Renal Insufficiency, ChronicPhase 4NCT02999204
Effect of Vitamin D3 Supplementation on Arterial and Bone Remodeling in Chronic Kidney Disease Patients
A Phase 4 study testing Vitamin D3 in people with Renal Insufficiency, Chronic and Vascular Stiffness, run by Jewish General Hospital at 1 site in Canada.
Trial summary
To evaluate in patients with chronic kidney disease the impact of two dosages of per os vitamin D3 supplementation (cholecalciferol) on large arterial stiffness (evaluated non invasively by pulse wave velocity and high-resolution echotracking system). Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Renal Insufficiency, Chronic, Vascular Stiffness, Bone Diseases, Metabolic
- What is being tested?
- Vitamin D3
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 57 participants
- Where
- 1 siteCanada
- Study dates
- Jan 2015to 1 Oct 2020
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients with CKD stage 3-4 [estimated glomerular filtration rate (GFR) by modification of diet in renal disease (MDRD) formula between 15 and 60 ml/min/1.73m2].
- Serum vitamin D level<50 nmol/L.
Who cannot join
- Patient with estimated GFR by MDRD formula below 15 or above 60 ml/min/1.73m2).
- Serum vitamin D level >50 nmol/L.
- Liver disease manifested by elevated alanine aminotransferase (ALT) more than 3 times the upper limit of normal reference range, elevated gamma-glutamyl transferase (GGT) and total bilirubin levels.
- History of malabsorption or chronic diarrhea.
- Patients on biphosphonates, estrogen replacement therapy, PTH analogs, glucocorticosteroids, calcimimetics, and active vitamin D [1,25(OH)].
- Patients on antiepileptic medications or other medications affecting vitamin D metabolism (e.g. phenobarbital, phenytoin, rifampicin).
Trial locations and contacts
1 site in 1 country.
About this study
To evaluate in patients with chronic kidney disease the impact of two dosages of per os vitamin D3 supplementation (cholecalciferol) on large arterial stiffness (evaluated non invasively by pulse wave velocity and high-resolution echotracking system). We will also study arterial calcification (lateral abdominal radiography and echocardiogram), arterial remodeling (high-resolution echotracking system), endothelial function (evaluated by a non-invasive finger biosensor device), and bone remodeling (evaluated by serum biomarkers and bone mineral density).
Read the detailed description
Structural changes to large arteries and abnormalities in mineral and bone metabolism are frequent manifestations in patients with chronic kidney disease (CKD). Together, they contribute in a large part to the heightened morbidity and mortality observed in this population.
Epidemiological data in end stage renal disease and in the general population suggest the existence of a bone-vascular axis. Metabolic bone disease (MBD) in CKD encompasses altered bone remodeling and the propensity for vascular calcification. These pathological processes are driven by the multiple disorders of mineral metabolism in CKD, among them, abnormalities of vitamin D metabolism.
Vitamin D deficiency [25(OH)D] is widely observed in CKD patients and has been associated with an increased rate of cardiovascular events in both the general population and in CKD patients. The mechanisms involved are not clearly established. Vitamin D influences blood pressure through effects on the renin-angiotensin system (via a vitamin D response element in the renin gene), vascular smooth muscle cells and cardiomyocyte proliferation and hypertrophy, vascular inflammation and calcification. Vitamin D deficiency has been associated with large arterial stiffness in end-stage renal disease patients. Aortic and carotid stiffness are independent predictors of cardiovascular and overall mortality in end-stage renal disease patients. Large arterial remodeling and stiffening could be the missing pathogenic link between vitamin D deficiency and increased cardiovascular event rate.
In terms of mineral metabolism, many CKD patients develop secondary hyperparathyroidism. This results from a combination of hyperphosphatemia, hypocalcemia and low levels of active Vitamin D [1,25(OH)D2]. Since several observational studies have shown that parathyroid hormone (PTH) levels are inversely correlated with blood 25(OH)D levels, it is possible that 25(OH)D deficiency may also be contributing to the hyperparathyroid state. Secondary hyperparathyroidism contributes to cardiovascular risk and to bone disease. Elevated PTH has been associated with large arterial stiffness and remodeling. Elevated PTH is also associated with high bone turnover and participates in the development of bone disease of CKD-MBD. Bone disease in CKD-MBD comprises abnormalities in bone turnover, mineralization, linear growth and strength. Bone biopsy remains the gold standard for evaluation of bone disease in CKD but its invasive nature limits its practice. Serum biomarkers of bone remodeling allow direct estimation of bone remodeling but lack evaluation and precision. Among them, guidelines issued by Kidney Disease Improving Global Outcomes (KDIGO) recommend PTH (1-84) and bone specific alkaline phosphatase (BSALP). Other biomarkers exist including osteocalcin, osteoprotegerin, tartrate-resistant acid phosphate-5b (TRAP-5b), pyridinoline and deoxypyridinoline, procollagen type 1 amino-terminal extension peptides, C terminal cross-link (CTX) , FGF-23 and fetuin-A. The major limitation of the use of these biomarkers is their kidney-dependent elimination that affects their measured levels depending on the degree of kidney dysfunction. We have chosen to study, in addition to PTH (1-84) and BSALP, CTX, osteoprotegerin, osteocalcin, fetuin-A and fibroblast growth factor-23 (FGF-23) because a relationship between these biomarkers and arterial disease has never been demonstrated.
