<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03234218</url>
  </required_header>
  <id_info>
    <org_study_id>IRRB/12/16</org_study_id>
    <nct_id>NCT03234218</nct_id>
  </id_info>
  <brief_title>Vitamin D Levels in Liver Transplantation Recipients Prospective Observational Study</brief_title>
  <acronym>D-LIVER-X</acronym>
  <official_title>Vitamin D Levels in Liver Transplantation Recipients Prospective Observational Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Mediterranean Institute for Transplantation and Advanced Specialized Therapies</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The Mediterranean Institute for Transplantation and Advanced Specialized Therapies</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Interest in vitamin D has seen an unprecedented revival sparked by the finding that vitamin D&#xD;
      has pleiotropic effects with an intriguing link to the critically ill patients. The recent&#xD;
      VITdAL-ICU RCT found a significant difference in mortality in patients with severe deficiency&#xD;
      when high doses of vitamin D supplementation were administered.&#xD;
&#xD;
      Vitamin D deficiency is extremely common in patients with chronic liver disease and/or&#xD;
      cirrhosis. It seems to be a marker of severity of the disease, but also a possible&#xD;
      contributing factor in determining poor outcomes.&#xD;
&#xD;
      Design of the study: Observational prospective study. Primary variable end point: Vitamin D&#xD;
      at baseline, and POD (post-operative day) 1, 3, 7, 28.&#xD;
&#xD;
      Secondary variable end points: ICU length of stay; SAPS 2 and SOFA score at POD 1, 7; Days of&#xD;
      mechanical ventilation; Hospital length of stay; Mortality at POD 28; Diagnosed invasive&#xD;
      infections; Graft rejection in the first 28 days; Bilirubin and INR at POD 7 and 28.&#xD;
&#xD;
      SAFETY. The patient will not undergo to additional procedure during the study and will be&#xD;
      asked for consent to treatment of personal data.&#xD;
&#xD;
      SAMPLE SIZE. Because of the lack of knowledge in this specific cohort no formal sample was&#xD;
      calculated beforehand. The sample size will be defined by one-year clinical activity: about&#xD;
      60 consecutive patients.&#xD;
&#xD;
      STATISTICAL ANALYSIS. All statistical analysis and results will be assessed and reported as&#xD;
      exploratory analysis. In order to describe the trend over time of the vitamin D levels,&#xD;
      descriptive statistics such as mean, median, interquartile range and standard deviation will&#xD;
      be evaluated. In addition, 95% confidence intervals for mean and standard deviation will be&#xD;
      reported. Comparisons between two temporal observations will be assessed with paired t-test.&#xD;
      Any univariate association between factors or covariates, will be explored. Statistical&#xD;
      analyses will be done with SAS 9.4,&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BACKGROUND Interest in vitamin D has seen an unprecedented revival sparked by the finding&#xD;
      that vitamin D has pleiotropic effects. The nuclear vitamin D receptor (VDR) is widely&#xD;
      present in different cell types and organs and regulates more than 200 genes.&#xD;
&#xD;
      The link between vitamin D and critical illness is new, but intriguing, because vitamin D&#xD;
      deficiency&#xD;
&#xD;
        -  has a very high prevalence in the ICU&#xD;
&#xD;
        -  is strongly associated with excess morbidity and mortality&#xD;
&#xD;
        -  is associated with increased susceptibility to sepsis thought its immunomodulating&#xD;
           effects&#xD;
&#xD;
        -  has a relation with acute kidney injury, acute respiratory failure, duration of&#xD;
           mechanical ventilation and ARDS Critically ill patients are at high risk of mortality&#xD;
           and standard care uses little or no vitamin D.&#xD;
&#xD;
      It may well be the case that vitamin D deficiency is indeed an &quot;invisible accomplice to&#xD;
      morbidity and mortality,&quot; as proposed by Paul Lee.&#xD;
&#xD;
      VITAMIN D IN PATIENTS WITH CHRONIC LIVER DISEASE AND/OR CIRRHOSIS Vitamin D deficiency is&#xD;
      extremely common in patients with chronic liver disease and/or cirrhosis. It seems to be a&#xD;
      marker of severity of the disease, but also a possible contributing factor in determining&#xD;
      poor outcomes.&#xD;
&#xD;
      Mechanisms Low synthesis. Severe liver disease decreases vitamin D hydroxylation and albumin&#xD;
      and DBP production. But lack of liver function is just one piece of the puzzle. Possible&#xD;
