Clinical Kidney Journal, 2018, 1–7 doi: 10.1093/ckj/sfy039 Original Article OR I G I N AL A R T I C L E Placebo-controlled, randomized clinical trial of high-dose cholecalciferol in renal dialysis patients: effect on muscle strength and quality of life 1,2 3,4 1,2 1,2 Richard Singer , Bobby Chacko , Girish Talaulikar , Krishna Karpe and 1,2 Giles Walters 1 2 Renal Unit, The Canberra Hospital, Garran, ACT, Australia, Australian National University School of Medicine, Acton, ACT, Australia, Nephrology and Transplantation Unit, John Hunter Hospital, New Lambton, NSW, Australia and School of Medicine and Public Health, University of Newcastle, NSW, Australia Correspondence and offprint requests to: Richard Singer; E-mail: Richard.firstname.lastname@example.org; Twitter handle: @richardfsinger ABSTRACT Background. The importance of vitamin D sufﬁciency in deﬁcient dialysis patients is uncertain. This study aimed to determine if high-dose cholecalciferol for 1-year affected symptoms, muscle strength, blood pressure (BP), cardiac ischaemia, parathyroid hormone, calcium or phosphate. Methods. This was a randomized, double-blind, placebo-controlled trial with 1-year follow-up that enrolled dialysis patients with 25-hydroxy-vitamin D [25(OH)D] concentration <50 nmol/L. Consenting patients were randomized to 50 000 U/week oral cholecalciferol or matching placebo. Dosage was adjusted at 3- and 6-month study visits, targeting a 25(OH)D concentration >80 nmol/L. The primary objectives were to assess the effect of supplementation on renal-speciﬁc symptoms and on hand-grip strength. Symptoms were assessed using the Kidney Disease Quality of Life Short Form and muscle strength with a hand grip-strength dynamometer. Hypothesis testing was by two-group t-test and Wilcoxon rank- sum on an intention-to-treat basis. Results. In all, 68 participants were randomized and received study medication. Median 12-month plasma 25(OH)D concentration was 119 nmol/L and 37 nmol/L in the cholecalciferol and placebo groups, respectively. There was no statistical difference in primary outcomes at 12 months. Mean symptom scores at 12 months were two lower in the cholecalciferol group (95% conﬁdence interval 10 to 6) and geometric mean grip-strength was 27 kg in both groups. Symptoms, strength, BP, plasma mineral bone parameters and adverse events were not different between the groups at follow-up. Conclusions. High-dose cholecalciferol in a deﬁcient dialysis population had no effect on muscle strength or symptoms but appears safe. Keywords: cholecalciferol, clinical trial, muscle strength, quality of life, renal dialysis Received: 13.2.2018. Editorial decision: 17.4.2018 V C The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact email@example.com Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy039/5032500 by Ed 'DeepDyve' Gillespie user on 07 June 2018 2| R. Singer et al. All participants provided written informed consent prior to INTRODUCTION enrolment. The study was approved by the ACT Health Human Vitamin D status is determined by the 25-hydroxy-vitamin D Research Ethics Committee (ETH.11.9.1004), the Hunter New [25(OH)D] concentration  and levels are often low in dialysis England Human Research Ethics Committee (12/12/12/4.01) and patients [2–4]. In the chronic kidney disease (CKD) population the NSW Human Research Ethics Committee (HREC/12/HNE/ there is an association between higher 25(OH)D levels and im- 466). It was prospectively registered on the ANZ Clinical Trials proved cardiovascular mortality [2, 5, 6], muscle strength and Register (ACTRN12611001260910). All persons gave informed blood pressure (BP) . However, available randomized trial data consent prior to their inclusion in the study and it was con- are negative for an effect on erythropoietin dose (n¼ 252) , pro- ducted in accordance with the Declaration of Helsinki. The brain naturiuretic peptide (n¼ 50) , muscle strength (n ¼ 45) study was part funded by The Canberra Hospital Private  and depressive symptoms (n ¼ 726) . There are limited Practice Fund and remaining funding was internal. non-randomized data in the non-CKD population that supports Study visits were at baseline, and 3, 6 and 12 months. At an effect of vitamin D on