This study seeks to compare the impact of standard versus aggressive Vitamin D3 supplementation (in Vitamin D deficient CKD patients) on important vascular and bone health endpoints.
- Being tested
- Vitamin D3
- Medical subject headings
- Renal Insufficiency, Chronic, Bone Diseases, Metabolic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Vitamin D3Drug
Also called cholecalciferol
Two different doses of Vitamin D3
| Study group | Role | What they receive |
|---|---|---|
| Vitamin D3 5,000 units per week | Active comparator | Patient receive a dose that is considered within the standard dosing range for Vitamin D3 for one year. Receives: Drug: Vitamin D3 |
| Vitamin D3 50,000 units per week | Experimental | Patients receive a more aggressive Vitamin D3 dosing regimen of 50,000 units weekly for the first 3 months. At this point Vitamin D3 levels are measured. If the patient is Vitamin D3 replete (>75 nmol/L) then the dose is reduced to the equivalent of 25,000 units per week for the next 9 months. If the level is below this threshold then 50,000 units per week is continued for the next 9 months Receives: Drug: Vitamin D3 |
What is being measured
The primary outcome is the main question the study is designed to answer.
Aortic stiffness evaluated by pulse wave velocity (PWV) (Sphygmocor ® )
Parameter measured in meters per second.
Measured: 12 months
Secondary outcomes (6)
Carotid stiffness evaluated by high resolution echotracking system (Art-lab®).
Parameter measured as the difference in millimeters in carotid artery diameter between systole and diastole.
Measured: 12 months
Endothelial function evaluated by Endo-PAT2000® system
Parameter measured as the reactive hyperemia index as calculated by the Endo-PAT2000® system software.
Measured: 12 months
Aortic valve calcification obtained from echocardiography.
Parameter measured using a semi-quantitative scoring system based on scale of 1-4 as described by Rosenhek et al, New England Journal of Medicine 2000;343 (9):611.
1-no calcification, 2-mildly calcified (small isolated spots), 3-moderately calcified (multiple larger spots), 4-heavily calcified (extensive thickening and calcification of all cusps).
Measured: 12 months
Calcification of the aorta obtained by plain lateral radiography.
Parameter measured using a semi-quantitative scoring system based on a scale of 0-3 as described by Kauppila et al, Atherosclerosis 1997;132:245.
0-no calcification, 1-small scattered calcific deposits filling less than 1/3 of the longitudinal wall of the aorta, 2-one third or more, but less than two thirds of the longitudinal wall of the aorta calcified, 3-two thirds or more of the longitudinal wall of the aorta calcified.
Measured: 12 months
Bone mineral density
Osteodensitometry of the lumbar spine, hip, and distal radius, using dual-energy X-ray absorptiometry and reported in grams per square centimeter.
Measured: 12 months
Parathyroid hormone levels
Measurement of parathyroid hormone levels using a commercially available intact parathyroid hormone ELISA kit with values reported in ng/L.
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Dec 2016 (estimated)
- Study startJan 2015
- Primary completion23 Sep 2020
- Study completion1 Oct 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Renal Insufficiency, ChronicStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Care provider
- Enrolment
- 57 participants (actual)
Sponsor and investigators
- Lead sponsor
- Jewish General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Mark L. Lipman, Jewish General Hospital
- Investigators
- Mark L Lipman, M.D., Principal investigator, Jewish General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02999204
- Sponsor's protocol ID
- #10-010
- Status last verified
- Feb 2021
- First submitted
- 29 Aug 2016
- Last updated
- 16 Feb 2021
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure. Circulation. 2001 Feb 20;103(7):987-92. doi: 10.1161/01.cir.103.7.987.
PubMed 11181474London GM, Guerin AP, Verbeke FH, Pannier B, Boutouyrie P, Marchais SJ, Metivier F. Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency. J Am Soc Nephrol. 2007 Feb;18(2):613-20. doi: 10.1681/ASN.2006060573. Epub 2007 Jan 3.
PubMed 17202417Kendrick J, Targher G, Smits G, Chonchol M. 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey. Atherosclerosis. 2009 Jul;205(1):255-60. doi: 10.1016/j.atherosclerosis.2008.10.033. Epub 2008 Nov 11.
