Introduction
In patients with chronic kidney disease on dialysis, one of the major complications is chronic kidney disease-mineral bone disorder. Chronic kidney disease-mineral bone disorder is often accompanied by secondary hyperparathyroidism, which nowadays is treated by vitamin D receptor activators (VDRAs) and calcimimetics. Calcimimetics allosterically bind to the calcium-sensing receptor of the parathyroid gland and not only strongly reduce serum parathyroid hormone (PTH) but also decrease serum calcium and phosphate levels. Therefore, the number of parathyroidectomies performed in patients with chronic kidney disease-mineral bone disorder has dramatically decreased.
The main target of treatment for chronic kidney disease-mineral bone disorder has been to reduce PTH levels; recently, the focus has been shifting to managing PTH levels to prevent the progression of vascular calcification. Once present, vascular calcification may progress rapidly, especially in patients on dialysis. Moe et al investigated the natural history of coronary artery calcification in haemodialysis patients and found a significant increase of 1.27 score/day.1 Vascular calcification occurs because of multiple conditions related to chronic kidney disease, including phosphate retention; apoptosis caused by vascular smooth muscle cells; transformation of vascular smooth muscle cells to osteoblast-like cells, which leads to extracellular accumulation of hydroxyapatite in the intravessel wall; and reduced amounts of matrix Gla protein and fetuin-A, both of which inhibit vascular calcification.
In patients on dialysis, hyperphosphataemia and hypercalcaemia are clinical risk factors for vascular calcification and hyperparathyroidism. Moreover, the severity of vascular calcification is related to mortality risk.2 International guidelines provide recommended target serum phosphate, calcium and PTH levels.3 Several trials have aimed to identify the efficacy of interventions to prevent vascular calcification. For example, Isaka et al showed that using phosphate binders to strictly control the serum phosphate level within the range of 3.5–4.5 mg/dL inhibits the progression of coronary artery calcification in haemodialysis patients.4 Sakaguchi et al found that in predialysis patients, magnesium oxide inhibits the progression of coronary artery calcification compared with carbon adsorbent.5 The CALIPSO study revealed that SNF 472, a selective inhibitor of hydroxyapatite formation and growth, attenuates the progression of vascular and cardiac valve calcification in haemodialysis patients.6 7 Regarding calcimimetics, the results of the prospective, randomised, controlled ADVANCE study indicated that cinacalcet attenuates the progression of vascular and cardiac valve calcification in haemodialysis patients with moderate to severe secondary hyperparathyroidism.8 Shoji et al showed that the calcimimetic etelcalcetide is more effective in increasing the T50 value, a surrogate marker of calcification stress, than the VDRA maxacalcitol in haemodialysis patients with secondary hyperparathyroidism.9 The main mechanisms by which calcimimetics are assumed to inhibit vascular calcification are by reducing not only the serum PTH level but also serum calcium and phosphate levels. Calcium-sensing receptors are located also on vascular smooth muscle cells, and stimulation of these receptors reduces vascular calcification in vitro and in vivo.10 11 Therefore, there is hope that the use of calcimimetics will be able to more effectively prevent or inhibit vascular calcification.
Moderate and severe vascular calcification is often already present in incident haemodialysis patients. For example, Kitamura et al reported that 37.5% of 96 incident haemodialysis patients had severe coronary artery calcification (defined as a coronary artery calcification score ≥400).12 Hence, management of vascular and cardiac valve calcification should be started early in haemodialysis patients, preferably just after dialysis initiation. Phosphate must be removed by dialysis in combination with phosphate binders. Moreover, calcimimetics can be used early if serum calcium levels are not too low and PTH is higher than the upper limit of the target range.
There were several previous reports about the inhibitory effects for progression of vascular calcification by calcimimetics. The dialysis duration of the patients in those studies was longer than that of our trial. However, to the best of our knowledge, no studies have included only participants with a relatively short dialysis duration. Vascular calcification has already much progressed at dialysis initiation and thereafter advanced rapidly. Under the condition, we emphasise that the feature of our trial is that we will enrol haemodialysis patients with a dialysis duration of <60 months.
Therefore, we plan to evaluate the efficacy and safety of early intervention with upacicalcet on coronary artery calcification in haemodialysis patients with secondary hyperparathyroidism in a multicentre, open-label, randomised controlled trial (UPCOMING).
