The Effect of REgulation of PArathyroId hoRmone in Patients With Chronic Kidney Disease to Investigate the Change in Bone Mineral Density (Biskjoldbruskkirtelhormon og knogletæthed Hos Patienter Med Kronisk Nyresygdom)
Phase: NA
Conditions: Chronic Kidney Disease Mineral and Bone Disorder
Sponsor: Herlev Hospital

REPAIR-CKD trial 
Protocol v. 3, 17-07-2025  
Trial number H-25038403 
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The Effect of REgulation of PArathyroId 
hoRmone in patients with Chronic Kidney 
Disease to investigate the change in bone 
mineral density 
 
(Biskjoldbruskkirtelhormon og knogletæthed hos patienter med kronisk 
nyresygdom) 
 
 
 
The REPAIR-CKD trial 
 
 
 
 

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Investigators 
Principal investigator 
Freja Stæhr Hassager, MD, PhD-student 
Department of Nephrology 
Herlev Hospital 
Borgmester Ib Juuls Vej 1, 2730 Herlev 
Telephone number + 45 22 55 47 07 
 
Collaborators/supervisors 
Ditte Hansen, MD, PhD, Professor at University of Copenhagen 
Iain Bressendorff, MD, PhD 
Anahita Rashid, MD, PhD-student 
Department of Nephrology 
Herlev Hospital 
Borgmester Ib Juuls Vej 1, 2730 Herlev 
 
Bo Abrahamsen, MD, Professor at University of Southern Denmark 
Department of Medicine 
Holbæk Hospital 
Smedelundsgade 60, Holbæk 
 
Alexandra Scholze, MD, Ass Professor at University of Southern Denmark 
Department of Clinical Research, University of Southern Denmark 
Campusvej 55, 5230 Odense M 
 
Richard Haynes, DM, FRCP  
Professor of Renal Medicine & Clinical Trials 
Nuffield Department of Population Health 
Richard Doll Building, Old Road Campus, 
Roosevelt Drive, Oxford OX3 7LF 
 
Bo Zerahn, MD 
Department of Clinical Physiology and Nuclear Medicine 
Herlev Hospital 
Borgmester Ib Juuls Vej 1, 2730 Herlev 
 
 

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Tor Biering-Sørensen, MD, PhD, MPH, MSc, Professor at University of Copenhagen 
Head of Center for Translational Cardiology and Pragmatic Randomized Trials, Department of 
Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen. 
Department of Cardiology, Herlev and Gentofte Hospital 
Gentofte Hospitalsvej 1, 2900 Hellerup 
 
& 
 
Kira Hyldekær Janstrup, Biostatistician, PhD 
Department of Cardiology, Herlev and Gentofte Hospital 
Gentofte Hospitalsvej 1, 2900 Hellerup 
 
Thomas Levin Andersen, PhD, Professor at University of Southern Denmark 
Department of Clinical Research – Research Unit of Pathology, University of Southern Denmark 
Campusvej 55, 5230 Odense M 
 
 
 
 

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Content 
Investigators ........................................................................................................................ 2 
Purpose ............................................................................................................................... 5 
Background .......................................................................................................................... 5 
Hypothesis ........................................................................................................................... 8 
Methods and Materials......................................................................................................... 8 
Study population ............................................................................................................... 8 
Study design ..................................................................................................................... 9 
Sample size .................................................................................................................... 10 
Interventions ................................................................................................................... 10 
Study parameters ........................................................................................................... 11 
Baseline characteristics ............................................................................................... 11 
Blood samples ............................................................................................................. 11 
DXA-scan .................................................................................................................... 12 
Pulse wave velocity ..................................................................................................... 12 
Muscle strength and function ...................................................................................... 13 
Bone biopsy ................................................................................................................ 13 
Questionnaire .............................................................................................................. 14 
Visit schedule ................................................................................................................. 14 
Biobank for future research ............................................................................................ 15 
Randomisation ................................................................................................................ 15 
Blinding ........................................................................................................................... 15 
Efficacy endpoints .......................................................................................................... 16 
Adverse events ............................................................................................................... 16 
Statistics ......................................................................................................................... 17 
Time schedule ................................................................................................................ 17 

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Rights and publication .................................................................................................... 18 
Ethics .............................................................................................................................. 18 
Financing ........................................................................................................................ 20 
Perspective ..................................................................................................................... 21 
References ........................................................................................................................ 22 
 
Purpose 
The purpose of The REPAIR-CKD trial is to determine if treatment of hyperparathyroidism 
improves the bone mineral density in patients with chronic kidney disease.  
During this trial it will also be evaluated if it is feasible to obtain a difference in PTH levels when 
targeting two different levels of PTH.  
Further this trial will explore if a difference in PTH influences on arterial stiffness, muscle mass, 
muscle function, bone histology and health related quality of life.  
 