strength and body pain . The Kidney study visits, each subject’s medical record was reviewed for any Disease Improving Global Outcomes (KDIGO) guideline suggests, plasma cardiac troponin tests that had been performed since with evidence grade C (low), that deficiency in dialysis patients is the last study visit and subjects were questioned about poten- treated the same as for the non-dialysis population . The 2011 tial adverse effects, admissions to hospital or cardiac events Endocrine Society Guidelines defined vitamin D deficiency as since the last study visit. All reported events were confirmed by plasma 25(OH)D <50 nmol/L and recommended supplementing examination of the clinical medical record. Cardiac troponins to a 25(OH)D >75 nmol/L . This definition of deficiency was were anticipated to be performed at different laboratories with adopted for the purposes of the current study. no study control over the specific method used. A troponin was The vitamin D dose required to reach a particular plasma considered ‘positive’ if it was recorded as being over the labora- 25(OH)D level varies . Doses of 70 000 U/week for 4 months tory reference range for the method used. At study visits muscle appear to be safe in non-CKD populations  and such dosing strength was tested, quality of life assessed and plasma; is similar to the estimated dose received from daily whole-body 25(OH)D, calcium and phosphate were collected. Plasma exposure to sunlight . It is accepted that sunlight exposure 25(OH)D was assayed using the LIAISON total vitamin D chemi- does not cause vitamin D toxicity , despite sometimes luminescence assay (DiaSorin, Saluggia, Italy). Quality of life resulting in serum concentrations of 250 nmol/L . There is, was assessed using the Kidney Disease Quality of Life Short however, no defined level that denotes vitamin D toxicity. Form (KDQOL-SF) 1.3 (Rand Corp., Santa Monica, CA, USA) . The primary objectives of this study were to determine if The KQQOL-SF is divided into domains, including a 12-item re- oral cholecalciferol supplementation to achieve a plasma nal failure specific symptom domain. All domains in the 25(OH)D concentration >80 nmol/L affected symptoms or hand KDQOL-SF have a possible range of 0–100, with higher scores in- grip muscle strength in a dialysis population with baseline dicating better quality of life. Muscle strength was assessed us- 25(OH)D concentration below 50 nmol/L. Hand grip strength, ing a Smedley hand grip dynamometer (Sportstek, Victoria, rather than proximal muscle testing, was selected because it is Australia). Subjects attempted three maximum contractions on simple to measure in a chair and because, based on previous ex- each side, in a seated position with the arm hanging by the side, perience of the authors in studying the local dialysis population, the forearm flexed to 90% and the wrist in a neutral position. it was considered likely that many potential study subjects The best recorded force on each side was recorded and primary would decline participation if testing was mandated at large analysis was based on the recording from the dominant hand. joints. Secondary objectives were to determine the effect on BP, cardiac ischaemia, and on plasma parathyroid hormone (PTH), Randomization calcium and phosphate. A target 25(OH)D >80 nmol/L was se- lected to ensure that all subjects in the active group achieved Randomization was by computer-generated random number concentrations >75 nmol/L. (http://www.randomizer.org) in balanced blocks of 10, stratified by the presence of diabetes and sex. Drug allocation codes were placed in separate, consecutively numbered, opaque, sealed MATERIALS AND METHODS envelopes that were opened in sequence at the time of Patients receiving peritoneal, satellite or home haemodialysis randomization. between 1 May 2012 and 30 April 2015 at the Canberra Hospital Renal Unit or between 1 August 2013 and 30 April 2015 at the Intervention, blinding and monitoring John Hunter Hospital Renal Unit were eligible for enrolment. Each participant was randomized to receive one capsule per Inclusion criteria were that patients gave written informed consent to participate, were clinically stable, had been receiving week