PubMed 19091317Motiwala SR, Wang TJ. Vitamin D and cardiovascular disease. Curr Opin Nephrol Hypertens. 2011 Jul;20(4):345-53. doi: 10.1097/MNH.0b013e3283474985.
PubMed 21519252Artaza JN, Mehrotra R, Norris KC. Vitamin D and the cardiovascular system. Clin J Am Soc Nephrol. 2009 Sep;4(9):1515-22. doi: 10.2215/CJN.02260409. Epub 2009 Aug 20.
PubMed 19696220Barreto DV, Barreto FC, Liabeuf S, Temmar M, Boitte F, Choukroun G, Fournier A, Massy ZA. Vitamin D affects survival independently of vascular calcification in chronic kidney disease. Clin J Am Soc Nephrol. 2009 Jun;4(6):1128-35. doi: 10.2215/CJN.00260109. Epub 2009 May 14.
PubMed 19443628
Study at a glance
From the registry record, last updated by the sponsor on 16 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Vitamin D3 Supplementation on Arterial and Bone Remodeling in Chronic Kidney Disease Patients
- ClinicalTrials.gov ID
- NCT02999204
- Acronym / sponsor ID
- #10-010
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 57 participants (actual)
- Lead sponsor
- Jewish General HospitalUniversity, hospital or other
- Study start
- Jan 2015 (actual)
- Primary completion
- 23 Sep 2020 (actual)
- Study completion
- 1 Oct 2020 (actual)
- First posted
- 21 Dec 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
To evaluate in patients with chronic kidney disease the impact of two dosages of per os vitamin D3 supplementation (cholecalciferol) on large arterial stiffness (evaluated non invasively by pulse wave velocity and high-resolution echotracking system). We will also study arterial calcification (lateral abdominal radiography and echocardiogram), arterial remodeling (high-resolution echotracking system), endothelial function (evaluated by a non-invasive finger biosensor device), and bone remodeling (evaluated by serum biomarkers and bone mineral density).
Detailed description
Structural changes to large arteries and abnormalities in mineral and bone metabolism are frequent manifestations in patients with chronic kidney disease (CKD). Together, they contribute in a large part to the heightened morbidity and mortality observed in this population.
Epidemiological data in end stage renal disease and in the general population suggest the existence of a bone-vascular axis. Metabolic bone disease (MBD) in CKD encompasses altered bone remodeling and the propensity for vascular calcification. These pathological processes are driven by the multiple disorders of mineral metabolism in CKD, among them, abnormalities of vitamin D metabolism.
Vitamin D deficiency [25(OH)D] is widely observed in CKD patients and has been associated with an increased rate of cardiovascular events in both the general population and in CKD patients. The mechanisms involved are not clearly established. Vitamin D influences blood pressure through effects on the renin-angiotensin system (via a vitamin D response element in the renin gene), vascular smooth muscle cells and cardiomyocyte proliferation and hypertrophy, vascular inflammation and calcification. Vitamin D deficiency has been associated with large arterial stiffness in end-stage renal disease patients. Aortic and carotid stiffness are independent predictors of cardiovascular and overall mortality in end-stage renal disease patients. Large arterial remodeling and stiffening could be the missing pathogenic link between vitamin D deficiency and increased cardiovascular event rate.
In terms of mineral metabolism, many CKD patients develop secondary hyperparathyroidism. This results from a combination of hyperphosphatemia, hypocalcemia and low levels of active Vitamin D [1,25(OH)D2]. Since several observational studies have shown that parathyroid hormone (PTH) levels are inversely correlated with blood 25(OH)D levels, it is possible that 25(OH)D deficiency may also be contributing to the hyperparathyroid state. Secondary hyperparathyroidism contributes to cardiovascular risk and to bone disease. Elevated PTH has been associated with large arterial stiffness and remodeling. Elevated PTH is also associated with high bone turnover and participates in the development of bone disease of CKD-MBD. Bone disease in CKD-MBD comprises abnormalities in bone turnover, mineralization, linear growth and strength. Bone biopsy remains the gold standard for evaluation of bone disease in CKD but its invasive nature limits its practice. Serum biomarkers of bone remodeling allow direct estimation of bone remodeling but lack evaluation and precision. Among them, guidelines issued by Kidney Disease Improving Global Outcomes (KDIGO) recommend PTH (1-84) and bone specific alkaline phosphatase (BSALP). Other biomarkers exist including osteocalcin, osteoprotegerin, tartrate-resistant acid phosphate-5b (TRAP-5b), pyridinoline and deoxypyridinoline, procollagen type 1 amino-terminal extension peptides, C terminal cross-link (CTX) , FGF-23 and fetuin-A. The major limitation of the use of these biomarkers is their kidney-dependent elimination that affects their measured levels depending on the degree of kidney dysfunction. We have chosen to study, in addition to PTH (1-84) and BSALP, CTX, osteoprotegerin, osteocalcin, fetuin-A and fibroblast growth factor-23 (FGF-23) because a relationship between these biomarkers and arterial disease has never been demonstrated.