      concomitant causes may include inadequate sun exposure, insufficient food intake, steroids,&#xD;
      jaundice-related deterioration of vitamin synthesis on the skin, and decreased vitamin D&#xD;
      absorption caused by intestinal edema secondary to portal hypertension or cholestasis-induced&#xD;
      bile salt disruption.&#xD;
&#xD;
      Signaling disruption. Vitamin D plays a role in reducing risk of chronic diseases. This most&#xD;
      likely results from local production of 1a25(OH)2D, with its autocrine and paracrine actions&#xD;
      in cellular proliferation and differentiation. These effects may also be relevant in liver&#xD;
      diseases.&#xD;
&#xD;
      Pro-inflammatory signals in monocytes and macrophages may regulate the local metabolism of&#xD;
      vitamin D, and the local production of α25(OH)2D. Almost 90% of tissue macrophages are in the&#xD;
      liver, suggesting that local production of vitamin D in liver inflammation is impaired.&#xD;
&#xD;
      Innate immunity. Vitamin D increases secretion of antibacterial proteins such as cathelicidin&#xD;
      and beta-defensin, promotes chemotaxis and macrophage phagocytosis, and regulate the&#xD;
      expression of several TLRs.&#xD;
&#xD;
      Adaptive immunity. Vitamin D seems to control excessive immune response by decreasing the&#xD;
      expression of class II HLA complex, and by modulating T cells, inducing differentiation and&#xD;
      expansion of regulatory T cells, which secrete IL-10 and TGF-β. This could explain an&#xD;
      association between vitamin D deficiency and autoimmune liver damage. Moreover in vitro and&#xD;
      in vivo studies of mouse models with liver fibrosis reported an anti-fibrotic effect for&#xD;
      vitamin D.&#xD;
&#xD;
      Hepatitis C. Data have shown that vitamin D supplementation during interferon and ribavirin&#xD;
      increased the level of sustained viral response. Furthermore, vitamin D seems to indirectly&#xD;
      inhibit HCV replication in human hepatocytes by stimulating IFB beta production.&#xD;
&#xD;
      NAFLD. Non-alcoholic fatty liver disease is a clinical entity ranging from steatosis to&#xD;
      non-alcoholic steatohepatitis and cirrhosis. Vitamin D deficiency has a possible role in it.&#xD;
&#xD;
      The impact of liver transplantation on vitamin D status: lack of knowledge Individual outcome&#xD;
      after liver transplantation varies widely due to multi-factorial variables. Vitamin D has not&#xD;
      been extensively evaluated in patients undergoing liver transplantation. In one cohort of&#xD;
      patients, vitamin D deficiency was associated with acute cellular rejection. It is still&#xD;
      unclear how it acts in the more critical days after transplantation, and what predictive role&#xD;
      it may play.&#xD;
&#xD;
      The relevant role of calcium metabolism and vitamin D after solid organ transplantation has&#xD;
      been highlighted by several meta-analyses in recent years, suggesting a possible impact on&#xD;
      prognosis.&#xD;
&#xD;
      To stress the relevance of the topic even in such a complex surgical procedure, low vitamin D&#xD;
      is associated with a worse outcome after various types of surgery.&#xD;
&#xD;
      Myriad considerations suggest its evaluation in liver transplantation recipients:&#xD;
&#xD;
        -  Vitamin D deficiency is a global health problem.&#xD;
&#xD;
        -  Patients affected with liver disease have much lower levels of vitamin D&#xD;
&#xD;
        -  Causes of low levels of vitamin D may be low production, low sun exposure, reduced&#xD;
           mobility, and other factors reducing the availability of vitamin D in the system.&#xD;
&#xD;
        -  Vitamin D has pleiotropic effects, and seems to act mainly on the immunomodulating&#xD;
           system. Infection is the main threat in the first 6 months after transplantation.&#xD;
&#xD;
        -  The number of patients receiving marginal donor organs is increasing. In many of them&#xD;
           the recovery of liver function proceeds slowly.&#xD;
&#xD;
        -  Some liver recipients become severely ill during the ICU stay. In these patients there&#xD;
           is a suspicion of severe vitamin D insufficiency.&#xD;
&#xD;
        -  Incidence of acute kidney injury is very high in complicated liver transplantation.&#xD;
&#xD;
        -  The VITdAL-ICU RCT found a reduced mortality in severe deficiency after high doses of&#xD;
           vitamin D.&#xD;
&#xD;
        -  Vitamin D may reveal itself as a marker of improving metabolic function, acting as a&#xD;