containing either 50 000 U of cholecalciferol or placebo. Capsules were identical in appearance and taste and were pre- maintenance dialysis for at least 3 months and had a 25(OH)D pared by Ainslie Chemmart Compounding Pharmacy (Ainsle, level <50 nmol/L. Exclusion criteria at enrolment were chronic granulomatous disorders, severe bilateral hand arthritis, ACT, Australia). The content of capsules (active or placebo) was not provided to investigators until after the final participant plasma albumin corrected calcium >2.55 mmol/L, plasma phos- phate >3.0 mmol/L, age <18 years, discharge from an overnight exited the study. Both participants and study personnel were hospital admission within the preceding 4 weeks, life expec- blinded as to drug allocation. tancy <12 months, commencement of calciferol within the pre- At each study visit, adherence to study medication dosing vious 3 months or unwillingness to avoid commencement of was assessed by means of a pill count on study medication bot- tles for home dialysis participants. Adherence for nurse admin- new non-study calciferol for the duration of the study. Patients whose renal replacement therapy was haemodialysis could not istered medication was by review of the hospital medication receive it >3 times/week or for >18 h/week or receive it less of- chart, and plasma 25(OH)D, calcium, phosphate and PTH con- ten than twice/week. centrations were measured. To minimize the risk of inadvertent Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy039/5032500 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Cholecalciferol in dialysis study | 3 un-blinding, data entry was based on a unique study ID and the (i) The distribution of KDQOL-SF symptom subscale scores in haemodialysis patients would be normally distributed, with actual plasma concentration of 25(OH)D was not visible to mean of 71 and SD of 16.6 . A score difference of 10 was investigators within the database. An albumin adjusted plasma considered to be clinically signiﬁcant and a sample size of calcium (mmol/L) was calculated from the total plasma calcium 88 was calculated to provide 80% power to detect a change (Ca) and plasma albumin (g/L) according the formula: of at least this magnitude, with a two-sided alpha of 5%. (ii) Mean hand grip strength in males on peritoneal dialysis, Adjusted Ca ¼ Total Caþð44 albuminÞ0:015 when measured using a Smedley hand dynamometer (Sportstek) is 24.8kgwith SD of 10.3 kg . Based on data At the 3- and 6-month study visits the dose of study medica- from a similar device showing 33% lower hand-grip strength tion was adjusted to between zero and three capsules per week, in malnourished (compared with well-nourished) men with based on the plasma 25(OH)D concentration (Table 1). All severe CKD , the same proportionate difference using the plasma calcium, phosphate and PTH results were also moni- Smedley device (8.3 kg) was considered clinically signiﬁcant. tored by participants’ usual physicians. Prescription of phos- A sample size of 50 subjects was calculated to provide 80% phate binders, calcitriol, dialysate calcium and cinacalcet were power, with two-sided alpha of 5% to detect an 8.3 kg strength adjusted according to the instructions of the treating physician. difference. The dose of calcium carbonate phosphate binders varied from 500 to 600 mg elemental calcium per tablet. Many patients pur- chased these without use of a written prescription and were RESULTS usually uncertain which strength calcium carbonate they were Enrolment commenced in May 2012 and the last patient was en- taking. For the purposes of reporting, all calcium containing rolled in April 2015. Participant flow through the study is shown phosphate binders were assumed to contain 550 mg elemental in Figure 1. In all, 70 participants were randomized to receive calcium. study medication. Two participants were withdrawn post-ran- domization but before receiving study medication and these Statistics withdrawals were not included in subsequent analyses. Participants that withdrew from the study were included in Data are presented as mean6 SD or median with interquartile analyses until the date of withdrawal only. The only exception range (IQR), as appropriate. Hypothesis