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

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

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

Study Overview

• Status: Terminated
• Conditions: Renal Insufficiency, Chronic; Anemia; Vitamin D Deficiency; Kidney Transplantation
• Intervention / Treatment: Dietary supplement: cholecalciferol; Other: High Hb target

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 Type: Interventional
• Enrollment (Actual): 161
• Phase: Phase 4

Contacts and Locations

Study Locations

• Japan
  • Osaka
    • Suita, Osaka, Japan, 565-0871
      • CANDLE Trial Study Group

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / 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	Dietary supplement: cholecalciferol; 1,000 IU (1 tablet)/day, orally. Tablets are repacked into blister package.; Other Names: Super vitamin D (Nature Made®); 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in allograft kidney function	As allograft kidney function, GFR is estimated by the modified MDRD equation for Japanese patients with chronic kidney disease.	2 years

Secondary Outcome Measures

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

Other Outcome Measures

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

Collaborators and Investigators

• Sponsor: CANDLE-KIT Trial Study Group
• Collaborators: Chugai Pharmaceutical; Roche Diagnostics; The Japan Kidney Foundation; Japanese Society for the Promotion of Science
• Investigators: Study Director: Takayuki Hamano, MD, PhD, Department of Inter-Organ Communication Research in Kidney Disease, Osaka University Graduate School of Medicine

Publications and helpful links

General Publications

• Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A; Collaborators developing the Japanese equation for estimated GFR. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009 Jun;53(6):982-92. doi: 10.1053/j.ajkd.2008.12.034. Epub 2009 Apr 1.
• Gallagher JC, Sai A, Templin T 2nd, Smith L. Dose response to vitamin D supplementation in postmenopausal women: a randomized trial. Ann Intern Med. 2012 Mar 20;156(6):425-37. doi: 10.7326/0003-4819-156-6-201203200-00005. Erratum In: Ann Intern Med. 2012 May 1;156(9):672.
• Choukroun G, Kamar N, Dussol B, Etienne I, Cassuto-Viguier E, Toupance O, Glowacki F, Moulin B, Lebranchu Y, Touchard G, Jaureguy M, Pallet N, Le Meur Y, Rostaing L, Martinez F; CAPRIT study Investigators. Correction of postkidney transplant anemia reduces progression of allograft nephropathy. J Am Soc Nephrol. 2012 Feb;23(2):360-8. doi: 10.1681/ASN.2011060546. Epub 2011 Dec 22.
• Stevens LA, Schmid CH, Zhang YL, Coresh J, Manzi J, Landis R, Bakoush O, Contreras G, Genuth S, Klintmalm GB, Poggio E, Rossing P, Rule AD, Weir MR, Kusek J, Greene T, Levey AS. Development and validation of GFR-estimating equations using diabetes, transplant and weight. Nephrol Dial Transplant. 2010 Feb;25(2):449-57. doi: 10.1093/ndt/gfp510. Epub 2009 Sep 30.
• Horio M, Imai E, Yasuda Y, Watanabe T, Matsuo S. Modification of the CKD epidemiology collaboration (CKD-EPI) equation for Japanese: accuracy and use for population estimates. Am J Kidney Dis. 2010 Jul;56(1):32-8. doi: 10.1053/j.ajkd.2010.02.344. Epub 2010 Apr 22.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2013
• Primary Completion (Actual): December 1, 2018
• Study Completion (Actual): December 1, 2018

Study Registration Dates

• First Submitted: March 21, 2013
• First Submitted That Met QC Criteria: March 21, 2013
• First Posted (Estimate): March 25, 2013

Study Record Updates

• Last Update Posted (Actual): February 4, 2019
• Last Update Submitted That Met QC Criteria: January 31, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: Cardiovascular Diseases; Neoplasms; Hematinics; Cholecalciferol; Graft Rejection; Bone Diseases, Metabolic; Methoxy polyethylene glycol-epoetin beta
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Hematologic Diseases; Nutrition Disorders; Avitaminosis; Deficiency Diseases; Malnutrition; Renal Insufficiency, Chronic; Vitamin D Deficiency; Renal Insufficiency; Anemia; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: CKDR-001; UMIN000009970 (Registry Identifier: UMIN Clinical Trials Registry)