           prognostic marker that may even contribute to outcome, and is easily modifiable.&#xD;
&#xD;
      Aims of the study Principal&#xD;
&#xD;
      - Describe the level and the trend of vitamin D levels in liver transplantation recipients&#xD;
      during the first 28 days after transplantation.&#xD;
&#xD;
      Secondary&#xD;
&#xD;
        -  Explore the association between vitamin D level post-transplant and critical conditions&#xD;
           (ICU stay, severity score, infections, mortality).&#xD;
&#xD;
        -  Explore the association between vitamin D level post-transplant and pre-transplant&#xD;
           conditions (vitamin D level and severity of liver disease).&#xD;
&#xD;
        -  Explore the association between pre-transplant vitamin D level and outcome (mortality at&#xD;
           28 days).&#xD;
&#xD;
        -  Explore the association between the quality of graft (marginal vs. standard) on&#xD;
           post-transplant vitamin D level.&#xD;
&#xD;
        -  Explore the association between vitamin D level and graft function.&#xD;
&#xD;
        -  Explore the association between post-transplant vitamin D level and long term patient&#xD;
           and graft outcomes.&#xD;
&#xD;
      Primary variable end point:&#xD;
&#xD;
      Vitamin D level measured at baseline, and POD (post-operative day) 1, 3, 7, 28. Secondary&#xD;
      variable end points ICU length of stay SAPS 2 and SOFA score at POD 1, 7 Days of mechanical&#xD;
      ventilation Hospital length of stay Mortality at POD 28 Diagnosed invasive infections Graft&#xD;
      rejection in the first 28 days Bilirubin and INR at POD 7 and 28&#xD;
&#xD;
      Data collection and timing of the observations:&#xD;
&#xD;
      Vitamin D level and metabolism:&#xD;
&#xD;
        -  Vitamin D at time of listing (wait list for liver transplantation); at time of hospital&#xD;
           admission for liver transplantation; POD 1, 3, 7, 28&#xD;
&#xD;
        -  Albumin POD 1, 3, 7, 28&#xD;
&#xD;
        -  Parathormone (PTH) at time of hospital admission for transplantation, and on 1, 7, 28&#xD;
           SAFETY. Vitamin D levels will be measured in blood samples drawn during standard&#xD;
           clinical practice. Clinical activity will follow well established protocols for liver&#xD;
           transplants at our institute. Given the observational nature of the study, insurance for&#xD;
           possible patient damage is waived.&#xD;
&#xD;
      The patient will be asked for consent to treatment of personal data. The person responsible&#xD;
      for this privacy consent will be the principal investigator.&#xD;
&#xD;
      STATISTICAL ANALYSIS. Because this is an exploratory study, all statistical analysis and&#xD;
      results will be assessed and reported as exploratory analysis. In order to describe the trend&#xD;
      over time of the vitamin D levels in patients undergoing liver transplantation, descriptive&#xD;
      statistics such as mean, median, interquartile range and standard deviation will be&#xD;
      evaluated. In addition, 95% confidence intervals for mean and standard deviation will be&#xD;
      reported. Comparisons between two temporal observations will be assessed with paired t-test.&#xD;
&#xD;
      In addition, mixed model repeated measures (MMRM) will be applied in order to assess the&#xD;
      vitamin D trend level over PODs 1-7-28.&#xD;
&#xD;
      In order to assess the secondary aims, the same methods given above will be applied. In&#xD;
      particular, for the secondary aim, for the association between quality of graft (marginal vs.&#xD;
      standard) on post-transplant vitamin D level, a logistic analysis for repeated measures will&#xD;
      be applied.&#xD;
&#xD;
      Any univariate association between factors or covariates, described in the data collection&#xD;
      section, will be explored. In addition, multiple MMRM analyses will applied in order to&#xD;
      explore association between vitamin D level and the most relevant variables.&#xD;
&#xD;
      All statistical analyses will be done with SAS 9.4, all results will be considered&#xD;
      exploratory for statistical testing, and p-values will be reported as &quot;nominally&#xD;
      statistically significant.&quot; ANALYTICAL METHODS. Vitamin D will be measured with the Bio-Rad&#xD;
      25-OH Vitamin D3/D2 HPLC assay (High Performance Liquid Chromatography). Parathormone will be&#xD;
      measured with a chemiluminescence technique using the IMMULITE® 2000 Intact PTH.&#xD;
&#xD;
      ANTICIPATED BENEFITS AND IMPACT OF FINDINGS. Vitamin D deficiency is a global health problem.&#xD;