Background 
The prevalence of chronic kidney disease (CKD) is estimated to afflict 10 % of the adult 
population, and it is increasing world-wide(1). CKD is a devastating disease due to the risk of 
kidney failure and thereby the need for dialysis or transplantation, but also because the presence of 
CKD increases the risk of bone fracture, cardiovascular disease and mortality(2–4).  
Parathyroid hormone (PTH) is a peptide hormone produced by the parathyroid glands(5). The main 
function of PTH is to regulate mineral metabolism, including the calcium and phosphate 
homeostasis(6). PTH increases as the kidney function declines, and at end stage kidney disease 
almost all patients have disturbances in the mineral metabolism(7,8). Treatment with activated 
vitamin D, phosphate binder and calcium supplementation has been used for more than 30 years to 
suppress hyperparathyroidism and keep calcium and phosphate within the normal range. Later 
calcimetics has been introduced as a treatment for secondary hyperparathyroidism(9).  
The risk of bone fracture is increased in patients with CKD and the risk increases as the kidney 
function declines(10,11).  A bone fracture leads to a direct burden on the individual. In addition, the 

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risk of complications after a bone fracture is higher in the CKD population compared to the general 
population(10,12). A fracture also constitutes a significant cost for the society(13). The increased 
risk of fracture in patients with CKD is associated to the presence of hyperparathyroidism(14). 
Bone mineral density (BMD) assessed by dual energy x-ray (DXA) scan is a highly used modality 
to diagnose osteoporosis and future fracture risk in the general population(15). Bone mineral 
density associates with the risk of future fracture in patients with CKD(16,17). In patients with 
CKD there is an association between decreasing eGFR and both low BMD and future fracture risk 
(18). It is unknown how elevated PTH associates with BMD and its changes at different stages of 
CKD, and it is unknown if treatment of hyperparathyroidism influence on BMD and fracture risk in 
patients with CKD. 
The risk of cardiovascular mortality, coronary heart disease, heart failure, stroke and peripheral 
arterial disease increase as the kidney function declines(19,20).  Elevated PTH associates with an 
increased risk of cardiovascular disease(14). However, hyperparathyroidism is tightly connected to 
the general disturbances in the mineral metabolism in CKD, i.e. hyperphosphatemia and elevated 
FGF-23, which associate with an increased risk of cardiovascular disease and mortality(21,22). 
Therefore, it is questioned if PTH is directly involved in the pathogenesis of cardiovascular disease, 
or if the increased risk of cardiovascular disease could be caused by other factors involved in the 
mineral metabolism(23). One way to approach precursors of vascular disease is measuring vascular 
stiffness with pulse wave velocity which is associated with cardiovascular outcomes in patients with 
CKD(24).  
The active circulating form of vitamin D is 1,25 dihydroxy vitamin D (calcitriol).  The level of 
calcitriol is regulated by the activity of the 1α hydroxylase enzyme located in the kidney. The 1α 
hydroxylase enzyme hydroxylate 25-hydroxy vitamin D at the 1-position(25). As kidney function 
declines the activity of 1α hydroxylase is reduced and thereby the circulating level of calcitriol is 
reduced(26). The reduced level of calcitriol, together with hypocalcaemia and hyperphosphatemia, 
leads to secondary hyperparathyroidism(27). Activated vitamin D is given to patients with 
hyperparathyroidism to try lowering PTH(28). In a randomized placebo-controlled trial with 36 
patients with CKD G3-5 the intervention group were treated with active vitamin D, which resulted 
in a difference in BMD by +4.2% in the spine compared to controls after 18 months (P< 0.05) (29). 
No clinical trials have aimed to explore the influence of targeting different levels of PTH and the 
influence on bone mineral density or bone fracture in patients with CKD. 

