Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06209268 |
| Other study ID # |
USplitSM111 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
October 1, 2024 |
| Est. completion date |
February 1, 2025 |
Study information
| Verified date |
May 2024 |
| Source |
University of Split, School of Medicine |
| Contact |
Vedran Kovacic, prof.dr. |
| Phone |
+385915902059 |
| Email |
vedran.kovacic.split[@]gmail.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Sufficient serum levels of vitamin D are important for immune system regulation with
protective effect against severe infection and overactivated inflammatory response in sepsis.
It is also not clear what level of vitamin D in the blood would be the trigger for vitamin D
administration. A more selective approach to VDR activation than cholecalciferol could have a
more significant role in the clinical outcomes of patients with sepsis. A study demonstrated
that low baseline serum level of vitamin D receptor (VDR) was associated with a high
incidence of 28-day mortality and negatively correlated with lactate, C-reactive protein,
APACHE II SOFA scores, and disease severity among patients with sepsis in an ICU setting.
The role of selective vitamin D receptor activation agents (paricalcitol or maxacalcitol) was
not studied in septic patients, despite its anti-inflammatory and immunomodulatory
properties. Vitamin D analogs have different effects on nuclear VDRs than does calcitriol,
through different response elements in various target genes, so it is possible that their
effect on a patient with sepsis will be more effective than cholecalciferol. As distribution
of VDRs is ubiquitous in many organs and tissues, selective VDR activation with paricalcitol
may have beneficial effects in preserving organs functionality and modulating the immune
response in sepsis.
Hypotheses
1. The immunoregulatory, anti-inflammatory, and anti-oxidative properties of selective
vitamin D receptor activator paricalcitol would result in improvement of inflammatory,
endothelial function, and antioxidative parameters and clinical outcomes in groups of
septic patient admitted to ICU.
2. The baseline septic patient serum 25(OH) D3 levels at admission time in ICU have
influence on clinical outcomes as well as on inflammatory, endothelial function, and
antioxidative parameters.
3. The inflammatory, endothelial function, and antioxidative parameters measured at ICU
admission time have significant impact on clinical outcomes in septic patients.
The aim
The main objective of study is to test hypothesis that that selective activator of vitamin D
receptors paricalcitol will improve outcomes of septic patient admitted in ICU. The study
aims to investigate the effects of paricalcitol on clinical outcomes, inflammatory markers,
organ dysfunction, endothelial function, vascular morphology, coagulation markers, and
haemodynamic parameters.
The additional objectives of the study are to test hypothesis that septic patient serum
25(OH)vitamin D3 have impact on inflammatory, endothelial function, and antioxidative
parameters including protein carbonylation; and to test hypothesis that these markers and
clinical outcomes are interconnected with significant impact on clinical outcomes.
Description:
There are evidences that decreased vitamin D levels among septic patients shown significant
associations with adverse outcomes.
The large PETAL-VIOLET trial was conducted in 44 hospitals in the United States and enrolled
1358 severe patients (more than 80% were admitted to the ICU for medical diseases) with
vitamin D deficiency. Study protocol included very early vitamin D3 supplementation (a single
enteral dose of 540,000 IU) in critically ill. Results showed that early high dose of vitamin
D3 supplementation had no advantage over placebo with respect to 90 day mortality or hospital
stay, and found no differences between the groups of participants.
Second large study, VITdAL-ICU randomized clinical trial, was conducted among 492 critically
ill adult patients with vitamin D deficiency (≤20 ng/mL) assigned to receive either vitamin
D3 given orally or via nasogastric tube once at a dose of 540,000 IU followed by monthly
maintenance doses of 90,000 IU for 5 months; or a placebo. There was no difference between
groups in length of hospital stay, hospital mortality, and 6-month mortality. In severe
vitamin D deficiency (≤12 ng/mL) subgroup analysis, only hospital mortality was significantly
lower for vitamin D3 receivers.
A recent metaanalysis included 11 randomized control trials with a total of 2187 patients
concluded that vitamin D supplementation in critically ill patients decreases the duration of
mechanical ventilation and ICU stay. There was no significant difference noted in mortality
and length of hospital stay.
Many of these studies on ICU population included mixed ICU population, including also septic
patients. Only minority of studies was conducted and dedicated exclusively for septic
population. VITdAL-ICU and PETAL-VIOLET trials included critically ill patients with a low
prevalence of sepsis at the enrolment time (7.7% and 33.3%), so sepsis subgroup analyses did
not allow clear conclusion on the efficacy of vitamin D supplementation in septic patients.
Also, in the future it is necessary to investigate the possible impact of selective
activators of vitamin D receptors (for example paricalcitol) among population of patient with
sepsis, as it is well known beneficial anti-inflammatory and anti-oxidative properties of
paricalcitol on renal and cardiovascular system.