      This study would be an actual description of vitamin D status in a cohort of recipients of&#xD;
      liver transplantation, indicating a possible group of patients in which routine measurement&#xD;
      of serum vitamin D may be mandatory.&#xD;
&#xD;
      A high prevalence of severe deficiency may suggest starting later high dosage supplementation&#xD;
      if new evidence confirms its positive effect in critically ill patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 2016</start_date>
  <completion_date type="Actual">September 2017</completion_date>
  <primary_completion_date type="Actual">September 2017</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Describe and explore the level and the trend of vitamin D levels in liver transplantation recipients during the first 28 days after transplantation.</measure>
    <time_frame>Preoperative and on the post-operative day 28</time_frame>
    <description>Change of the Vitamin D level during the first 28 days after liver transplantation</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Explore the association between vitamin D level and critical condition;</measure>
    <time_frame>Post-operative day 28</time_frame>
    <description>ICU length of stay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Explore the association between pre-transplant vitamin D level and outcome</measure>
    <time_frame>Post-operative day 28</time_frame>
    <description>Mortality at Post-Operative Day 28</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Explore the association between vitamin D level and graft function</measure>
    <time_frame>Post-operative day 28</time_frame>
    <description>Graft rejection in the first 28 days</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Explore the association between vitamin d level and incidence of early post-operative infections</measure>
    <time_frame>Post.operative day 28</time_frame>
    <description>Diagnosed invasive infections</description>
  </secondary_outcome>
  <enrollment type="Actual">68</enrollment>
  <condition>Liver Transplant Disorder</condition>
  <condition>Vitamin D Deficiency</condition>
  <eligibility>
    <study_pop>
      <textblock>
        The study presented in this protocol is the first to focus on vitamin D status in patients&#xD;
        undergoing liver transplantation. The primary objective is to study, explore, and describe&#xD;
        the level and the trends of vitamin D values over time in liver transplantation recipients&#xD;
        in the first days after transplantation, i.e., POD 1, POD 7, and POD 28.&#xD;
&#xD;
        Because of the lack of knowledge on the association between vitamin D levels and outcomes&#xD;
        in this specific cohort no formal sample was calculated beforehand.&#xD;
&#xD;
        The sample size will be defined by one-year clinical activity: about 60 consecutive&#xD;
        patients undergoing liver transplantation will be enrolled during this period.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  All recipients of liver transplantation at Ismett, aged 18 or more&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Lack of informed consent for the treatment of personal data. otherwise all the&#xD;
             patients will be included if the accept to sign the informed consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Gennaro Martucci, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>The Mediterranean Institute for Transplantation and Advanced Specialized Therapies</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Ismett</name>
      <address>
        <city>Palermo</city>
        <zip>90133</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>July 14, 2017</study_first_submitted>
  <study_first_submitted_qc>July 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2017</study_first_posted>
  <last_update_submitted>May 22, 2018</last_update_submitted>
  <last_update_submitted_qc>May 22, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">May 23, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>vitamin D, liver transplantation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin D Deficiency</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03234218
org study id: IRRB/12/16
nct id: NCT03234218
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Interest in vitamin D has seen an unprecedented revival sparked by the finding that vitamin D
      has pleiotropic effects with an intriguing link to the critically ill patients. The recent
      VITdAL-ICU RCT found a significant difference in mortality in patients with severe deficiency
      when high doses of vitamin D supplementation were administered.