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Two randomized placebo-controlled trials aimed to address effect of 1 year of active vitamin D 
treatment on the left ventricular mass, a surrogate endpoint for development of heart failure. No 
difference between the treatment groups was found in any of the trials(30,31). Cohort studies in 
dialysis patients have found increased survival in patients treated with active vitamin D, but the 
result could be biased having the design in mind(32). One Japanese randomized controlled trial 
compared alfacalcidol with placebo in 976 patients on dialysis(33). Of importance, not all the 
included participants did have hyperparathyroidism. No difference was found in fatal and non-fatal 
cardiovascular events, additionally no difference was found in risk of fracture during the study. If 
this finding would have differed in patients with hyperparathyroidism or in patients with earlier 
stages of kidney disease and thereby preventable progression of vascular calcification, remains to be 
determined.  
Treatment with active vitamin D, phosphate binders and calcimetics has been used for patients with 
CKD for decades. Recommendations regarding the appropriate dose and PTH target for different 
stages of CKD has varied during years and between guidelines(34,35), reflecting the lack of 
randomized clinical trials with clinical important end points (BOX 1). 
BOX 1 | Guideline recommendations for research
 
In patients with CKD G3b-5, it is currently recommended to monitor the PTH every 3-6 month(3).  
As more than 50 % of the patients have elevated PTH already at CKD G3b, it is an everyday 

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consideration for the clinician if the patients should be treated to reduce PTH. This is both time- and 
cost consuming. At present, there is no evidence to advise if secondary hyperparathyroidism should 
be treated in patients with CKD.  
To improve our knowledge about when secondary hyperparathyroidism should be treated, we want 
to conduct a randomized clinical trial with one group of patients being treated if PTH is elevated 
versus a second group of patients not being treated if PTH is elevated.  
Hypothesis 
We hypothesize that suppression of initially elevated PTH will improve BMD, arterial stiffness, 
muscle mass and muscle strength in patients with CKD.  
Methods and Materials 
Subjects will be recruited from the patient population in the outpatient clinic at the Department of 
Nephrology at Herlev and Gentofte Hospital, Herlev, Denmark.  
Study population 
Inclusion criteria (all four needs to apply) 
1. ≥50 years of age at screening 
2. CKD G4-5nonD (eGFR < 30 mL/min/1.73m2) based on local laboratory assessment of 
serum creatinine and eGFR estimated by the CKD-EPI formula) 
3. Plasma PTH > upper normal limit of local laboratory reference range (> 8,5µmol/L) and/or 
treated with active vitamin D (Alphacalcidol) or calcimetics (Cinacalcet) initially 
4. Written informed consent 
Exclusion criteria 
1. Patients who have received a kidney transplant 
2. Patients receiving treatment with specific anti-osteoporosis medication 
(denosumab/bisphosphonates) (because of the profound effect on calcium/phosphate fluxes 
and BMD) 
Withdrawal from intervention but continued follow-up (included in intention-to-treat analysis) 
1. Withdrawal of consent 
2. Kidney transplantation 

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3. Parathyroidectomy 
4. Necessity to initiate dialysis treatment 
Patients may withdraw from both intervention and follow-up at any time if desired.  
 
 
Study design 
The REPAIR-CKD trial will be an investigator-initiated pragmatic randomized controlled clinical 
trial. Included patients will be randomized 1:1 into one of two treatment arms with different targets 
levels for plasma-PTH: A liberal PTH target (< 5 x upper normal limit = 42,5 µmol/L) or an 
intensive PTH target (within interval of lower and upper normal limits = 2,0 – 8,5 µmol/L) (Figure 
1). The cut-off for the liberal PTH target (<5 x upper normal limit) was discussed in the national 
CKD-MBD group. It is chosen to allow the clinician initiate treatment if PTH reaches unusually 
high levels, no studies have focussed on PTH-targets before, consequently the cut-off is chosen as 
part of the pragmatic design.  
The trial will also pilot the feasibility to obtain a difference in the PTH levels between treatment 
groups. 
 

