Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02876354 |
| Other study ID # |
SGH001 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
August 11, 2016 |
| Last updated |
September 18, 2016 |
| Start date |
August 2016 |
| Est. completion date |
September 2016 |
Study information
| Verified date |
September 2016 |
| Source |
Saint-Joseph University |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Lebanon: Ministry of Public Health |
| Study type |
Interventional
|
Clinical Trial Summary
Vitamin K2 deficiency has been shown to be profound in hemodialysis patients. It is
reflected by high plasma levels of dephosphorylated-undercarboxylated Matrix Gla protein
(dp-ucMGP) and seems to be correlated with vascular calcifications. Vascular calcifications
can be assessed using the AC24 score on a lateral abdominal X-ray.
The aim of this study is to assess first the rate of decrease of dp-ucMGP in a hemodialysis
cohort after supplementation with vitamin K2 and the correlation between this rate of
decrease and the Aortic Calcification Severity (AC24) score. The factors associated with
high levels of dp-ucMGP will be analyzed as well.
Description:
Background The majority of patients reaching end-stage renal disease (ESRD) and dialysis
have vascular calcifications. Those vascular calcifications tend to increase mortality in
this specific population. It has been shown that high scores of vascular calcifications in a
healthy patient with no cardiovascular risk factors lead to a higher mortality rate compared
with someone with ≥3 risk factors without calcification. In hemodialysis (HD) patients,
cardiovascular risk factors are numerous and they include the traditional ones such as age,
smoking, diabetes, hypertension, hyperlipidemia and those specific to chronic kidney disease
(CKD) as for instance hyperparathyroidism. All those facts are compelling arguments to look
seriously for a treatment against vascular calcifications. Therefore the 2009 Kidney
disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for the Diagnosis,
Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder
(CKD-MBD) has suggested to measure those vascular calcifications scores by a lateral
abdominal radiograph that is a cost-effective alternative to the standard computed
tomography-based imaging.
In order to lower or prevent vascular calcifications in chronic kidney disease (CKD)
patients, many interventions have been studied in the past. They have included treatments
such as statins, non-calcium-based phosphate binders and cinacalcet. So far, the
non-calcium-based phosphate binders showed significant benefit on mortality but none of the
studies manifested a solid beneficial effect on vascular calcifications.
In the last years, remarkable data emerged concerning the association between vascular
calcifications and plasmatic levels of dephosphorylated-undercarboxylated MGP (dp-ucMGP).
dp-ucMGP is the inactive form of Matrix gla protein (MGP). MGP is a small protein known to
act locally in the tissues as a calcification inhibitor and it is vitamin K dependent. High
dp-ucMGP levels reflect low activity of MGP. Vitamin K2 deficiency is one of the factors
that increase dp-ucMGP. There have been several reports also showing that dp-ucMGP levels
increase gradually after the age of 40 and are significantly higher in those older than 65,
in patients with diabetes, aortic stenosis, heart failure and on vitamin K antagonists
(VKA). They are also extremely high in ESRD patients on dialysis. Moreover the combination
of VKA and dialysis increases the incidence of calciphylaxis.
Since high dp-ucMGP levels suggest vitamin k2 deficiency and are associated with vascular
calcification, supplementing high-risk patients especially CKD patients with vitamin k2
(menaquinone) seems very promising. Vitamin k2 can be provided to the patient as a pill or
through a specific food diet. Food that seems to affect dp-ucMGP levels includes natto and
fermented cheese such as camembert, goat cheese or gouda.
Vitamin K2 supplementation was analyzed in several European HD cohorts. In 2012, Westenfeld
et al. demonstrated that vitamin k2 supplements in hemodialysis patients lead to a
dose-dependent decrease in plasma dp-ucMGP levels. This was reproduced by Caluwé at al in
2014 and they both showed that a dose of 360 μg /d lower the dp-ucMGP by 30-33%.
Studies in patients with normal renal function showed a higher decrease of dp-ucMGP ~50%
under 180 μg /d of menaquinone and this could be explained in many ways. Either vitamin K2
deficiency is very profound in CKD and particularly dialysis patients or dp-ucMGP does not
only reflect vitamin k2 deficiency in those patients. High dp-ucMGP could be associated with
other risk factors for calcifications in chronic kidney disease such as phosphate, calcium
or parathyroid hormone (PTH).
Middle-Eastern diet is different from European countries and MGP activity as well as vitamin
K2 supplementation have not yet been studied in dialysis populations in this part of the
world.
Therefore this study will be conducted in a Lebanese hemodialysis center where patients will
receive vitamin k2 for 4 weeks. The investigators will assess first the rate of decrease of
dp-ucMGP after supplementation with vitamin K2 and the correlation between this rate of
decrease and the AC24 score. They will analyze as well the factors associated with high
levels of dp-ucMGP. Finally they will define the rate of decrease of dp-ucMGP after VKA
withdrawal in a small subgroup before including them in the study.
