Reversal Of Arterial Disease by modulating Magnesium And Phosphate

Cardiovascular disease (CVD) is the leading cause of death in patients with
chronic kidney disease (CKD). Accumulating evidence suggests that CVD and
mortality are partially driven by inflammation and an increased calcification
propensity, both features that affect arterial stiffness. Recently, clinical
quantification of calcification propensity, i.e. the tendency to develop
calcifications, has become feasible by measuring calciprotein particle (CPP)
maturation time in-vitro from patient samples (T50). Besides their direct
effect on vascular mineralization, CPP*s seem to induce inflammation, that
contributes to vascular calcification and endothelial dysfunction, contributing
to increased arterial stiffness as well. Importantly, both magnesium deficiency
and excess phosphate are associated with increased arterial stiffness as can be
measured by pulse wave velocity (PWV). The influences of lower magnesium and
higher phosphate concentrations on arterial stiffness are possibly explained by
their modulating, detrimental effect on endothelial function and their ability
to aggravate CPP formation, respectively. Moreover, multiple observational
studies among CKD patients have linked magnesium deficiency to cardiovascular
events and mortality.
The previous NIGRAM consortium (Nijmegen, Groningen, Amsterdam) addressed the
role of mineral metabolism markers and the renin-angiotensin-system (RAS) in
relation to vascular disease, demonstrating that deregulated mineral
metabolism, i.e. high plasma phosphate concentration, but also novel players
such as high concentrations of fibroblast growth factor-23 (FGF-23) and low
Klotho, contribute to vascular calcification and dysfunction. Within the NIGRAM
2+ consortium, of which the current protocol is part, this focus will now be
expanded by the role of magnesium as a powerful endogenous calcification
inhibitor, examining the effect of magnesium supplementation on arterial
stiffness and calcification propensity. In addition, we will determine whether
phosphate binding therapy in CKD patients without overt hyperphosphatemia can
amplify the presumed beneficial effect of magnesium. By focusing on the role of
magnesium and phosphate as targets that can modulate arterial stiffness, this
research aims to improve cardiovascular outcomes in the CKD population.
Moreover, the hypothesis will be tested, if the effects on arterial stiffness
and inflammation, are mediated by changes in calcification propensity. If this
hypothesis can be confirmed, this will enable personalized medicine on this
aspect of CKD, by directing interventions on the T50 score.

Primary Objective:
- Determine the effect of 24 weeks of oral magnesium supplementation and/or the
phosphate binder sucroferric oxyhydroxide on arterial wall stiffness in CKD
patients, as measured by pulse wave velocity.

Secondary Objectives:
- Determine the effect of 24 weeks of oral magnesium supplementation and/or the
phosphate binder sucroferric oxyhydroxide on calcification propensity and
vascular inflammation in CKD patients, measured by markers including T50, CPP
concentrations, FGF-23, Klotho and hsCRP.
- Explore the effect of 24 weeks of oral magnesium supplementation and/or the
phosphate binder sucroferric oxyhydroxide on vascular calcification and
vascular inflammation, assessed by 18F-NaF-PET scans and 18F-FDG-PET,
respectively, in a subsample of 40 participants.

Randomised Controlled Trial, multi center

This study has 4 intervention arms:

A) Magnesium citrate
B) Magnesium Placebo
C) Magnesium citrate + sucroferric oxyhydroxide
D) Magnesium Placebo + sucroferric oxyhydroxide

Concluding: a doubble blind placebo controlled magnesium intervention with
addition of an open label phosphate binder (sucroferric oxyhydroxide)
intervention

An extensive overview on burden risk and benefits can be found in the ROADMAP
protocol, paragraph 11.4 and 13.1. Reference numbers relate to the references
used in the protocol.

Burden
For all participants there will be 4 or 5 study visits over a period of
approximately 9 to 12 months (5th visit is optional). All study visits will
take place at the hospital where participants are included, except for the two
visits including additional PET scans that will be performed at the VUmc (only
concerning a subsample of participants). If possible some visits will be
combined with regular CKD or other hospital visits. During the screening an
electrocardiography (ECG) will be taken a single X-ray of the abdominal aorta
(lateral and anterior/posterior) will be performed. Fasting blood samples will
be collected by venepuncture during all visits (a total of 65 or 86 ml blood
will be withdrawn). PWV measurements will be performed 3 times, which is
non-invasive nor painful. Within each allocation arm 10 out of 45 participants
will undergo a 18F-NaF-PET or 18F-FDG-PET scan twice, combined with a low-dose
computer tomography (CT). For this subsample of participants, time investment
will be approximately an additional 2,5 hours both times, to perform the PET
scans at location VUmc. 18F-FDG-PET and 18F-NaF-PET are imaging techniques that
can capture unexpected, incidental findings such as questionable, possible
malignant nodule*s. Although these techniques can facilitate detection at an
early stage, it can potentially be a burden if it leads to false positive
findings. The PET requires overnight fasting and PWV measurements will be
preceded by only some minor restrictions. Pill burden consists of 3 or 5 pills
a day: 3 capsules of magnesium citrate or matching Mg-placebo (intervention A
and B), or 3 capsules of magnesium citrate or Mg-placebo with 2 tablets of SFOH
(intervention C and D), in addition to regular medication use. Capsule intake
will be divided over breakfast, lunch and dinner. Magnesium citrate and SFOH
can both cause bowel discomfort and sometimes diarrhoea, although mostly these
symptoms will disappear or decrease after the first 2 weeks. Another possible
side effect of SFOH is dark stools, however, this is only seen in some users
and because of the low dose of SFOH, dark colouration may be minimal. 24-hour
urine will be collected twice during the study, and participants will be ask to
fill in a very short questionnaire concerning medication tolerability and
compliance during two of their study visits.