This study seeks to compare the impact of standard versus aggressive Vitamin D3 supplementation (in Vitamin D deficient CKD patients) on important vascular and bone health endpoints.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, care provider)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Vitamin D3 5,000 units per week | Active comparator | Drug: Vitamin D3Patient receive a dose that is considered within the standard dosing range for Vitamin D3 for one year. |
| Vitamin D3 50,000 units per week | Experimental | Drug: Vitamin D3Patients receive a more aggressive Vitamin D3 dosing regimen of 50,000 units weekly for the first 3 months. At this point Vitamin D3 levels are measured. If the patient is Vitamin D3 replete (>75 nmol/L) then the dose is reduced to the equivalent of 25,000 units per week for the next 9 months. If the level is below this threshold then 50,000 units per week is continued for the next 9 months |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Patients with CKD stage 3-4 [estimated glomerular filtration rate (GFR) by modification of diet in renal disease (MDRD) formula between 15 and 60 ml/min/1.73m2].
- Serum vitamin D level<50 nmol/L.
Key exclusion criteria (6 listed)
- Patient with estimated GFR by MDRD formula below 15 or above 60 ml/min/1.73m2).
- Serum vitamin D level >50 nmol/L.
- Liver disease manifested by elevated alanine aminotransferase (ALT) more than 3 times the upper limit of normal reference range, elevated gamma-glutamyl transferase (GGT) and total bilirubin levels.
- History of malabsorption or chronic diarrhea.
- Patients on biphosphonates, estrogen replacement therapy, PTH analogs, glucocorticosteroids, calcimimetics, and active vitamin D [1,25(OH)].
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Vitamin D3Also: cholecalciferolTwo different doses of Vitamin D3 | Drug | Vitamin D3 5,000 units per week, Vitamin D3 50,000 units per week |
Primary outcome
Aortic stiffness evaluated by pulse wave velocity (PWV) (Sphygmocor ® )
Time frame: 12 months
Parameter measured in meters per second.
6 secondary outcomes
Carotid stiffness evaluated by high resolution echotracking system (Art-lab®).
Time frame: 12 months
Endothelial function evaluated by Endo-PAT2000® system
Time frame: 12 months
Aortic valve calcification obtained from echocardiography.
Time frame: 12 months
Calcification of the aorta obtained by plain lateral radiography.
Time frame: 12 months
Bone mineral density
Time frame: 12 months
Parathyroid hormone levels
Time frame: 12 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 Feb 2021.
- Results publication: PubMed 11181474Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness attenuation on survival of patients in end-stage renal failure. Circulation. 2001 Feb 20;103(7):987-92. doi: 10.1161/01.cir.103.7.987.
- Results publication: PubMed 17202417London GM, Guerin AP, Verbeke FH, Pannier B, Boutouyrie P, Marchais SJ, Metivier F. Mineral metabolism and arterial functions in end-stage renal disease: potential role of 25-hydroxyvitamin D deficiency. J Am Soc Nephrol. 2007 Feb;18(2):613-20. doi: 10.1681/ASN.2006060573. Epub 2007 Jan 3.
- Results publication: PubMed 19091317Kendrick J, Targher G, Smits G, Chonchol M. 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey. Atherosclerosis. 2009 Jul;205(1):255-60. doi: 10.1016/j.atherosclerosis.2008.10.033. Epub 2008 Nov 11.
- Results publication: PubMed 21519252Motiwala SR, Wang TJ. Vitamin D and cardiovascular disease. Curr Opin Nephrol Hypertens. 2011 Jul;20(4):345-53. doi: 10.1097/MNH.0b013e3283474985.
- Results publication: PubMed 19696220Artaza JN, Mehrotra R, Norris KC. Vitamin D and the cardiovascular system. Clin J Am Soc Nephrol. 2009 Sep;4(9):1515-22. doi: 10.2215/CJN.02260409. Epub 2009 Aug 20.
- Results publication: PubMed 19443628Barreto DV, Barreto FC, Liabeuf S, Temmar M, Boitte F, Choukroun G, Fournier A, Massy ZA. Vitamin D affects survival independently of vascular calcification in chronic kidney disease. Clin J Am Soc Nephrol. 2009 Jun;4(6):1128-35. doi: 10.2215/CJN.00260109. Epub 2009 May 14.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Mark L Lipman, M.D. principal investigator
Jewish General Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Vitamin D3 in people with Renal Insufficiency, Chronic and Vascular Stiffness, run by Jewish General Hospital at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 16 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Aortic stiffness evaluated by pulse wave velocity (PWV) (Sphygmocor ® ) (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02999204, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 Feb 2021.