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Figure 1. Visit overview.  
Sample size 
The primary outcome will be difference in the change in total hip BMD between treatment groups.  
In an observational study, the decline in total hip BMD (g/cm2) was -1.19%/year (men) 
and -1.51%/year (women) The decline in men is chosen for a conservative estimate (36). In the 
dialysis population, the standard deviation (SD) of the one-year decline in BMD is +/- 5.2% (37). 
The variance in the BMD change in dialysis patients is expected to be higher than in the CKD 
population, and therefore this is considered a conservative estimate.  Based on these observations 
the expected decline in BMD in the liberal target group during 18 months is -1.8% (5.2%). 
 
In a previous trial, alendronate was able to increase BMD in total hip by 2.8% during the first year 
of treatment and 3.4% during 2 years treatment, and thus to increase BMD by 3.1% in 18 months 
(38).  We expect to obtain a similar effect in the intensive target group. 
 
A sample size of 70 participants is estimated (β=0.10; α=0.05 (two-sided), drop out 20 % during the 
study) to detect a difference of 4.9 % change in total hip BMD (effect size) during 18 months. 
To ensure that the trial can also provide information about the other fields of interest, we did some 
statistical considerations about these as well. A minimal relevant difference in the level of PTH 
after 18 months of intervention is expected to be a difference in PTH of 0.5 times the upper limit of 
normal range (8.5 µmol/L (Atellica IM PTH)). PTH has a skewed distribution and thus log 
transformed to obtain normality. In a population of patients with CKD G4-5 the mean and standard 
deviation of the logPTH was 1.191 (0.380) (own data, not published). To obtain a difference of 4.25 
µmol/L in PTH = logPTH of 0.628 ((β=0.10; α=0.05) a sample size of 22 participants is estimated 
(including drop-out margin of 20%). Based on former studies the sample size should be sufficient to 
demonstrate a difference of 1 m/s in pulse wave velocity which is considered a difference of clinical 
relevance for future cardiovascular events(39). 
Interventions 
The trial is estimated to run for 24 months, as patients will be included during a 6-months period 
following 18 months follow-up. Following inclusion there will be a 4 weeks run-in period where 
patients will not be treated with active vitamin D or calcimetics. After run-in patients will be 

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randomized to either a liberal PTH target (< 5 x upper normal limit = 42,5 µmol/L) or an intensive 
PTH target (within interval of lower and upper normal limits = 2,0 – 8,5 µmol/L). In the intensive 
PTH target group, treatment will be initiated as soon as the PTH rise above the upper limit of 
normal. In the liberal PTH target group, treatment will not be initiated until PTH rise above five 
times the upper limit of normal.  
PTH will be measured as intact PTH with Atellica IM PTH assay at Herlev Hospital laboratory 
(normal range 2,0 – 8,5 µmol/L).  
Medications used for management of the disturbances in the mineral metabolism in CKD are native 
vitamin D, activated vitamin D, phosphate binders and calcimetics. As this is a pragmatic trial 
embedded in the clinic with usual care, these may be used after the run-in period according to the 
international guidelines to regulate PTH in the trial cohort (3). All medications for management of 
disturbances in the mineral metabolism will be registered and reported as part of results.  
Study parameters 
Baseline characteristics 
Age, height, weight, sex, ethnicity(40), smoking status and alcohol use will be registered. Further 
comorbidity, medical history, biochemical data and medication (including native vitamin D, 
activated vitamin D, phosphate binders and/or calcimetics) will be collected from participants’ 
medical record and interviews during the trial. The consent will allow the principal investigator, the 
sponsor and the sponsor’s representatives, as well as regulatory authority, direct access to obtain 
information from the patient’s medical records, including electronic records, in order to review 
information about the trial subject’s health condition that is necessary for the conduct of the 
research project and for control purposes, including self-monitoring, quality control, and 
monitoring, which they are obligated to perform.  
Blood samples 
Standard blood samples will be drawn at initiation and month 1, 3, 6, 9, 12 and 18 to measure PTH, 
ionized calcium, phosphate, creatinine, eGFR, magnesium, haemoglobin, sodium and potassium. 
25-hydroxy vitamin D will be measured at initiation and month 3, 9 and 18. Standard blood sample 
analyses will be run immediately at the local department of clinical biochemistry. Any remaining 
material after analysis will be destroyed.  