Methods and analysis
Study design
The purpose of this study is to evaluate the efficacy and safety of upacicalcet, a calcimimetic, in the prevention of coronary artery calcification in haemodialysis patients with secondary hyperparathyroidism. This is a multicentre, open-label, randomised, parallel-group controlled study comprising an early intervention group, which will be treated by upacicalcet plus a VDRA, and a conventional therapy group, which will be treated only by a VDRA. The study period will be from 25 January 2023 to March 2025. The study will comprise a 24-week observation period, followed by a 52-week treatment period (figure 1). Patients who provide written informed consent to participate in the study will be tentatively enrolled, screened in the observation period to verify eligibility, enrolled and allocated to treatment. The early intervention group will receive upacicalcet plus a low-dose VDRA, and the conventional therapy group will receive only a VDRA. Coronary artery calcification will be evaluated with a calcium volume score and the Agatston score during the observation period and at week 52.
Study design. Ca, calcium; MDCT, multidetector CT; PTH, parathyroid hormone; VDRAs, vitamin D receptor activators.
The study will be conducted at seven university and general hospitals in Japan: Fujita Health University Bantane Hospital, Fujita Health University Hospital, Okazaki City Hospital, Daido Hospital, Toyota Memorial Hospital, Tokoname City Hospital and Nishichita General Hospital. The principal investigator of the study will be Dr. Daijo Inaguma at the Fujita Health University Bantane Hospital (Toyoake, Japan). Central laboratory tests will be performed by LSI Medience (Tokyo, Japan). The central evaluation of the calcium volume score and Agatston score will be performed by Musashi Image Joho Co. (Tokyo, Japan).
The study will be audited by CTA Corporation, an entity independent from the sponsor and investigators of this study. Audits will be conducted remotely (by using an electronic trial master file system (Agatha) and Zoom) or on site after the study is complete, and they will also be conducted at any other times as deemed necessary through consultation between the auditors and the principal investigator. The principal investigator, subinvestigators, study collaborators, clinical study office and any other relevant parties will be audited. Sites with the following characteristics will be selected for audits: high number of enrolled participants, fast enrolment rate, reports of serious adverse events, repeated protocol deviations, monitoring reports that indicate a number of issues with study conduct or use of a site management organisation. Documents to be reviewed will include the protocol, records of informed consent, medical records, records of procedures for reporting adverse events/non-compliance, electronic data capture (and correction) records and any other documents required for specified clinical trials. Auditors will prepare a report outlining the audit details and findings; they will submit the report to the principal investigator, who will prepare a response to any findings requiring corrective action. The auditors will review the response and request actions to be taken until all identified issues are resolved.
Statistical analysis, data management and monitoring will be performed independently by Satt Co (Tokyo, Japan). All study data will be accessible only to involved research staff. Personally identifiable information will be either protected with a password or deidentified to ensure confidentiality. Any important protocol modifications will be communicated promptly to investigators and study participants by Satt Co.
Outcomes
Primary endpoint
The primary endpoint of this study is the amount of change in the log coronary artery calcium volume score from baseline (observation period) to week 52.
Secondary endpoints
The study will have five secondary endpoints: (1) amount of change in the log-transformed Agatston score from baseline to week 52; (2) all-cause mortality during the study treatment period; (3) incidence of major adverse cardiovascular events during the study treatment period; (4) per cent change in blood chemistry parameters (phosphate (P), corrected calcium (Ca), product of p×corrected Ca, intact fibroblast growth factor 23, intact PTH) from baseline to each measurement during the study treatment period and (5) comparison of the severity of aortic valve stenosis at baseline and week 52.
Exploratory endpoints
In addition, the study will have seven exploratory endpoints, as follows: (1) amount of change in Agatston score; (2) aortic valve stenosis indexes based on echocardiography (maximum flow velocity at aortic valve (m/s), mean pressure gradient (mm Hg), peak pressure gradient (mm Hg), aortic valve area (cm2), aortic valve area index (cm2/m2), velocity ratio) and cardiac hypertrophy indexes (ratio of peak velocity between E wave of left ventricular inflow velocity waveform on septum side and lateral wall side to e’ wave of mitral annulus velocity waveform; mitral annulus velocity; left ventricular mass index; left atrial dimension; left atrial volume; left ventricular ejection fraction; left ventricular end-diastolic volume; left ventricular end-systolic volume; ratio of flow velocity between left ventricular early diastolic inflow velocity waveform and atrial contraction wave; inferior vena cava dimension; left ventricular end-diastolic dimension; left ventricular end-systolic dimension; interventricular septum thickness at end-diastole; posterior wall thickness at end-diastole); (3) haematology and blood chemistry values; (4) symptoms (nausea, vomiting, taste abnormality, diarrhoea, pruritus, numbness of limbs); (5) hypocalcaemia, hypercalcaemia; (6) change over time in use of phosphate binder and calcium preparations and (7) change over time in use of the study drug.
