 PTH) bone-type alkaline phosphatase tartrate-resistant acid phosphatase 5b (TRACP-5b) For vitamin D supplementation study only.
Bone mineral density of lumber spine and femoral neck. [2 years]
For vitamin D supplementation study only.
Hypercalcemia [2 years]
Corrected calcium ≥11 mg/dL For vitamin D supplementation study only.
Time to the renal composite endpoint [2 years]
renal composite endpoint consists of 50% increase in serum creatinine, subsequent transplantation, and reinitiation of dialysis.
Time to admission-required cardiovascular events [2 years]
Cardiovascular events includes myocardial infarction, angina, congestive heart failure, stroke, and peripheral artery disease.
Time to all-cause death [2 years]
Time to Cancer development or recurrence [2 years]

Other Outcome Measures

C-reactive protein [1 year]
For vitamin D supplementation study only.
Time to the adverse composite endpoint [2 years]
The adverse composite endpoint consists of death, admission-required cardiovascular diseases, and the renal composite endpoint.
Time to hospitalization for opportunistic infections [2 years]
Opportunistic infections includes polyomavirus-associated nephropathy, tuberculosis, Pneumocystis carinii pneumonia, cytomegalovirus infection, herpes zoster, bacterial pneumonia. For vitamin D supplementation study only.

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 79 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CANDLE Trial Study Group	Suita	Osaka	Japan	565-0871

Sponsors and Collaborators

CANDLE-KIT Trial Study Group
Chugai Pharmaceutical
Japanese Society for the Promotion of Science
The Japan Kidney Foundation
Roche Diagnostics

Investigators

Study Director: Takayuki Hamano, MD, PhD, Department of Inter-Organ Communication Research in Kidney Disease, Osaka University Graduate School of Medicine