testing for categorical to this was for the single participant that was withdrawn after outcomes was by Fisher’s exact test and for continuous out- deciding to cease all active medical treatment (including dialy- comes was by t-test, analysis of variance or Wilcoxon rank- sis). That patient died soon after withdrawal and was counted sum, as appropriate. Analysis of secondary endpoint was con- as a death during the study. sidered exploratory. Statistical analysis was performed using Participants were well matched at baseline. Mean age at en- Stata14 (StataCorp, College Station, TX, USA). Analysis was by rolment was 59.56 15.6 years (cholecalciferol group) and intention-to-treat (randomized group) with all P-values two 63.86 14.2 years (placebo group)—P-value for difference 0.25. sided. The null hypothesis was rejected at a significance level A total of 32% of participants were female and half were diabetic. of <0.05. There were no significant differences in KDQOL-SF domain scores. Baseline data are summarized in Table 2. Mean baseline Sample size and power analysis 25(OH)D levels were similar between groups and did not vary according to season of enrolment (P¼ 0.31). Adherence was ex- A target sample size of 88 was calculated to achieve at least 80% cellent; however, the introduction of a new electronic medical power, with two-tailed alpha 5%, to detect a minimum clinically record during the study period resulted in incorrect transcribing significant change in both primary outcomes. This calculation of some nurse-administered medications. This affected four was based on the following assumptions: participants, with another five missing doses due to changing their dialysis location or delays in posted medication reaching Table 1. Study medication dose adjustment algorithm at 3- and them. In total, 31 study medication doses were not received by 6-month visits participants during the study (representing 1% of the prescribed doses). Adherence in three home dialysis participants was un- 25(OH)D certain as they failed to return study medication bottles for a pill concentration Study medication dose adjustment count. 250 nmol/L Dosing ceased until next study visit At the 12-month visit all patients in the active group and 200 to <250 nmol/L Dosing withheld for 4 weeks and then re- 13% of patients in the placebo group had a plasma 25(OH)D con- sumed at quadruple the previous dosing centration over 80 nmol/L. The median plasma 25(OH)D was interval 82 nmol/L higher in the cholecalciferol group (119 nmol/L; IQR 175 to <200 nmol/L Dosing interval doubled 101–157 nmol/L) than the in the placebo group (37 nmol/L; IQR 80 to <175 nmol/L Dosing continued at current frequency or, if 28–57 nmol/L). The highest 25(OH)D recorded at any time during previous 25(OH)D level 250 nmol/L, then the study in the active group was 185 nmol/L. The median dose recommence dosing at one capsule every 4 of active and placebo tablets at 12 months was one and three weeks capsules, respectively. <80 nmol/L Double the weekly dose (to a maximum of Three participants completed 12 months in the study but did three capsules per week) or halve the dos- not provide 12-month primary outcome data and 12-month BP ing interval if current dosing interval is lon- data (one received a cadaveric renal transplant on the day of the ger than weekly. If previous 25(OH)D level 12-month study visit at a different hospital, one was uncon- 250 nmol/L, then recommence dosing at scious in the intensive care unit and another declined). one capsule every 2 weeks Geometric mean dominant hand strength was 27 kg in both the Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy039/5032500 by Ed 'DeepDyve' Gillespie user on 07 June 2018 4| R. Singer et al. FIGURE 1: Study participant ﬂow. cholecalciferol and placebo study groups at 12 months and the groups was 10 to 6. Re-analysis restricted to those with more median strength was 26 kg (IQR 22–38 kg) and 27 kg (IQR 19–39 severe baseline vitamin D deficiency [those with 25(OH)D kg), respectively. The P-value for the comparison of medians plasma concentration <27.5 nmol/L] did not alter these findings. was 0.81. The data were not suitable for hypothesis testing by No significant differences