Paricalcitol Several new vitamin D analogues have been developed for treatment of secondary
hyperparathyroidisms with a reduced risk of hypercalcemia and hyperphosphatemia. The third
generation of vitamin D analogues is composed of a group of 1- and 25-hydroxylated vitamin D
compounds with either ring structure modifications (19-nor-1,25-dihydroxyvitamin D2 or
paricalcitol). Vitamin D analogues have different effects on nuclear vitamin D receptor than
calcitriol, through different response elements in various target genes. Such new vitamin D
analogues because of unique properties of nuclear vitamin D receptor are named selective
vitamin D receptor activation agents. The term selective means that this molecule acts mostly
to parathyroid gland than to intestine and bone, resulting in lower serum calcium and
phosphorus blood concentrations. Such selective vitamin D receptor activation agents are
reported to have beneficial effects such as anti-inflammatory and antithrombotic effects,
inhibition of vascular smooth muscle cell proliferation, inhibition of renin-angiotensin
system, inhibition of vascular calcification and stiffening, and regression of left
ventricular hypertrophy. Antioxidative properties of paricalcitol are demonstrated in animal
model of contrast induced nephropathy as lower levels of serum malondialdehyde and kidney
thiobarbituric acid-reacting substances in the paricalcitol group. Paricalcitol was found to
decrease angiotensinogen, renin, renin receptor, and vascular endothelial growth factor mRNA
levels in rat model of chronic renal failure. In VITAL study, a randomised clinical trial,
paricalcitol demonstrated additional lowering effect on albuminuria in patients with diabetic
nephropathy. Antifibrotic effects of paricalcitol is demonstrated in animal model that
paricalcitol reduces myocardial fibrosis and preserves diastolic left ventricular function
due to pressure overload which was associated with a reduced fibrosis. Paricalcitol may
prevent the cisplatin-induced kidney injury by suppressing the fibrotic, apoptotic and
proliferative factors in animal model; paricalcitol suppressed the expression of TGF-β1, Smad
signaling, mitogen-activated protein kinase signaling, p53-induced apoptosis, and p27(kip1).
The aim Effect of selective activation of vitamin D on clinical outcomes in sepsis is
completely unknown and there are lack of human studies that would clarify the role of
selective activation of receptors for vitamin D in sepsis. Although there is some piece of
evidence, which is sometimes controversial, of a beneficial effect of vitamin D on the
outcomes of patients with sepsis, a study examined the impact of paricalcitol on septic
patients is missing. Therefore, we think that the research of paricalcitol in sepsis is
important. Except clinical outcomes, we will included in study markers of inflammation,
endothelial function, arterial stiffness and oxidation in aim to provide additional insight
into pathophysiological concept of sepsis. It is very important to investigate the possible
influence of paricalcitol on some of these markers, and the interrelationship between the
markers and the possible favourable clinical impact of paricalcitol on clinical outcomes.
Additionally, the second important aim of the study is provide evidence of the association of
oxidative, endothelial, inflammatory and other markers with clinical outcomes and with the
concentration of vitamin D in the plasma of septic patients.
Participants The participants of this study will be patients admitted as sepsis in a medical
ICU. The including criteria for sepsis will be defined according The Third International
Consensus Definitions for Sepsis and Septic Shock. The sepsis will be defined as suspected
infection with SOFA score>=2. The subgroup of participants with septic shock will be defined
as sepsis with vasopressor requirement to maintain a mean arterial pressure of 65 mm Hg or
greater and serum lactate level greater than 2 mmol/L despite adequate fluid resuscitation.
Exclusion criteria will be initial total serum calcium ≥2.60 mmol/L, significant chronic end
stage heart, kidney or liver disease, active treatment with corticosteroids or cytotoxic
drugs, autoimmune diseases, malignancies, and cachexia. Subjects should have not previously
been on active vitamin D therapy minimally within the last four months prior to the study
period.
All subjects will receive standard care for patients with sepsis according international
guidelines for sepsis treatment.
Sample size calculation with confidence level of 90% and margin of error of 10% estimated
minimal number of 69 subjects need for the study. We plan to enrolled approximately 40-50
participants in each group of subjects.
Study protocol
All subjects will be randomised (computer generated process) in 1:1 ratio to received placebo
or paricalcitol. Enrolment of the subjects will be demonstrated as CONSORT flow diagram.
Intervention phase will last 5 days during ICU staying, whereupon will start follow up phase
of trial.
Participants will be randomised to receive 5 μg intravenous paricalcitol (1 mL) per day in
five consecutive days, or to receive placebo (1 mL 0.9% NaCl). If serum calcium exceeded 2.65
mmol/L, the intervention will be stopped.
Ethic issues The participants will be informed about the purpose and nature of the study and
gave written consent. The study protocol will be accepted by the local University's Hospital
Ethics Committee.
Outcome measures
For all subjects will be recorded data on previous diseases, smoking habits, body mass index
(BMI) (kg/m2), SOFA score (on 0 and 7 day), SAPS score (on 0 and 7 day), need for RRT, need
for mechanical ventilation, classification as sepsis or as septic shock, survival at 7 and 28
days.