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For analyses of 1,25-dihydroxy vitamin D, fibroblast growth-factor 23 (FGF23), T50, TRAB5b, 
bone specific alkaline phosphatase, total alkaline phosphatase and iP1NP, blood samples will be 
taken at day 0 and at 18 months and stored in the research biobank. PTH will also be measured at in 
these samples. The biobank will contain samples at -80oC and be analysed in bulk to minimize cost 
and intra-assay-variability. All residual samples therein will be destroyed after end of study (no 
later than 1/9-2027).  
Volume of the standard blood samples at each visit is 16 ml. Further there will be drawn 14 ml at 
baseline visit and 18-months visit for the research biobank and 18 ml once for the biobank for 
future research (discussed in more details in p. 14 “Biobank for future research”). Maximal volume 
blood drawn at once is 48 ml (baseline visit). Total amount of blood drawn in the study will not 
exceed 200 ml.  
DXA-scan 
DXA-scan will be used to measure BMD (amount of calcium and phosphate per area in g/cm2 
followed by calculation of T-score) in lumbar spine, left hip (if not applicable, then right) and non-
dominant forearm (if not with a fistula). Whole body scan will be performed to measure whole-
body BMD and appendicular lean body mass as an approximation of muscle mass. Additionally, 
vertebral fracture assessment (VFA) will be performed to assess any fractures in lumbar spine. 
Efforts will be made to optimize that baseline and follow-up procedure will be performed by the 
same person to minimize interobserver variance. The research laboratory at Herlev Hospital has 
research staff and DXA-scan (Hologic Horizon, 2021-2022) for performing the measures. The 
above-mentioned procedures will be carried out after validation on a spine fantom performed daily 
and calibration of body composition takes place simultaneously (Refer to the Horizon User Guide 
(MAN-08072-002) for operating instructions). All patients included will have a DXA-scan at day 0 
and at 18 months.  
Bioimpedance 
Body composition parameters, including segmental lean mass (arms, legs, trunk), skeletal muscle 
mass, fat-free mass, and body fat percentage, will be measured at baseline and 18 months follow-up 
by bioelectrical impedance analysis (BIA; multi-frequency InBody 570). 
Pulse wave velocity 

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Pulse wave velocity will be assessed at day 0 and at 18 months by applanation tonometry with 
Sphygmocor. Pulse wave analysis is a non-invasive way of estimating to which extent peripheral 
reflection is augmenting central blood pressure. Pulse wave velocity is a direct measure of arterial 
stiffness. This procedure will be performed in accordance with a standard operating procedure and 
in accordance with guidelines from DaHS (Danish Hypertension Society). The Sphygmocor exists 
at the research laboratory at Herlev Hospital.  
Muscle strength and function 
Muscle strength and function will be assessed at day 0 and at 18 months by hand grip strength, 10 
meter walk test, and sit-to-stand test. Hand grip strength will be measured by using a Jamar 
dynanometer (Sammons Preston Rolyn, Chicago, Illinois, USA). The procedure will take place with 
the patient sitting and will be measured three times in each arm performed with a pause for 45 
seconds between each test. 10 meter walk test is done with stopwatch (timed to closest 0.1 second) 
and takes place in the corridor in the research laboratory at Herlev Hospital. Walking speed will be 
calculated as meter/second. Sit-to-stand test is performed by observing and documenting how many 
times the patient is able to sit and stand within 30 seconds with crossed arms from a standardized 
chair.  
Bone biopsy 
All participants will be invited to have a bone biopsy performed at 18 months follow-up to explore 
how the intervention influences on bone histology. Tetracycline labelled bone biopsy is performed 
by a trained physician experienced in performing bone biopsies from the iliac crest after a 
standardised procedure. At randomisation, we will start with a single labelling of the bone with 
tetracycline, for us to be able to tell how the bone was at the time of randomisation. Before the 
biopsy procedure the bone is again labelled with tetracycline. 
The bone biopsy is performed with local anaesthesia and a sterile technique, and the entire 
procedure takes approximately 30 minutes. After the procedure the patient will rest at the study site 
for approximately 2 hours. Before going home patients are also instructed on which pain medication 
they can take if needed. The size of the biopsy is 4,5 mm x 10-15 mm. The bone biopsy is kept in 
formalin and will be pseudo-anonymized before shipment to Odense University Hospital for 
analysis. This procedure will not be mandatory, as our experience shows that some patients are 

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hesitant about undergoing a bone biopsy. Therefore, we will not risk that some may choose not to 
participate in the trial due to this hesitation. 
Questionnaire 
Health related quality of life will be evaluated at initiation and after 18 months through 
questionnaire “Kidney Disease and Quality of Life” (KDQOL-SF1.3, Danish version). The 
questionnaires will be sent by e-mail or e-boks from the primary investigator to the participants. If 
an answer has not been received after 14 days a reminder will be e-mailed. If the questionnaire has 
not been answered 14 days after the reminder, the research team will contact the participant by 
phone and ask if they need assistance for the questionnaire by the site staff or by receiving it by 
ordinary mail. 
 
