Participants
Eligible subjects are > 18 years old and receiving chronic haemodialysis therapy for at least 3 month prior to screening in any of nine Danish haemodialysis outpatient clinics. After a period of minimum 6 weeks wash out, without any kind of vitamin D supplement, and sufficiently regulated p-phosphate (<1.8 mmol/l) and ionised p-calcium (<1.25 mmol/l), the patients are candidates for inclusion if p-iPTH is >350 pg/ml (37,1 pmol/l). The maximal allowed dose of calcium-containing phosphate-binders is 1600 mg elementary calcium a day at the time of inclusion. The patients may not be scheduled for parathyroidectomy or planned to start treatment with calcimimetics according to the local guidelines in the participating departments. Anticonception and negative pregnancy test should be present for fertile women. They are not admitted to the study if any of the following criteria are present (1) malignancy during the past five years (2) expected survival less than one year (3) pregnancy or breast feeding (4) allergy to any ingredient of Etalpha® or Zemplar® (5) in treatment with calcimimetics (6) participating in any other clinical trials which could affect the endpoints.
Interventions
The study design is a crossover design where the patients are randomised into two treatment arms (Figure 1). The randomisation is performed after 6 weeks wash out during which the patients are not allowed to receive any kind of vitamin D supplement. The first arm receives alfacalcidol for 16 weeks and then goes through another 6 weeks wash out period before they receive paricalcitol for 16 weeks. The second arm receive paricalcitol for 16 weeks and then goes through another 6 weeks wash out period before they receive alfacalcidol for 16 weeks. The drugs are given at the end of haemodialysis treatment two or three times a week depending on the frequency of haemodialysis treatment. The start dose of alfacalcidol (Etalpha®Injection) is 3 μg a week and the start dose of paricalcitol (Zemplar®Injection) is 9 μg a week. Every second week the dose is titrated 50% according to p-phosphate, p-calcium and p-iPTH. As long as p-phosphate <1.8 mmol/l and ionised p-calcium <1.30 mmol/l and p-iPTH>150 pg/ml the dose is increased. When p- iPTH ≤ 150 pg/ml and p-phosphate <1.8 mmol/l and ionised p-calcium <1.35 mmol/l the dose is retained. If at any time p-phosphate >1.8 mmol/l or ionised p-calcium >1.35 mmol/l in two repeated measurements the dose is reduced.
After inclusion the dose of calcium-containing phosphate-binders can only be unchanged or reduced. Elevated p-phosphate should be treated thoroughly with calcium-free phosphate-binders, dietary intervention and re-evaluation of the dialysis dose. Elevated p-calcium should lead to dietary intervention and reduction of calcium containing phosphate binders. The calcium concentration of dialysate is fixed to 1.25 mmol/l.
Objectives
In the current study we test the hypothesis, that there is a difference between the ability of alfacalcidol and paricalcitol to suppress secondary hyperparathyroidism in patients receiving chronic haemodialysis without causing hyperphosphatemia and hypercalcemia.
Outcomes
The primary efficacy end point is the proportion of patients achieving ≥ 30% reduction in iPTH from baseline until the last 4 weeks of treatment with alfacalcidol or paricalcitol. The secondary outcomes is changes in ionised p-calcium, p-phosphate, calcium × phosphate product, p-alkaline phosphatase, p-25(OH)vitamin D, p-1,25(OH)2vitamin D, blood pressure, pulse and pulse pressure from baseline until the end of treatment with alfacalcidol or paricalcitol respectively. The frequency of parathyroidectomy or need for calcimimetics is registered.
Safety endpoints are b-haemoglobin, b-leukocytes, b-trombocytes, p-sodium, p-potassium, p-magnesium, p-bicarbonate, p-creatinine, p-urea, urea reduction rate, p-albumin, p-alanine aminotransferase, p-bilirubin, p-C-reactive protein and weight measured at the beginning and after each treatment period.
All laboratory samples are drawn from the blood lines of the dialyzer before start of the dialysis. P-iPTH, ionised p-calcium and p-phosphate are measured every second week during the treatment periods, the others parameters are measured at the beginning and the end of each treatment period. The urea reduction rate is calculated from a urea measured before dialysis and a urea measured immediately after dialysis. All laboratory analyses are performed at the participating departments' local laboratories.
Blood pressure and pulse are measured after 5 minutes rest before dialysis, and weight is measured before the dialysis session with clothes but no shoes.
Sample size
We assume that the proportion of patients achieving ≥ 30% reduction in iPTH in the last four weeks of the treatment period would be 50% in the alfacalcidol group and 68% in the paricalcitol group [13, 14]. Based on 0.8 power to detect a significant difference (P = 0.05, McNemars test), 117 patients is required for inclusion.
Randomisation
A randomisation list is computer generated by an external statistician. The patients are randomised in blocks of ten, to secure equal distribution in the two groups in each department. Assignments are enclosed in sequentially numbered, opaque, sealed envelopes. When a patient is included an envelope is opened sequentially and the patient's initials and identification number written on the assignment. The patients are enrolled and treatment assignment ascertained by the primary investigator or any of his/her delegated at each centre. The envelopes are generated by the coordinator and afterwards the allocation list is packed in a sealed, opaque envelope and stored by the coordinator.
Blinding
This is an open-label study.
Statistical methods
The frequency of reaching a 30% reduction in iPTH for a minimum of 4 weeks is compared between the two treatments in the same person by McNemar test for paired observations. It is tested whether the effect is dependent of the order of the periods.
Furthermore the effect of the two treatments after the first period will be analysed separately from the second period.
The distribution of the variables and the changes in the variables from the start until the end will be described. Mean, median, standard deviation and range will be reported.
All tests are two-sided tests α = 0.05. The changes during the two treatments will be compared using tests for paired observations.
Parametric tests (paired t-test) will be used if the distributions are normal and non-parametric test (McNemar test and Wilcoxon signed ranks test) for ordered or continuous data.
All participants that are evaluable will be included in the statistical analysis.
The analysis will be performed in Statistica with the procedures: UNIVARIATA, FREQ and ANOVA.
The data analysis will be performed blinded. While doing the statistical analysis the treatment groups will be unknown.
All data will be described and the reason for missing values will be described. Every violation from the statistical plan will be described in the final publication.
All eligible subjects receives a written description of the study objective, schedule, benefits and risks, other treatment possibilities, funding and contact information.
They are offered a consultation providing further information. Here they can bring their relatives.
If the subject agrees to participate a written informed consent is signed.
The study is in compliance with the Helsinki Declaration and is approved by the Danish National Committee on Biomedical Research Ethics (SJ-27), the Danish Medicines Agency (EudraCT: 2006-005981-37) and Danish Data Protection Agency (2007-41-0503)