Randomized Clinical Trial for The Evaluation of The Effects Of Cholecalciferol Supplementation On The Parathyroid Hormone In Hemodialysis Patients
Phase: PHASE4
Conditions: Vitamin D Deficiency, Hemodialysis Patient
Sponsor: Cooperativa Asistencia Sindicato Médico Uruguay

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Randomized Clinical Trial for The Evaluation of The Effects Of Cholecalciferol 
Supplementation On The Parathyroid Hormone In Hemodialysis Patients  
  
Effect of Cholecalciferol Supplementation  on Parathyroid Hormone in 
Hemodialysis Patients  
  
  
  
Project coordinator:  Dr Laura Solá  
Associate Professor of Preventive Medicine at UDELAR  
Director of Chronic Hemodialysis Centre at CASMU=IAMPP  
Contact private address:  Av. Rivera 4437, Montevideo 11400, Uruguay  
Email:  solalaura11@gmail.com, lsola@casmu.com  
Cell phone No. 099176517  
Land line No. 24870421/ext. 4102   Fax: 24870421/ext. 4100  
Research team:  
Susana González. Mail: lacuin@gmail.com  
Manuela Bello. Mail: mbello@casmu.com  
Ricardo Hermo. Mail : rhermo1055@gmail.com  
Sandra Fleitas. Mail: sandrafleitas560@gmail.com  
  
  
 
SUMMARY  
 
Introduction.  Vitamin D regulates mineral metabolism, playing a crucial role in 
maintaining adequate bone density.  Immunomodulatory, cardioprotective and 

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antiproliferative effects have been described recently.  Its deficiency has been 
associated with diabetes, cancer and increased mortality. 25OH vitamin D (25VD) 
is stable (with a half-life of over 2 weeks) and suitable for the evaluation of vitamin 
D sufficiency.  It has been found that levels of 25VD are inversely related to those 
of the parathyroid hormone (iPTH), and its supplementation has been associated 
with a decrease in levels of iPTH in patients with Chronic Kidney Disease, 
although these results have not been uniform in patients on hemodialysis (HD). 
The usual treatment for secondary hyperparathyroidism in HD with active and 
analogous forms of vitamin D increases the risk of hyperphosphatemia and 
vascular calcifications.  
The aim of the study is to evaluate whether cholecalciferol supplementation for a 
period of 12 weeks can normalize decreased levels of 25VD and reduce 
increased iPTH in HD patients with a vitamin D deficiency.  Secondary aims:  to 
evaluate decrease in inflammation, anemia or use of erythropoietin (epo).  
Design.  Randomized, double blind clinical trial in two arms of HD patients with 
25VD deficiency and secondary hyperparathyroidism, one arm to be treated with 
cholecalciferol supplementation and the other with a placebo, for a period of 12 
weeks.  
Population.  Patients over 18 years of age on HD for more than 3 months and 
levels of 25VD < 30 ng / ml and iPTH >300 ng/ml , who sign a consent form.  
Patients will be recruited over a period of one year.  Once their consent has been 
obtained, iPTH and 25VD levels will be measured.  Randomization will be 
achieved by using a table of random numbers at the pharmacy, and neither 
doctors nor patients will know which group they have been assigned to. 

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Treatment.  Supplementation will consist of one 5000 IU 25VD tablet or placebo 
during dialysis for a period of 12 weeks.  
Monthly monitoring will include: hemoglobin (g/dl), Calcium (mg/dl), Phosphorous 
(mg/dl), iPTH (ng/ml), epo dose (IU/kg/week), epo resistance (IU/kg/week/g Hb). 
At the beginning and end of the study the following will be measured:  alkaline 
Phosphatase (IU/ml), PCR (mg/L), 25VD (ng/ml), ferritin (ng/ml) and transferrin 
saturation, quality of life (SF36).  
During the study, doses of calcitriol or paricalcitol will not be modified.  
The study will be discontinued if calcemia ≥ 10.5 mg/dL is detected on two 
occasions.  
Size of sample is estimated at 120 patients for a iPTH decrease of 20% in 35% 
of patients in group treated (assuming 15% follow-up losses).  Analysis will be 
done for Intention to treat for the primary outcome.  
Ethical aspects:  Authorization has been obtained from the Ethics Committee of 
the institution as regards Good Clinical Practices, Helsinki Declaration and 
national regulations.  The test will be registered with Cochrane and the Ministry 
of Public Health.  
  