      Vitamin D deficiency is extremely common in patients with chronic liver disease and/or
      cirrhosis. It seems to be a marker of severity of the disease, but also a possible
      contributing factor in determining poor outcomes.

      Design of the study: Observational prospective study. Primary variable end point: Vitamin D
      at baseline, and POD (post-operative day) 1, 3, 7, 28.

      Secondary variable end points: ICU length of stay; SAPS 2 and SOFA score at POD 1, 7; Days of
      mechanical ventilation; Hospital length of stay; Mortality at POD 28; Diagnosed invasive
      infections; Graft rejection in the first 28 days; Bilirubin and INR at POD 7 and 28.

      SAFETY. The patient will not undergo to additional procedure during the study and will be
      asked for consent to treatment of personal data.

      SAMPLE SIZE. Because of the lack of knowledge in this specific cohort no formal sample was
      calculated beforehand. The sample size will be defined by one-year clinical activity: about
      60 consecutive patients.

      STATISTICAL ANALYSIS. All statistical analysis and results will be assessed and reported as
      exploratory analysis. In order to describe the trend over time of the vitamin D levels,
      descriptive statistics such as mean, median, interquartile range and standard deviation will
      be evaluated. In addition, 95% confidence intervals for mean and standard deviation will be
      reported. Comparisons between two temporal observations will be assessed with paired t-test.
      Any univariate association between factors or covariates, will be explored. Statistical
      analyses will be done with SAS 9.4,
BACKGROUND Interest in vitamin D has seen an unprecedented revival sparked by the finding
      that vitamin D has pleiotropic effects. The nuclear vitamin D receptor (VDR) is widely
      present in different cell types and organs and regulates more than 200 genes.

      The link between vitamin D and critical illness is new, but intriguing, because vitamin D
      deficiency

        -  has a very high prevalence in the ICU

        -  is strongly associated with excess morbidity and mortality

        -  is associated with increased susceptibility to sepsis thought its immunomodulating
           effects

        -  has a relation with acute kidney injury, acute respiratory failure, duration of
           mechanical ventilation and ARDS Critically ill patients are at high risk of mortality
           and standard care uses little or no vitamin D.

      It may well be the case that vitamin D deficiency is indeed an "invisible accomplice to
      morbidity and mortality," as proposed by Paul Lee.

      VITAMIN D IN PATIENTS WITH CHRONIC LIVER DISEASE AND/OR CIRRHOSIS Vitamin D deficiency is
      extremely common in patients with chronic liver disease and/or cirrhosis. It seems to be a
      marker of severity of the disease, but also a possible contributing factor in determining
      poor outcomes.

      Mechanisms Low synthesis. Severe liver disease decreases vitamin D hydroxylation and albumin
      and DBP production. But lack of liver function is just one piece of the puzzle. Possible
      concomitant causes may include inadequate sun exposure, insufficient food intake, steroids,
      jaundice-related deterioration of vitamin synthesis on the skin, and decreased vitamin D
      absorption caused by intestinal edema secondary to portal hypertension or cholestasis-induced
      bile salt disruption.

      Signaling disruption. Vitamin D plays a role in reducing risk of chronic diseases. This most
      likely results from local production of 1a25(OH)2D, with its autocrine and paracrine actions
      in cellular proliferation and differentiation. These effects may also be relevant in liver
      diseases.