Risks:
Knowledge of both magnesium citrate and SFOH are sufficient, as an
over-the-counter supplement without safety concerns and a registered,
frequently used phosphate binder in clinical practice, respectively. This study
is in continuation to other studies in which CKD patients have been exposed to
increasing magnesium levels and (higher doses of) SFOH [40, 69, 75, 76].
A daily dose of 350 mg magnesium citrate is not expected to raise plasma
magnesium to unacceptably high levels (> 1.5 mmol/L). A meta-analysis
demonstrated a significant rise of plasma magnesium concentration of 0.04
mmol/L (95% CI: 0.02, 0.06) at a median dose of 365 mg/day (range: 197-994
mg/day) after 12 weeks. A recent intervention study by Joris et al., showed a
0.02 mmol/L rise in plasma magnesium with a similar dose and formulation after
24 weeks of supplementation [25]. Risk of hypermagnesemia includes
gastro-intestinal manifestations such as nausea and vomiting and in more severe
hypermagnesemia it can induce bradycardia, arrhythmia, low blood pressure,
ileus, hyporeflexia and respiratory depression. Symptomatic hypermagnesemia is
not expected by oral intake of magnesium, since plasma magnesium levels are not
expected to exceed 2.0 mmol/L, with the threshold when symptomatic
hypermagnesemia typically develops. Therefore, we do not expect any of these
symptoms during our study related to inacceptable high magnesium
concentrations. Magnesium citrate intake is expected to increase plasma
magnesium levels, yet it is very unlikely magnesium concentration will rise to
unacceptable concentrations (>1.5 mmol/L). In case of hypermagnesemia (>1.5
mmol/L) the magnesium citrate supplementation frequency will be reduced. The
risk for severe hypermagnesemia and/or hypophosphatemia is minimized by regular
monitoring (at week 0, week 6, week 12 and week 24). By means of a ECG during
the screenings visit we will detect participants at risk of cardiac
arrhythmia*s due to (minimally) increased plasma magnesium.
SFOH is a registered product, clinically used as one of the phosphate
binding agents in CKD for patients with high plasma phosphate concentration.
Although, literature does not describe any specific phosphate level at which
phosphate binding therapy should be started, it is suggested that phosphate
binding therapy should only focus on CKD patients with hyperphosphatemia.
Therefore, SFOH prescription in this study will be mostly off-label, since
participants will have normal to moderately elevated phosphate concentration. A
clinical trial doubting the safety of phosphate binding agents in CKD patients
with normal phosphate concentrations did not distinguish calcium containing
phosphate binders from non-calcium containing phosphate binders in their
analysis. Although not proven, it is suggested that the safety concern (higher
incidence of coronary calcification) is due to calcium loading within the
calcium-containing phosphate binder group. Since SFOH is a non-calcium
containing phosphate binder, we do not expect safety concerns related to this
off-label use. Hypophosphatemia is not expected with the moderate dose
prescribed in this study, however, if plasma phosphate concentration will reach
the lower limit of 0.7 mmol/L, SFOH will be reduced or stopped to restore
normal phosphate concentration. Since iron absorption from SFOH in the
intestine is very low (in healthy subjects only 0.43%) there is minimal risk of
iron accumulation or overload in the circulation [76, 79]. However, SFOH use in
hemochromatosis or other iron storage diseases is not recommended and thus one
of the exclusion criteria. SFOH may interfere with absorption of various types
of antibiotics, therefore participants with a maintenance dose of antibiotics
of multiple times a day will be excluded. Incidental use of antibiotics during
the study will be evaluated per case. If the combination of the specific
antibiotic and SFOH is not reliable, study exclusion will be the consequence in
order to warrant safety of the concerning participant. SFOH is also known to
influence thyroid replacement therapy if taken at the same time. However,
because thyroid replacement medication intake is always (only) in the morning
and SFOH will be prescribed during lunch time and diner, this will not
interfere and therefore thyroid replacement therapy is not an exclusion
criterion. The same applies to vitamin D containing medicine, because intake
can be separated with a few hours from the SFOH intake without any consequence.
Participants that will be prescribed SFOH (allocation arm C and D, open label)
will be instructed for correct oral hygiene, because without proper oral
hygiene participants using SFOH are at risk of permanent teeth discoloration.
To reduce the risk of persistent diarrhoea with possible subsequent
micronutrient deficiency, study medication will be reduced if not tolerated
(see flow diagram paragraph 6.6, Figure 4).
Risk related to 18F-NaF-PET or 18F-FDG-PET scans are very limited. Both
are commonly used and safe tracers for clinical practice without any serious
side-effects. However, as with any injectable drug allergic reaction or
anaphylaxis may occur and as any radioactive compound it may increase the
almost negligible carcinogenic risk. Since it will be a low-dose CT with only
radiation to the abdomen and thorax, radiation burden will be smaller to
conventional CT scanning, reducing the carcinogenic risk that is known of high
dose and cumulative radiographic radiation. Total radiation burden for combined
18F-NaF-PET + low-dose CT or 18F-FDG-PET + low-dose CT will be approximately 10
to 12.4 millisievert (mSv) in total, 5 to 6.2 mSv both times with 24 weeks in
between. As a comparison, every person living in the Netherlands receives a
natural background radiation dose of 2-2.5 mSv per year.