  
  
  
 
 
INTRODUCTION  
Vitamin D regulates the metabolism of calcium and phosphorous and plays a 
crucial role in maintaining adequate bone density.  Apart from mineral 

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metabolism, immunomodulatory, cardioprotective and antiproliferative effects of 
vitamin D (1,2) have been described recently.    
Studies in the general population have found a correlation between deficiency of 
25OH vitamin D (25VD) and mortality and morbidity (3).  Said correlation was 
also confirmed in patients with end stage renal disease treated with hemodialysis 
and peritoneal dialysis (4, 5, 6).  25VD is very stable and has a lengthy half-life 
(close to 2 weeks) which makes it the optimum metabolite for the measurement 
and evaluation of vitamin D sufficiency (7).  
The synthesis of the active form of vitamin D3 (1,25 (OH) 2 D3) or calcitriol is 
carried out by means of a second hydroxylation mediated by 1α hydroxylase 
produced in the proximal tubule of the kidney.  The presence of cells that contain 
1α hydroxylase capable of synthesizing calcitriol in non-renal sites is significant 
as renal function deteriorates, but adequate levels of 25VD in the blood are also 
required (8).  
Normal levels of 25VD are considered to be those above 30 ng/ml, moderate 
deficiency or insufficiency when levels are between 10 and 30 ng/ml, while severe 
deficiency is when concentration is below 10 ng/ml (9).  
It has been found that levels of 25VD are inversely related to those of parathyroid 
hormone (iPTH) (10), and its supplementation has been associated with a 
decrease in levels of iPTH in patients with Chronic Kidney Disease (CKD), 
especially in those with a glomerular filtration rate (GFR) higher than 30 ml/min.  
The reported results for patients on dialysis have been less consistent.  Some 
studies have reported a decrease in iPTH levels after 25VD supplementation in 
patients on dialysis as well.  

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Among the effects of vitamin D not related to mineral and bone metabolism we 
can find those related to inflammation, angiotensin renin system, arterial pressure 
and cancer (11).  Some studies suggest that it could be through inflammation that 
25VD might influence erythropoiesis, thus explaining the association reported in 
recent observational studies (12, 13).  It has been reported that the decrease of 
25VD and the higher levels of C reactive protein (CRP) were associated 
independently with less hemoglobin in individuals with kidney disease not 
requiring dialysis (14, 15, 16, 17), and that higher doses of erythropoietin are 
needed in patients on dialysis.  
For decades secondary hyperparathyroidism has been treated with active forms 
of vitamin D (calcitriol) and analogous forms of vitamin D (paricalcitol) (8,9).  
The use of calcitriol is associated with a risk of phosphorous increase and of 
vascular calcifications.  While these effects are less significant with paricalcitol, 
the cost is several times higher which makes it unaffordable for many countries 
and many patients.  
There are not enough randomized clinical trials that confirm the possibility of 
treating secondary hyperparathyroidism with cholecalciferol (28-31).  This is a 
drug with minor side effects and low cost so it would be very advantageous for all 
patients, both in developing and developed countries.  
  
  
 AIMS  
The aim of the study is to evaluate whether cholecalciferol supplementation for a 
period of 12 weeks can normalize decreased levels of 25VD and reduce 
increased iPTH in HD patients with a vitamin D deficiency.  A secondary aim is to 

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evaluate whether this treatment will reduce anemia or the need for erythropoietin 
in this population.  
 Specific Aims  
  
1. 
Primary aim:  to analyze whether it is possible to normalize levels of 
25VD and reduce high levels of IPTH  
2. 
Secondary aim:  to evaluate whether it is possible to improve renal 
anemia in hemodialysis patients with a 12-week course of  
cholecalciferol  
3. 
Secondary aim:  to investigate whether cholecalciferol supplementation 
in 
HD 
patients 
is 
associated 
with 
hypercalcemia 
and 
hyperphosphatemia  
  
METHODS  
  
Design.  Randomized, double blind clinical trial in two arms of chronic HD patients 
with vitamin D deficiency and secondary hyperparathyroidism, one arm to be 
treated with cholecalciferol supplementation and the other with a placebo, for a 
period of 12 weeks.  
  