      Pro-inflammatory signals in monocytes and macrophages may regulate the local metabolism of
      vitamin D, and the local production of α25(OH)2D. Almost 90% of tissue macrophages are in the
      liver, suggesting that local production of vitamin D in liver inflammation is impaired.

      Innate immunity. Vitamin D increases secretion of antibacterial proteins such as cathelicidin
      and beta-defensin, promotes chemotaxis and macrophage phagocytosis, and regulate the
      expression of several TLRs.

      Adaptive immunity. Vitamin D seems to control excessive immune response by decreasing the
      expression of class II HLA complex, and by modulating T cells, inducing differentiation and
      expansion of regulatory T cells, which secrete IL-10 and TGF-β. This could explain an
      association between vitamin D deficiency and autoimmune liver damage. Moreover in vitro and
      in vivo studies of mouse models with liver fibrosis reported an anti-fibrotic effect for
      vitamin D.

      Hepatitis C. Data have shown that vitamin D supplementation during interferon and ribavirin
      increased the level of sustained viral response. Furthermore, vitamin D seems to indirectly
      inhibit HCV replication in human hepatocytes by stimulating IFB beta production.

      NAFLD. Non-alcoholic fatty liver disease is a clinical entity ranging from steatosis to
      non-alcoholic steatohepatitis and cirrhosis. Vitamin D deficiency has a possible role in it.

      The impact of liver transplantation on vitamin D status: lack of knowledge Individual outcome
      after liver transplantation varies widely due to multi-factorial variables. Vitamin D has not
      been extensively evaluated in patients undergoing liver transplantation. In one cohort of
      patients, vitamin D deficiency was associated with acute cellular rejection. It is still
      unclear how it acts in the more critical days after transplantation, and what predictive role
      it may play.

      The relevant role of calcium metabolism and vitamin D after solid organ transplantation has
      been highlighted by several meta-analyses in recent years, suggesting a possible impact on
      prognosis.

      To stress the relevance of the topic even in such a complex surgical procedure, low vitamin D
      is associated with a worse outcome after various types of surgery.

      Myriad considerations suggest its evaluation in liver transplantation recipients:

        -  Vitamin D deficiency is a global health problem.

        -  Patients affected with liver disease have much lower levels of vitamin D

        -  Causes of low levels of vitamin D may be low production, low sun exposure, reduced
           mobility, and other factors reducing the availability of vitamin D in the system.

        -  Vitamin D has pleiotropic effects, and seems to act mainly on the immunomodulating
           system. Infection is the main threat in the first 6 months after transplantation.

        -  The number of patients receiving marginal donor organs is increasing. In many of them
           the recovery of liver function proceeds slowly.

        -  Some liver recipients become severely ill during the ICU stay. In these patients there
           is a suspicion of severe vitamin D insufficiency.

        -  Incidence of acute kidney injury is very high in complicated liver transplantation.

        -  The VITdAL-ICU RCT found a reduced mortality in severe deficiency after high doses of
           vitamin D.

        -  Vitamin D may reveal itself as a marker of improving metabolic function, acting as a
           prognostic marker that may even contribute to outcome, and is easily modifiable.

      Aims of the study Principal

      - Describe the level and the trend of vitamin D levels in liver transplantation recipients
      during the first 28 days after transplantation.

      Secondary

        -  Explore the association between vitamin D level post-transplant and critical conditions
           (ICU stay, severity score, infections, mortality).

        -  Explore the association between vitamin D level post-transplant and pre-transplant
           conditions (vitamin D level and severity of liver disease).

        -  Explore the association between pre-transplant vitamin D level and outcome (mortality at
           28 days).

        -  Explore the association between the quality of graft (marginal vs. standard) on
           post-transplant vitamin D level.

        -  Explore the association between vitamin D level and graft function.

        -  Explore the association between post-transplant vitamin D level and long term patient
           and graft outcomes.