 
 
 
 
Visit schedule 
Visit 
/ Procedure 
Visit 1 
- >30 
days 
Visit 2 
- <30 
days 
Visit 3 
Day 0 
Visit 4 
1 month 
Visit 5 
3 months 
Visit 6 
6 months 
Visit 7 
9 months 
Visit 8 
12 months 
Visit 9 
18 months 
Information 
X 
 
 
 
 
 
 
 
 
Sign informed consent 
 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
Screening 
 
 
X 
 
 
 
 
 
 
Baseline characteristics 
 
 
X 
 
 
 
 
 
 
Comorbidities, medical history, 
medication 
 
 
X 
 
 
 
 
 
 
Standard blood samples 
 
 
X 
X 
X 
X 
X 
X 
X 
25-hydroxy vitamin D 
 
 
X 
 
X 
 
X 
 
X 
Research biobank samples 
 
 
X 
 
 
 
 
 
X 
DXA-scan 
 
 
X 
 
 
 
 
 
X 
Pulse wave velocity  
 
 
X 
 
 
 
 
 
X 

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Hand grip strength, 10 meter 
walk test and sit-to-stand 
 
 
X 
 
 
 
 
 
X 
Questionnaire 
 
 
X 
 
 
 
 
 
X 
Bone biopsy 
 
 
 
 
 
 
 
 
X* 
Adverse event collection 
 
 
X 
X 
X 
X 
X 
X 
X 
Table 1. Visit schedule. *indicates that it is optional.  
For visit 4-8 there will only be taken blood samples with follow-up by phone to minimize time 
consume for both patient and the investigator. Patients with CKD4-5nonD are usually scheduled in 
the outpatients clinic 4 times annually, investigators will try to plan the study visits on the same 
days.  
Biobank for future research 
There will be established a biobank for future research consisting of 10 ml serum and 8 ml EDTA-
plasma from each patient signing the separate informed consent regarding the biobank for future 
research. The biobank material will be pseudonymised and kept in a locked freezer at -80oC. This is 
not mandatory for participating in the trial.  Patients may at any time contact the primary 
investigator to have their plasma and serum destroyed. Analyses on the biobank material can only 
be performed after application and approval by the Ethics Committee System. Samples will be 
destroyed after 20 years.  
 
Randomisation 
Patients will be randomised in a 1:1 ratio to either the intensive PTH target group or the liberal PTH 
target group for an 18-month period. Randomisation will be performed within computer software.  
Blinding 
PTH is routinely measured in the clinic and blinding is not feasible as unblinding of the allocated 
treatment group will easily occur. The open-label design may influence the adherence, as the 
treating physician or the patient may favour a specific PTH target. It is therefore of great 
importance to monitor the adherence to the allocated treatment target through levels of PTH, and 
doctors as well as participants will be encouraged to comply.  
The DXA-scan and analysis of this will be blinded, as the investigator performing the intervention 
will not perform the scans.  

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Efficacy endpoints 
Primary endpoint:  
Difference in % change in bone mineral density (BMD) between the treatment groups.  
This is the generally accepted outcome for trials comparing treatment effects on BMD. 
Secondary endpoints:  
- 
Difference in follow-up BMD between treatment groups  
- 
Difference in follow-up arterial stiffness between the treatment groups   
- 
Differences in follow-up muscle mass between the treatment groups 
- 
Differences in follow-up muscle function between the treatment groups 
- 
Differences in bone histology between the treatment groups 
- 
Differences in follow-up health-related quality of life between the treatment groups 
- 
Differences in number of spinal fractures between the treatment groups  
The feasibility to obtain a differential PTH level of at least 0.5 times the upper limit of normal 
between the two groups will be determined. During the piloting the number of withdrawals of 
consent and crossovers will be determined to improve the set-up, to increase retention and 
adherence and adjust the sample size estimation.  
 