POPULATION  
  
Criteria for inclusion:  Age 18 or over, signed informed consent form, CKD with 
regular dialysis treatment for at least 3 months, levels of 25VD < 30 ng / ml and 
iPTH >300 ng/ml, stable doses of calcitriol or paricalcitol over the last 30 days. 
Criteria for exclusion:  Congestive heart failure class III or IV or unstable angina 

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or myocardial infarction or stroke during the previous 3 months, active malignant 
neoplasm, use of any trial medication, life expectancy lower than 6 months, 
corrected calcemia ≥ 10.5 in the 2 months prior to recruitment, intake of 
cholecalciferol or ergocalciferol in the 2 months prior to recruitment, prospective 
move to another city or transfer to PD in the following 6 months.  
Patient recruitment.  Patients will be recruited over a one-year period when the 
study will be explained to them, and samples will be taken to assess whether they 
fulfill the criteria for inclusion in the trial.  Once iPTH and 25VD testing has taken 
place, eligible participants will be requested to sign an informed consent form, 
and will be told that they will be treated either with cholecalciferol or a placebo.  
They will be assigned to one of the arms using a table of random numbers at the 
pharmacy of the institution, stratified in two subgroups according to vitamin D 
levels:  below 15 ng/ml or between 15 and 29.   
Randomization.  Once approval has been received from the Ethics in Research 
Committee and the consent form has been signed, patients will be assigned to 
one arm by using a table of random numbers, according to a number from 0 to 9 
which will be drawn at random at the time the patient is included.  For purposes 
of randomization, one fixed number will be skipped from the starting point which 
is only known by the person who does the randomization at the pharmacy, using 
a starting point selected initially on the table.  Notification of the arm allocated will 
arrive in sealed envelopes with the medication to be taken (either cholecalciferol 
or the placebo) which will be administered orally during dialysis.  
The laboratory that prepares the medication and the placebo will send them to 
the pharmacy labelled as medication A and B.  Then the pharmacy of the  

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institution will send the tablets to the patient, neither the doctors nor the patient 
knowing what arm he has been assigned to.  The medication will be administered 
by the nurse during dialysis.  
It will not be necessary to make changes to the dietary intake of vitamin D as dairy 
products, which are the main source of dietary vitamin D, are strictly limited in the 
diets of these patients.    
Treatment:  Supplementation will consist of one 5000 IU tablet of 25VD or placebo 
taken during dialysis for a period of 12 weeks.  A nurse from the team will ensure 
access to the medication by being in permanent contact with the pharmacy.  
Monthly follow-up of the patients in the study will include evaluation of laboratory 
tests as well as normal clinical controls during dialysis (weight, arterial pressure 
and intra-dialysis hypotension events), and monthly report of dosage of 
erythropoietin (IU/kg/week) for the calculation of the index of resistance to 
erythropoietin (IU/kg/week / g of Hb).  
Laboratory testing to be done monthly will include: hemoglobin (g/dl), Calcium 
(mg/dl), Phosphorous (mg/dl), and iPTH (ng/ml).  At the beginning and at the end 
of the study the following will be measured:  Alkaline Phosphatase (IU/ml), CRP 
(mg/L), ferritin (ng/ml), transferrin saturation, and 25VD (ng/ml).  
The measuring of hemoglobin will be done by Siemens Healthcare Diagnostics’ 
Advia 2120 haematological analyzer using the cyanmetahemoglobin method 
modified without cyanide, with Siemens controls and calibrators.  Dosing of 
vitamin D, iPTH and ferritin will be done by Siemens Healthcare Diagnostics’ 
Advia Centaur XP analyzer using the chemiluminescence method, with BIORAD 
controls and Siemens calibrators.  

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Other measures will be taken as follows:  for calcium, by the Arsenazo III endpoint 
method, for phosphorous, by the UV phosphomolibdate method, for alkaline 
phosphatase, by the kinetic technique of paranitrophenol phosphate, for iron, by 
the endpoint ferrocin method, for transferrin, by the immunoturbidimetric method 
maximized with PEG, and for reactive C Protein, by the immunoturbidimetric 
method maximized with latex.  All of these will be done by Siemens Healthcare 
Diagnostics’s Advia Chemistry 1800 autoanalyzer with BIORAD controls and 
Siemens calibrators.  
Both prior to the start of the study and after it has ended, quality of life will be 
evaluated using SF36 auto-administered protocol.  
During the 12 weeks of the study, doses of calcitriol or paracalcitol must not be 
modified.  The study will be discontinued in those patients who present levels of 
calcemia ≥ 10.5 mg/dL on two occasions.  
Operational Definitions: 25VD levels are considered normal when above or equal 
to 30 ng/ml, and severe deficiency (SD-25VD) when below 10 ng/ml.  Anemia is 
defined as presenting levels of Hb below 10g/dl or the need for epo.  It is classified 
as mild anemia when patients have no anemia or require doses of epo below or 
equal to 2000 IU per week, and, failing this, very mild anemia.  Ferritin is 
considered to be high when over 500 ng/ml.  Measurements of all analytes will 
be done with Siemens equipment at the CASMU laboratory.  
  