To assess coronary artery calcification, multidetector CT (MDCT) will be performed at each site, and data will be centrally evaluated and analysed.
Observation and examination
Table 1 summarises the schedule for collecting data on patient characteristics; haematology and blood chemistry values; MDCT; echocardiography findings; symptoms; use of the study drugs and concomitant drugs; onset of hypocalcemia (<7.5 mg/dL) and hypercalcaemia (≥11.5 mg/dL) and adverse events. Use of the study drugs and onset of hypocalcaemia and hypercalcaemia will be monitored throughout the study treatment period, whereas use of concomitant drugs and adverse events will be monitored throughout the observation and study treatment periods. If a serious adverse event occurs, investigators will provide appropriate treatment promptly. All adverse events determined as related to the study drug will be reported to the head of the site and the principal investigator according to the site’s standard operating procedures.
Study schedule
Interventions
Early intervention group
The early intervention group will receive upacicalcet plus a low-dose VDRA. Concerning VDRAs, dose increases and decreases within the allowable range predefined for this study, discontinuation and non-use will be allowed. Upacicalcet 25 µg/dose (initial dose) will be administered three times a week. An initial dose of upacicalcet of 50 µg/dose will be allowed when the serum-corrected Ca level is ≥9.0 mg/dL. The therapeutic targets of serum-corrected Ca, phosphate and PTH level were decided according to the Japanese guideline for the management of chronic kidney disease-mineral and bone disorder.13 The dose of upacicalcet can be increased every 2–4 weeks; the criteria for increase are an intact PTH>240 pg/mL with a serum-corrected Ca level ≥8.4 mg/dL. The dose can also be decreased; the criterion for a decrease is an intact PTH<60 pg/mL. Upacicalcet should be withdrawn if the intact PTH value is <60 pg/mL while upacicalcet 25 µg is being administered; the criterion for withdrawal of upacicalcet is a serum-corrected Ca level of <7.5 mg/dL. The dose of upacicalcet will be adjusted by applying these criteria so that the concentration of intact PTH is maintained in the range of 60–240 pg/mL.
In the early intervention group, only one type of VDRA may be used. The VDRA must be administered at a low dose, as follows: intravenous maxacalcitol, <7.5 µg/week; intravenous calcitriol, <1.5 µg/week and oral VDRAs, the lower limit of dose defined in the package insert. The VDRA dose can be increased every 2–4 weeks; the criterion for a dose increase or new start of a VDRA is a serum-corrected Ca level of <8.4 mg/dL even after the dose of a Ca preparation has been increased or such a preparation has been newly started. The criterion for a decrease in dose or withdrawal of VDRAs is a high level of serum-corrected Ca (≥ 11.0 mg/dL). After a dose decrease or withdrawal, the preparation can be readministered at the original dose.
Conventional therapy group
The conventional therapy group will receive one of the following VDRAs: calcitriol, maxacalcitol, alfacalcidol, falecalcitriol or eldecalcitol. Use of more than one type of VDRA is prohibited. The highest allowable dose is the dose specified in the dosage and administration section of the respective package insert. The dose can be increased every 2–4 weeks, whereby dose increases or decreases should be performed as specified in the respective package insert. Withdrawal should be considered when hypercalcaemia (ie, a serum-corrected Ca level ≥11.5 mg/dL) is noted. The dose of VDRAs should be adjusted as described to maintain an intact PTH value in the range of 60–240 pg/mL.
Prohibited concomitant therapy
Use of upacicalcet is prohibited in the conventional therapy group. Use of other calcimimetics, bisphosphonate, thyroid hormone preparations, antireceptor activator of nuclear factor-kappa B ligand (RANKL) monoclonal antibody and anti-sclerostin monoclonal antibody is prohibited in both groups.
Restricted concomitant therapy
In the event that the serum-corrected Ca level is <8.4 mg/dL or symptomatic hypocalcaemia occurs, the dose of Ca preparations should be increased or such preparations should be newly started. A change in the treatment regimen or a new start during the study treatment period is prohibited for oestrogen hormone preparations, synthetic oestrogen hormone preparations, selective oestrogen receptor modulators and calcitonin preparations. Furthermore, a change in the Ca concentration in dialysis solution is prohibited during the study treatment period.
Criteria for study discontinuation for each participant
Participation in the study will be discontinued if a participant meets any of the following criteria and the investigator considers that it is no longer possible for the individual to participate in the study: (1) transfer to another hospital; (2) worsening of condition or rejection of treatment; (3) deemed ineligible for the study after enrolment; (4) use of prohibited concomitant therapy; (5) request to be withdrawn from the study or withdrawal of consent to participate; (6) study treatment is discontinued for more than 4 weeks or (7) continuing participation in the study is not appropriate for other reasons.