Methods and design
Trial design, participants and data collection This is a prospective, pre-post intervention
clinical trial. All patients in a single dialysis center older than 18 years on chronic
hemodialysis since more than one month will be included. Patients who are taking VKA and can
not stop it (heart valve replacement cases) will be excluded. The total expected trial
duration is 4 weeks.
Data for demographics, comorbidities, medications and laboratory results are collected from
the patients' medical records. Variables that will be studied are: age, gender, months on
dialysis, residual diuresis, BMI, urea reduction ratio (URR), diabetes, hypertension,
smoking, hyperlipidemia, calcium and non-calcium-based phosphate binders, cinacalcet,
alfacalcidol, AC-24 score, dp-ucMGP level, albumin, coronary artery disease, mean of
calcium, phosphorus and parathyroid hormone (PTH).
Calcium, phosphorus, PTH, LDL cholesterol and serum albumin levels will be collected from
the medical record of the patient. Calcium and phosphorus are measured monthly on a routine
basis; the mean of the last 12 measurements will be calculated. PTH is measured every 4-6
months; all PTH levels of each patient will be collected since the start of dialysis in
order to obtain the mean PTH level.
Definitions Coronary artery disease is defined as a history of coronary artery disease
treated medically or interventionally. Diabetes and hypertension are defined as taking
antidiabetic treatment or antihypertensive treatment respectively.
Normal phosphate and calcium are defined respectively as 3.5-4.5 mg/dL and 8.4-9.5 mg/dL.
Non-calcium phosphate binders available are sevelamer and lanthanum. The only active vitamin
D that patients will take is alfacalcidol.
Ethical considerations The study is approved by the ethical committee of the Saint-Joseph
University-Beirut and complies with the Declaration of Helsinki of 1975. All patients have
to give written informed consent to participate.
The supplementation with vitamin K2 does not put the patient at risk of hypercoagulability
and a previous prospective cohort of 35000 healthy subjects supplemented with vitamin K
showed no increase in ischemic stroke events.
Intervention:
Patients will be eligible for the trial if they sign the informed consent. All patients will
receive 360 μg of menaquinone once daily. Menaquinone will be provided by Omicron, Lebanon.
The chosen dose in this trial was established from two previous trials done on hemodialysis
patients. A daily dose of 360 μg Menaquinone reduces the amount of inactive MGP by 30-33% in
hemodialysis patients. The dose of the day of dialysis will be given in the center to ensure
at least the compliance towards the half of the dose per week.
Before starting the trial, patients on vitamin k antagonists as a prevention for vascular
access thrombosis will withdraw the VKA and be included in the study after stabilization of
their dp-ucMGP levels. The investigators will assess the average time necessary to reach a
stable level of dp-ucMGP after VKA withdrawal. Patients will be assigned to receive 360 μg
of menaquinone once daily.
Analysis of dp-ucMGP and AC-24 score measurements dp-ucMGP will be measured twice, once
before the vitamin k2 supplementation and second after four weeks of the treatment.
Pre-dialysis venous blood samples will be processed to the same laboratory.
Circulating dp-ucMGP will be quantified using a dual antibody enzyme-linked immunosorbent
assay provided by Immunodiagnostic Systems Ltd, United Kingdom.
Lateral abdominal X-ray of the lumbar aorta will be performed at the inclusion of the study.
For each patient the abdominal aortic calcifications will be estimated using the Aortic
Calcification Severity (AC-24) score. The AC-24 score will be calculated by two independent
physicians. If the difference is one point, the higher score will be recorded. If the
difference is more than one point a third opinion will be sought and the mean of the three
levels will be retained.
Clinical data and Follow-up Patients will have their pre-dialysis blood pressure measured
after 15 min of rest and recorded at the beginning and the end of the study using validated
automated electronic monitors. Their blood pressure levels will be checked also during the 4
weeks period three times per week in the dialysis center.
Assessment of adverse events Patients will be evaluated for any side-effect at each dialysis
session, especially regarding their vascular access patency or other thrombotic event.
Statistical analysis Descriptive statistics will be used to represent important variables of
known risk factors, exposures and treatment options. Continuous variables that are normally
distributed will be presented as means and standard deviation. Otherwise median and range
will be the appropriate method. Student t test and one way ANOVA will be used for parametric
variables comparison and Mann Whitney U and Kruskal Wallis for non parametric variables.
Categorical variables will be presented by count and percentage. Χ2 fischer exact test and
logistic regression will be used to compare two or more categorical variables respectively.
Pearson correlation will be calculated to investigate the association of vascular
calcifications score with dp-ucMGP level as well as with potential covariates. A stepwise
multivariable linear regression will be employed to adjust for the association of MGP with
calcification score in the presence of significant covariates. P < 0.20 will be considered
valid for inclusion in the model. A 2-sided P < 0.05 will be considered significant. To
determine the effect of vitamin K2 intake on dp-ucMGP, the pre- and post-levels will be
compared using matched t-test. All analyses will be done using SPSS statistics (22.0
version, SPSS Inc, Chicago, III).