Adverse events 
All serious adverse events (SAE) will be recorded during trial period. SAE is any case of death, life 
threatening event, persistent or significant disability, hospitalisation, prolongation of existing 
hospitalisation or treatment necessary to avoid the above and congenital anomaly/birth defect. It is 
the responsibility of the investigator to assess whether any SAE is with reasonable possibility 
causally related to the study intervention. Within 7 days after becoming a 
ware of a SAE, the investigators will report these to the local scientific ethics committee. Once 
annually the primary investigator will report a summary of SAEs to the local scientific ethics 
committee.   
All cases of hyper/hypocalcaemia and hyperphosphatemia will be registered as adverse events of 
interest.  
 

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Statistics 
All included participants will be accounted for and presented in a CONSORT diagram. 
Baseline characteristics will be presented as mean ± standard deviation or median and interquartile 
range, and number and percentages.  
The primary endpoint % change in BMD during 18 months will be compared between groups with 
unpaired t-test.  
This will be further explored by comparison of BMD after 18 months by ANCOVA adjusted for 
baseline BMD. 
For secondary outcomes with a baseline and a single follow-up measurement, comparison between 
treatment groups will be performed by ANCOVA, adjusted for the baseline value. If more suitable, 
this analysis will be done with mixed effect model.   
Secondary outcomes with baseline and multiple post-randomization measurements will be 
compared as baseline-adjusted follow-up values using a mixed model repeated measures approach. 
Categorical outcomes will be compared by Chi2-test. Continuous outcomes will be presented as 
graphs of means and standard error of the means at each time point.  Continuous outcomes with 
non-normal distribution will be logarithmic transformed to obtain normality before analysis.  
Two-sided P-values < 0.05 is considered statistically significant.  
All data will be described including data-incompleteness as well as reasons for data-
incompleteness. Imputation will be used, if reasonable, to manage data-incompleteness in the 
analyses.  
Analyses will be run in R studio, SAS and STATA. A statistical analysis plan will be decided 
before data lock. 
Time schedule 
The study will not be initiated until approved by the local scientific ethics committee, expected in 
summer of 2025. Recruitment is expected to last 6 months followed by 18 months follow-up. The 
study period will last 18 months for each patient.   
 

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Rights and publication 
Principal investigator Freja Stæhr Hassager, MD will coordinate the study. Freja Stæhr Hassager 
will be first author on any subsequent publications.  
Ditte Hansen will be final author on any subsequent publications.  
Authorship will be granted to any person who contribute to the subsequent publications according 
to the Vancouver Guidelines.  
All results, either positive, negative or inconclusive, will be submitted for publication in peer-
reviewed journals.  
Ethics 
The trial is investigator-initiated by Ditte Hansen and will not be initiated before approval from the 
local scientific ethics committee. The trial will be conducted according to local legislation 
(Databeskyttelsesloven, Databeskyttelsesforordningen and Sundhedsloven) and Declaration of Helsinki 
2013. Further, the trial will be registered at ClinicalTrials.gov before initiated. Since activated 
vitamin D, calcimetics and phosphate binders are already used to treat hyperparathyroidism and 
there is no evidence of the optimal PTH-target, the trial is not considered a drug study 
(correspondence with the Danish Medicines Agency, DMA, case number 2025030893) and will not 
be monitored by the Good Clinical Practice Unit. 
Screening and inclusion 
The study will be streamlined and integrated as much as possible into the usual care to reduce the 
burden on the participants and study staff.  
The treating physician in the outpatient clinic at Department of Nephrology may pre-screen the 
patients for possible enrolment in the study. The pre-screening will involve patients in the 
outpatient clinic at the Department of Nephrology. Pre-screening will include access to information 
about age, status on kidney transplant, eGFR, PTH and medication in the patients’ medical journal 
to clarify if patients meet inclusion criteria. Data used for screening patients will be from the time 
the patient is pre-screened and back to 2015. During trial period there will be pre-screened 
approximately 500 patients to include 70. The pre-screening process will make the clinicians deliver 
personal information (personal identification number and telephone number) to the primary 
investigator prior to the written consent.  