Participants and informed consent
Patients meeting all of the inclusion criteria and none of the exclusion criteria will be enrolled in the study. Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research. The following inclusion criteria will be applied: (1) age 18 years or older at the time of informed consent; (2) use of dialysis is planned or dialysis duration <60 months at the time of informed consent; (3) serum intact PTH level >240 pg/mL or whole PTH level >140 pg/mL during the observation period (baseline); (4) serum-corrected Ca level >8.4 mg/dL during the observation period; (5) Agatston score >30 during the observation period; (6) no use of calcimimetics within 4 weeks prior to enrollment; (7) no use or dose change of VDRAs within 4 weeks prior to enrolment and (8) dose of VDRAs within 4 weeks prior to enrolment within the following range: intravenous maxacalcitol, <7.5 µg/week; intravenous calcitriol, <1.5 µg/week, oral α-calcidol or calcitriol, <0.5 µg/day.
The following exclusion criteria will be applied: (1) change in regimen or start/discontinuation of Ca preparation, phosphate binder or therapeutic drug for dyslipidaemia within 4 weeks prior to enrolment; (2) history of parathyroid intervention or fracture within 12 weeks prior to enrollment; (3) history of myocardial infarction, stroke or leg amputation within 12 weeks prior to enrolment; (4) history of coronary angioplasty; (5) heart failure of New York Heart Association class III or worse; (6) serious disease with life expectancy of 1 year or less; (7) aspartate transaminase or alanine transaminase >3 times the institutional upper limit of normal; (8) pregnancy, breast feeding or desire to become pregnant within 1 year; (9) allergy to upacicalcet or VDRAs and (10) use of bisphosphonate, thyroid hormone preparation (teriparatide acetate), anti-RANKL monoclonal antibody or antisclerostin monoclonal antibody within 6 months prior to enrolment and (11) being unsuitable for the study in the opinion of the investigator.
Randomisation
The patients will be enrolled into the study centrally. They will be randomised by dynamic allocation with the minimisation method to either the early intervention group or the conventional therapy group at a ratio of 1:1, with age (18–64 years old, ≥65 years old), Agatston score during the observation period (30–400, 401–1000, ≥1001) and study site as stratification factors.
Patient and public involvement
Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this study at any stage of the research process.
Sample size
The planned sample size for this study is 250 patients: 125 patients in the early intervention group (study treatment group) and 125 patients in the conventional therapy group (control group). A power analysis was performed by considering the primary endpoint, that is, the change in log coronary artery calcium volume score from baseline (observation period) to 52 weeks after the start of study treatment. The hypotheses are (1) the early intervention group will improve by 0.104 (SD 0.215) and (2) the conventional therapy group will improve by 0.182 (SD 0.218). The sample size needed to test these hypotheses at a two-sided 5% level of significance and 80% power was 250 cases (for both groups combined). The predictive value of these hypotheses was based on the results of three studies (CALIPSO, EPISODE, ADVANCE).4 7 8
Data management and statistical analysis
All statistical analyses will be performed by Satt Co. with Statistical Analysis Software (V.9.4 for Windows; SAS Institute). Analyses of efficacy endpoints will be performed in the intention-to-treat population, full analysis set (FAS) and per-protocol set (PPS); the analysis in the PPS will be a reference analysis. No interim analysis is planned.
The FAS will include all enrolled and randomly assigned study participants, apart from the following:
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Study participants for whom written informed consent has not been obtained; study participants at sites where certified review board approval has not been obtained; study participants who are in serious non-compliance with ethical guidelines.
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Study participants who never received any study treatment.
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Study participants for whom no post-enrolment efficacy data are available.
The PPS will be the FAS population without the following participants:
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Study participants who do not meet the inclusion criteria or who violate the exclusion criteria.
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Study participants who have been continuously administered prohibited concomitant therapies.
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Study participants with other serious study protocol violations.
If any endpoint measurements are missing, the last observation carried forward method will be applied. Data obtained after the start of study treatment will also be used.
For the primary endpoint, the following will be calculated for each treatment group: (1) log coronary artery calcium volume score; (2) summary statistics (mean, SD, median, IQR, range) of the measured values in the observation and 52-week study treatment periods and (3) change from the observation period. The summary statistics will be displayed as inverse log-transformed values. The log-transformed calcium volume score will be used as the dependent variable. The linear mixed model will be analysed with the subjects as a random effect and the treatment group, time period (observation period and 52-week study treatment period) and their interaction (treatment group×time period) as fixed effects. The calcium volume score in the observation period will be used as a covariate. A compound symmetry covariance structure will be selected. Estimates (least squares means) at each time point for each treatment group, estimates of the amount of change in each treatment group and estimates of the difference in the amount of change between treatment groups will be calculated with 95% CIs. Tests with the linear mixed model will include a test of the difference in the amount of change between treatment groups and a test of the difference between time periods in each treatment group.