Outcome measurements will be performed at baseline, and for some of the outcomes at the seven
day of ICU or post-ICU staying. For survival outcome participants will be followed up at 7
and the 28 day.
Clinical outcomes: delta SOFA score (0 and 7 day), delta SAPS score (0 and 7 day), days need
for RRT, days need for mechanical ventilation, ICU days stay, survival at 7 and 28 days, days
need for catecholamines, admission time MAP, average MAP at day 5 with delta MAP (0 and 5
day), ECG abnormalities during the first 5 days.
Standard laboratory measurements, coagulation and inflammation markers: (at admission time
and at day 7): from venous blood specimen: leucocytes count, hemoglobin, plateless count,
activated partial thromboplastin time (aPTT), prothrombin time (PT), serum concentration of:
urea, creatinine, calcium, phosphorus, albumins, total cholesterol, high-density lipoprotein
(HDL)-cholesterol, C-reactive protein (CRP), serum 25(OH)D3, albumins, troponin-I,
NT-proB-type natriuretic peptide (NT-proBNP), ferritin, iPTH, fibrinogen, D-dimers,
procalcitonin (PCT), bicarbonate, lactate; and blood gasses analysis from arterial specimen.
Changes in variables between 0 and 7 days will be recorded.
Oxidative stress: at admission time from venous blood specimen (at admission time): lipid
peroxidation products TBARS (ThioBarbituric Acid Reactive Substances) and FOX (Ferrous
Oxidation - Xylenol orange assay), and malondialdehyde. Additionally, at admission time from
venous blood specimen will be assessed measurement of plasma protein carbonylation as protein
carbonyl groups are early markers of protein oxidative damage. The protein carbonyl
concentrations will be recorded for all subjects.
Non-invasive assessments of Arterial Stiffness: (at admission time): Applanation tonometry
will be used for arterial stiffness assessment. Tonometric transducer will be placed on the
carotid and femoral artery to obtain pulse wave velocity (PWV) and for pulse wave analysis
(PWA) assessment, a tonometric transducer will be placed on the radial artery. PWA will be
consisted from peripheral and central augmentation index (pAIx, cAIx), central pulse pressure
(cPP), central systolic and diastolic blood pressure (cSBP, cDBP), central mean blood
pressure (cMBP), peripheral pulse pressure (pPP), peripheral systolic and diastolic blood
pressure (pSBP, pDBP) and peripheral mean blood pressure (pMBP).
Ultrasonographic studies:
1. Assessment of endothelial function: (at admission time and at day 7): Endothelial
function will be determined by recording the dilator response of the brachial artery to
increased blood flow generated during reactive hyperaemia of the downstream forearm.
Baseline recordings of arterial diameter will be made for one minute before inflation of
a blood pressure cuff placed just distal to the elbow. End-diastolic images of the
artery were acquired. Reactive hyperaemia will be induced by a pneumatic cuff placed on
the forearm distal to the scanned brachial artery, to a pressure of 250 mmHg for 5 min.
Analysis of the diameter of brachial artery will be performed at the end of diastole to
the rest, 1 min., 2 min., 3. min. and 4 min. after cuff deflation using electronic
callipers on the computed system in M-mode of frozen images scanning. Recorded values
will be baseline diameter of brachial artery (mm), and differences between baseline
deflation diameter, recorded as maximal difference between baseline and diameters after
deflation (given as absolute values and as percent of baseline values). Changes in
variables between 0 and 7 days will be recorded.
2. Intrarenal arteries spectral analysis: assesment of vascular resistance (at admission
time and at day 7): 2D and Doppler ultrasound examination of the both kidneys with
estimation of resistance index and pulsatility index (RI and PI) of the intrarenal
arterial branches will be measured and recorded as RI and PI mean (left and right
kidney). Changes in variables between 0 and 7 days will be recorded.
3. Ultrasound measurement of quadriceps muscle thickness: (at admission time and at day 7):
using high-frequency linear probe the muscle thickness of the quadriceps femoral muscle
will detected by ultrasound in a transverse scan, including the thickness of the rectus
femoris and vastus intermedius. The ultrasound probe will be placed perpendicular to the
long axis of the right femur (transverse) on its anterior surface, at the midpoint of
the length between the anterior superior iliac spine and the patella. The Quadriceps
muscle layer thickness (QMLT) will be provided by measuring the distance between the
cortex of the femur and the most superficial muscular fascia by applying maximal
compression on the ultrasound probe in order to prevent the reading errors due to
subcutaneous edema. Changes in the QMLT between 0 and 7 days will be recorded.
4. ultrasound of the spleen (B-mode) (on admission and on the 7th day): to assess the
degree of hardness of the spleen using point shear wave elastography (P-SWE) by repeated
measurements of the spleen tissue. The mean value of the degree of hardness (kPa) as
well as the degree of attenuation (ATT) (dB/cm/MHz) will be recorded. Finally, the
volume of the spleen will be determined. Changes between 0 and 7 days will be recorded.