were seen between study groups in t-test (as had been planned prior to commencing the study). other KDQOL-SF domains. There was no significant difference at the 12-month visit for the There was no difference between study groups at 12 months other primary outcome, with no difference in KDQOL-SF symp- in BP or in adjusted plasma calcium, phosphate or PTH. Cardiac tom scores between the active (score 736 15) and the placebo ischaemia was assessed as either the occurrence of a myocar- dial infarction (as diagnosed by the treating physicians), or as a group (score 756 14), with P-value 0.66. The 95% confidence in- terval for the difference in symptom scores between study participant recording a positive troponin I (no positive troponin Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy039/5032500 by Ed 'DeepDyve' Gillespie user on 07 June 2018 Cholecalciferol in dialysis study | 5 Table 2. Baseline data Variable Cholecalciferol (n ¼ 36) Placebo (n ¼ 32) P-value Age (years) 59.56 15.6 63.86 14.2 0.25 Female sex 13 9 0.61 Peritoneal dialysis 3 3 1.0 Mean systolic BP (mmHg)6 SD 142.16 18.8 142.26 19.4 0.98 Mean diastolic BP (mmHg)6 SD 74.96 13.3 71.66 11.2 0.26 Peritoneal dialysis 3 3 1 Median dialysis vintage in months (IQR) 21.7 (5.3–54.9) 7.6 (3.7–43.1) 0.27 Diabetic 18 16 1.0 Median adjusted plasma calcium in mmol/L (IQR) 2.3 (2.11–2.4) 2.33 (2.25–2.41) 0.25 Median plasma phosphate in mmol/L (IQR) 1.59 (1.22–2.15) 1.64 (1.41–2.14) 0.51 Median plasma PTH in pmol/L (IQR) 37 (15.3–62.6) 33 (13.9–57.4) 0.45 Mean 25(OH)D (nmol/L)6 SD 33.96 9.0 33.86 11.2 0.96 Median dominant hand strength in kg (IQR) 27.5 (22–37.5) 24 (20–35.8) 0.46 Mean KDQOL-SF symptom score6 SD 70.46 13 73.26 13.8 0.39 t-test of log transformed data. Table 3. Secondary outcomes at 12 months Outcome Cholecalciferol (n ¼ 29) Placebo (n ¼ 26) P-value a b Mean systolic BP (mmHg) 6 SD 1426 21 1436 19 0.78 Mean diastolic BP (mmHg)6 SD 736 15 736 15 0.86 Median adjusted plasma calcium in mmol/L (IQR) 2.35 (2.23–2.46) 2.38 (2.32–2.45) 0.49 Median plasma phosphate in mmol/L (IQR) 1.78 (1.51–2.20) 1.49 (1.32–1.9) 0.11 Median plasma PTH in pmol/L (IQR) 24 (11–55) 34 (21–63) 0.26 Data missing in two cholecalciferol and one placebo participants for BP outcome and in one placebo participant for PTH outcome. t-test of log transformed data. T measurements were recorded). Since troponins were often Table 4. Adverse events performed serially in the same participant, only the first posi- tive for a given participant was analysed. Two participants suf- Cholecalciferol Placebo fered a myocardial infarction, both in the placebo group Event (n ¼ 36) (n ¼ 32) P-value (P ¼ 0.22). A positive troponin was recorded in eight participants Mild rash (%) 3 (8) 0 (0) 0.24 from the placebo group and in four participants from the chole- Cramps (%) 0 (0) 1 (3) 0.47 calciferol group (P ¼ 0.34 by Fisher’s exact test). Examination of Death (%) 1 (3) 0 (0) 0.54 the clinical record indicated that, apart from participants with Hypercalcaemia (%) 9 (25) 6 (19) 0.57 diagnosed myocardial infarction, the raised troponins were of Parathyroidectomy (%) 0 (0) 1 (3) 0.47 doubtful clinical significance. Other secondary endpoint data Bacteraemia (%) 0 (0) 1 (3) 0.48 are shown in Table 3. Exploratory analysis of within cholecalcif- Hospital admissions (%) 22 (61) 17 (53) 0.63 erol group changes showed that the mean adjusted plasma cal- Overnight hospital admissions, excluding admission for creation or revision of cium was 0.05 mmol/L higher at 12 months [95% confidence vascular accesses. interval (CI) 0.04 to 0.15], the mean plasma phosphate was 0.12 mmol/L higher (95% CI 0.11 to 0.36) and the median PTH after their 12-month follow-up visit. This participant had been was 13 pmol/L lower (P ¼ 0.73). None of these within group changes was statistically significant. in the cholecalciferol group. Reanalysis of study data with inclu- sion of this out-of-study death did not materially alter the sta- Government funding for cinacalcet ceased in August 2015. At the time of funding withdrawal, eight participants were re- tistically insignificant P-value shown in Table 4. ceiving study drug and three of these had been prescribed cina- calcet at some stage during the