      Primary variable end point:

      Vitamin D level measured at baseline, and POD (post-operative day) 1, 3, 7, 28. Secondary
      variable end points ICU length of stay SAPS 2 and SOFA score at POD 1, 7 Days of mechanical
      ventilation Hospital length of stay Mortality at POD 28 Diagnosed invasive infections Graft
      rejection in the first 28 days Bilirubin and INR at POD 7 and 28

      Data collection and timing of the observations:

      Vitamin D level and metabolism:

        -  Vitamin D at time of listing (wait list for liver transplantation); at time of hospital
           admission for liver transplantation; POD 1, 3, 7, 28

        -  Albumin POD 1, 3, 7, 28

        -  Parathormone (PTH) at time of hospital admission for transplantation, and on 1, 7, 28
           SAFETY. Vitamin D levels will be measured in blood samples drawn during standard
           clinical practice. Clinical activity will follow well established protocols for liver
           transplants at our institute. Given the observational nature of the study, insurance for
           possible patient damage is waived.

      The patient will be asked for consent to treatment of personal data. The person responsible
      for this privacy consent will be the principal investigator.

      STATISTICAL ANALYSIS. Because this is an exploratory study, all statistical analysis and
      results will be assessed and reported as exploratory analysis. In order to describe the trend
      over time of the vitamin D levels in patients undergoing liver transplantation, descriptive
      statistics such as mean, median, interquartile range and standard deviation will be
      evaluated. In addition, 95% confidence intervals for mean and standard deviation will be
      reported. Comparisons between two temporal observations will be assessed with paired t-test.

      In addition, mixed model repeated measures (MMRM) will be applied in order to assess the
      vitamin D trend level over PODs 1-7-28.

      In order to assess the secondary aims, the same methods given above will be applied. In
      particular, for the secondary aim, for the association between quality of graft (marginal vs.
      standard) on post-transplant vitamin D level, a logistic analysis for repeated measures will
      be applied.

      Any univariate association between factors or covariates, described in the data collection
      section, will be explored. In addition, multiple MMRM analyses will applied in order to
      explore association between vitamin D level and the most relevant variables.

      All statistical analyses will be done with SAS 9.4, all results will be considered
      exploratory for statistical testing, and p-values will be reported as "nominally
      statistically significant." ANALYTICAL METHODS. Vitamin D will be measured with the Bio-Rad
      25-OH Vitamin D3/D2 HPLC assay (High Performance Liquid Chromatography). Parathormone will be
      measured with a chemiluminescence technique using the IMMULITE® 2000 Intact PTH.

      ANTICIPATED BENEFITS AND IMPACT OF FINDINGS. Vitamin D deficiency is a global health problem.
      This study would be an actual description of vitamin D status in a cohort of recipients of
      liver transplantation, indicating a possible group of patients in which routine measurement
      of serum vitamin D may be mandatory.

      A high prevalence of severe deficiency may suggest starting later high dosage supplementation
      if new evidence confirms its positive effect in critically ill patients.
observational model: Cohort
time perspective: Prospective
measure: Describe and explore the level and the trend of vitamin D levels in liver transplantation recipients during the first 28 days after transplantation.
time frame: Preoperative and on the post-operative day 28
description: Change of the Vitamin D level during the first 28 days after liver transplantation
measure: Explore the association between vitamin D level and critical condition;
time frame: Post-operative day 28
description: ICU length of stay
measure: Explore the association between pre-transplant vitamin D level and outcome
time frame: Post-operative day 28
description: Mortality at Post-Operative Day 28
measure: Explore the association between vitamin D level and graft function
time frame: Post-operative day 28
description: Graft rejection in the first 28 days
measure: Explore the association between vitamin d level and incidence of early post-operative infections
time frame: Post.operative day 28
description: Diagnosed invasive infections
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Gennaro Martucci, MD
role: Principal Investigator
affiliation: The Mediterranean Institute for Transplantation and Advanced Specialized Therapies
facility: 
country: Italy
responsible party type: Sponsor
mesh term: Vitamin D Deficiency