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Patients meeting the inclusion criteria will be contacted in one of two ways:  
1) Treating physician giving short information to the patient in the outpatient clinic and the 
patient giving oral consent to be contacted at telephone by an investigator. Primary 
investigator will call the patient within 14 days after consent.  
2) Recruitment letter: The patient will be contacted through e-boks where they will receive an 
invitation to participate in the trial. Within the letter there will be e-mail and phone number 
to primary investigator for them to contact. If the patient does not contact the primary 
investigator within 14 days after receiving the letter, primary investigator will call the 
patient to make sure they received and read the letter. Otherwise, primary investigator will 
give short information about the trial and encourage the patient to read the letter.  
Regardless of the pre-screening method, if the patient desires to participate in the trial, an 
appointment with principal investigator for informing the patient will be scheduled. Such a meeting 
must take place in an undisturbed room and the patient may bring a family member or friend to aid 
in decision-making. The facilities for an undisturbed meeting is in place at the research department 
at Herlev Hospital. Written informed consent must be signed within 30 days after this meeting. 
Upon giving written informed consent, the study participants give permission to the study 
investigators to access the participants’ health records to collect relevant information for the study.  
Participation in this trial will be voluntary and participants may withdraw consent from 
intervention, follow-up and biobank for future research separately during the trial.  
Risk for participants 
Treatment of hyperparathyroidism has been performed for decades. Activated vitamin D, phosphate 
binders and calcimetics are all highly recognized treatments in patients with CKD. Participation in 
this trial does not provide the participants with any additional risk than the present everyday 
treatment which depends on the clinical decision by the individual physician.  
Blood samples will be drawn from a peripheral vein using standard sterile technique which includes 
risk of discomfort, bleeding, hematoma and rarely infection. 
The DXA-scan is performed without pain for the patient and does not require infusion of any 
contrast. DXA expose the participants to a low dose of radiation (3-15 µSv), corresponding to <1 
week of background radiation (41,42).  

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Pulse wave velocity measurement using SphygmoCor is non-invasive and do not expose any risk to 
the patient.  
Test of hand grip strength, 10 meter walk test and sit-to-stand test is not expected to add any risk of 
complications to the patients.  
Bone biopsy from the iliac crest is an invasive procedure. The most common complication after the 
biopsy is pain, which usually disappears within a few days. The patient will be given paracetamol 
from the hospital after the procedure to use for the following days. 2-3 in 1000 patients experience 
hematoma, neuropathy or pain lasting for more than a week. Less than 1 in 1000 patients experience 
infection in the skin that required antibiotics. Extremely rarely (1 in 10.000) patients experience 
infection in the bone or fracture as complication to the procedure(43). Risk of complications is 
minimized by having a trained physician experienced in performing bone biopsies doing the biopsy. 
The treatment with tetracycline can provoke allergic reaction and gastrointestinal problems.  
The future health related benefit for the patients with CKD is expected to balance the above-
mentioned minimal risk added to the patients in the trial. Hopefully in the future we will be able to 
treat patients with CKD and hyperparathyroidism based upon evidence to lower risk of fractures.  
If significant health-related findings about an included patient should be made, the patient will be 
informed, unless they have requested not to be informed.  As the results from the trial are published 
the patients will also be informed of the results of the trial. Each patient will be given written 
contact information of the primary investigator if they wish to be given more detailed information 
regarding the trial. Subjects participating in the trial will be insured by the Patient Compensation 
Association (Patienterstatningen). 
Data 
Data on individual study participants will be kept in an electronic case report form (CRF, REDCap). 
Data from CRFs will be kept for 20 years and deleted afterwards.  
Financing 
The patients will not be paid for their participation in the trial.  
The salary to primary investigator and additional expenses to analyses and publications is covered 
by funding by the Novo Nordisk Foundation (2.4 mio. kr) and the Augustinus Foundation (1.6 mio. 
kr.).. Salary to primary investigator is handled through the department.  

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The investigators do not have any conflicts of interest in this project.  
Perspective 
The presented project will increase the knowledge of how PTH influences on bone mineral density 
and arterial stiffness in patients with chronic kidney disease. It will inform a large-scale randomized 
trial exploring the influence of targeting PTH in patients with chronic kidney disease. The aim is to 
improve treatment of hyperparathyroidism, and to avoid cost in time and money monitoring and 
treating patients with chronic kidney disease if the treatment is useless. 
 
 

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