trial. No surgical DISCUSSION parathyroidectomies were performed on study participants af- This randomized, double blind, placebo-controlled trial aimed to ter August 2015. Elemental calcium dose, calcitriol dose and cinacalcet usage were similar in both study groups at determine if oral cholecalciferol targeting a 25(OH)D >80 nmol/L affected symptoms or hand grip muscle strength in a deficient di- 12 months. Adverse events are summarized in Table 4. Possible adverse alysis population. There was no difference between groups in ei- events were reported by four participants and none of these ther symptoms or hand grip strength after 12 months of follow- up. Treatment was safe, with no apparent differences in hyper- events (rash or cramps) was considered related to study medi- cation by the treating physician. There was one death during calcaemia, hospital admissions or other adverse events between the study (in a participant that had withdrawn from all active the groups and no participants recording 25(OH)D concentrations treatment). One further death occurred in a participant 1 day higher than those reported from sunlight exposure . Downloaded from https://academic.oup.com/ckj/advance-article-abstract/doi/10.1093/ckj/sfy039/5032500 by Ed 'DeepDyve' Gillespie user on 07 June 2018 6| R. Singer et al. The effect of cholecalciferol on symptoms or strength in di- calcification and so cannot comment on this surrogate out- alysis patients were studied in two previous randomized pla- come. However, animal data suggest vascular calcification from cebo-controlled studies. One study looked at depression scores vitamin D toxicity occurs concomitantly with hypercalcaemia in 726 subjects over one year . That study found no differ-  and hypercalcaemia was not more frequent in the cholecal- ence in outcome between study groups, however most subjects ciferol group. enrolled had baseline plasma 25(OH)D concentrations In conclusion, high-dose weekly oral cholecalciferol com- >50 nmol/L, which may have reduced study power. The other pared with placebo in a deficient dialysis population does not study looked at 45 subjects and found no difference in muscle affect muscle strength or symptoms. Such treatment appears to strength in the hand, shoulder, elbow and knee joints after 6 be safe, with no significant difference in the frequency of hyper- months’ follow-up and no difference in symptom scores . calcaemia observed between groups. No differences were seen However, study power in that study may also have been re- in the secondary endpoints examined. duced by enrolment of participants with higher baseline 25(OH)D (<60 nmol/L) and failure to achieve 25(OH)D target in ACKNOWLEDGEMENTS some of the active group. The most likely reason for our not finding a difference in strength or symptoms is that vitamin D The authors acknowledge Patricia Johnson (Renal unit, status, as assessed by 25(OH)D concentration, has no impact on Canberra Hospital), Susan Sheehan and Leanne Garvey muscle strength or on common symptoms in renal failure. An (Renal clinical trial unit, John Hunter Hospital) for assistance alternative explanation for the lack of effect is that 25(OH)D with recruitment and data collection. We thank The concentrations at baseline were not low enough to induce mus- Canberra Hospital Private Practice Fund for funding the cle weakness or symptoms. Evidence against this alternate ex- study. planation is that results were unchanged when our primary outcome analysis was restricted to those participants with FUNDING more severe vitamin D deficiency. A secondary objective in this study was to assess the effect This study received a grant of A$38267 from The Canberra of supplementation on cardiac ischaemia. There were only two Hospital Private Practice Fund to conduct this study. episodes of diagnosed acute myocardial infarction during the study, both in the placebo group, and twice as many recorded a positive troponin I. These results were not statistically signifi- CONFLICT OF INTEREST STATEMENT cant, and the troponin result is of doubtful clinical relevance None declared. 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Published: Jun 2, 2018
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