Security Measures  
Patients will be evaluated for early detection of side effects, particularly in relation 
to increases in calcemia and fosfatemia.  Both calcium and phosphorous will be 
measured monthly.  

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If it were necessary to open the blinding, it will be requested from the person in 
charge of assigning the medication at the pharmacy.  
  
Calculation of sample size  
It was estimated, by using free access epidemiological calculator Open Epi (to be 
found 
at 
http://www.openepi.com/v37/SampleSize/SSCohort.htm), 
that 
necessary sample size to show a IPTH decrease of 20% in 35% of patients in the 
group treated (information we found in a previous observational study) is 102, 
and assuming a 15% loss of follow-up, a sample size of 120 was decided on.  
This size is more demanding than the 50 patients needed to demonstrate the 
correction of 25VD in 50% of patients.    
  
Expected Results  
Primary end point:  A difference in the percentage of patients normalizing levels 
of 25VD of at least 45% of the group treated vs placebo.  
Percentage of patients of at least 30% in the group treated vs placebo presenting 
a decrease of 20% from previous levels of IPTH.  
Secondary end point:  Percentage of patients with an increase in Hb or a 
decrease in resistance to erythropoietin  
  
Ethical Aspects  
Authorization has been obtained from the Ethics Committee of the institution.  The 
study will be carried out following Good Clinical Practices, the Helsinki  
Declaration and national and Mercosur regulations, according to the Ottawa 
Declaration.    

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The test will be registered in the Cochrane and WHO Clinical Trials Register, and 
authorization and registration will be requested from the Uruguayan Ministry of  
Public Health.  
  
Data Analysis and Statistics  
Reference demographic data will be collected related to:  age, gender, race, 
cause of kidney disease, length of time on dialysis, presence of diabetes and use 
of active forms of vitamin D.  
Clinical data will be taken from electronic medical records of dialysis (SISDIA): 
body weight, height, body mass index, monthly average of systolic and diastolic 
arterial pressure pre-dialysis, and monthly average percentage of inter-dialysis 
weight increase.    
Both clinical information and laboratory data will be entered in a case report form  
(CRF) which will be attached as Annex 1.  
Laboratory test data will be collected in Table 1 Schedule of measures.  
  
TABLE I. SCHEDULE OF MEASURES  
 
 
 
 
   
Time  
 0  
week  
 4  
week  
8  
week  
12  
week  
16  
25VD  
   
   
   
   
   
iPTH  
   
   
   
   
   
Ca  
   
   
   
   
   
P   
   
   
   
   
   
Alkaline Phosphatase  
   
   
   
   
   
Hb  
   
   
   
   
   

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CRP  
   
   
   
   
   
Ferritin  
   
   
   
   
   
Sat Transferrin  
   
   
   
   
   
SF36  
   
   
   
   
   
Mean SAP  
   
   
   
   
   
Mean DAP  
   
   
   
   
   
Mean inter-dialytic weight gain  
   
   
   
   
   
Number of hipotensive events   
   
   
   
   
   
The information obtained from patients’ CRFs will be entered in a database which 
will be treated as confidential.  Sensitive data will be kept confidential and 
patients’ identity will remain anonymous during the whole procedure.    
In order to ensure the quality of the information, all data entered will be checked 
by a second member of the research team prior to statistical analysis.  
  
Statistics  
Continuous variables with normal distribution will be compared using Student’s 
test for independent or dependent samples as appropriate and will be presented 
as the mean ± standard deviation.  Categorical variables will be compared using 
Chi square test for paired or independent samples as appropriate 
  
Feasibility  
The execution of the study will not involve any costs for the patient nor for the 
institution.  The medication and the placebo will be supplied by Laboratorio 
Celsius.  Costs of laboratory testing for the study as well as of the laboratory 

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technician will be financed by CSIC if funding is approved, and, if not by 
Laboratorio Celsius.  
  
Funds  
They will be allocated to laboratory expenses for the measured analytes 
according to the schedule, to medication and the placebo, and to cover human 
resources for the execution of the study, data input, pharmacy handling, statistical 
analyses and preparation of report.  
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