For secondary endpoints, continuous variables will be analysed in the same manner as the primary endpoint. For all-cause mortality and occurrence of cardiovascular events, a Kaplan-Meier survival curve will be plotted; in addition, a log-rank test will be performed with the zero-point set at the start of study treatment. For nominal variables, frequencies and percentages will be calculated.
In addition, a sensitivity analysis will be performed in which the change in the endpoints will be corrected for the number of follow-up days (baseline to endpoint acquisition date). This analysis will add the follow-up period as a covariate to the linear mixed model analysis for the primary endpoint and some secondary endpoints.
The safety analysis population will comprise all randomised study participants who have received at least one study treatment. Safety endpoints will be analysed in the safety analysis population. For the safety analysis, summary statistics of vital signs and laboratory tests at each time point will be calculated and evaluated. In addition, the frequency of adverse events and diseases will be tabulated.
Stratified analysis by some variables including age, sex, comorbidity of diabetes, history of coronary artery disease, coronary artery calcium volume and interim are planned for this study.
Discussion
This study is an open-label, randomised controlled trial designed to evaluate the efficacy and safety of upacicalcet, a calcimimetic, in preventing the progression of coronary artery calcification in patients on haemodialysis with a dialysis duration of <60 months.
According to the evaluation of vascular calcification, we used coronary artery calcium volume. There are some vascular sites evaluated for calcification among previous reports. Thoracic and abdominal aorta calcification were also measured. Although the mechanisms between calcification of coronary artery and aorta were not same completely, Zhang et al showed that prevalence and progression rate were similar in coronary artery and abdominal aorta.14 In addition, we thought that the participants needed to prevent extra radiation exposure.
We have decided to use the amount of change in the log coronary artery calcium volume score instead of Agatston score from baseline to week 52 as the primary endpoint. Agatston score was one of the best to evaluate calcification in various sites including artery and cardiac valve. Since the Agatston score is widely used, we thought it would be easy to use to select targets when implementing research results in society. Therefore, it was used as an eligible criterion. On the other hand, it has been reported that calcium volume score is more robust, has higher reproducibility and has a smaller variance than Agatston, so we used calcium volume score as the primary endpoint.6 15
Currently, the calcimimetics clinically used in Japan include oral cinacalcet, oral evocalcet, intravenous etelcalcetide and intravenous upacicalcet. Among these drugs, upacicalcet, which was developed in Japan, has advantages in terms of pharmacokinetics and pharmacology.16 It has fewer inhibition and induction effects on various drug-metabolising enzymes; it is excreted by dialysis because it is not metabolised in vivo, so when it is administered to patients on dialysis, its effects last until the next dialysis session; and patient adherence to treatment does not need to be considered because it is administered to the dialysis circuit as an injection.16 So far, no reports describe the efficacy of upacicalcet in preventing coronary artery calcification or the effects of upacicalcet on prognosis, so our study aims to close this knowledge gap. Evidence that upacicalcet-based early intervention is beneficial for preventing coronary artery calcification may lead to updates in the treatment strategy for chronic kidney disease-mineral bone disorder.
A limitation of this study is that it is open label. However, the open-label design is likely to have no or at most a limited effect on the results because the primary endpoint, the calcium volume score, will be rated by an independent body blinded to patient group allocation.
Ethics and dissemination
This study will be performed in accordance with the ethical principles of the Declaration of Helsinki. It will also comply with the Japanese Clinical Trials Act (Act No. 16, 2017), the Regulation for Enforcement thereof (Ministerial Ordinance No. 17, 28 February 2018) and relevant notifications. The study was approved by the Fujita Health University Certified Review Board (Toyoake, Japan; file no. CR22-052; Protocol V.1.3 dated 16 December 2022). It was registered in the Japan Registry of Clinical Trials on 25 January 2023 (registration number: jRCTs041220126). The investigators will fully explain the nature and procedure of this study to the candidate participants, confirm that they have sufficiently understood the information, and obtain written consent from them to voluntarily participate in the study.
To minimise the participants’ risk of exposure to radiation, MDCT will be performed only twice (at baseline and the final evaluation).
The findings obtained from this study will be presented at academic meetings and in peer-reviewed academic journals.
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