<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/NCT02195050</url>
  </required_header>
  <id_info>
    <org_study_id>APOB2012</org_study_id>
    <secondary_id>R03301</secondary_id>
    <nct_id>NCT02195050</nct_id>
  </id_info>
  <brief_title>Abnormal Lipids - Causes and Effects</brief_title>
  <official_title>Hypertriglyceridaemia: Therapeutic Targets, Genetic Causes, and Associated Neuropathy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Manchester University NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Manchester University NHS Foundation Trust</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      1. At target LDL-C levels, apoB100 concentrations will be higher than recommended levels in&#xD;
           the following populations:&#xD;
&#xD;
             1. Tertiary centre lipid clinic patients with raised TG treated with statins.&#xD;
&#xD;
             2. Patients with type 2 diabetes treated with statins.&#xD;
&#xD;
             3. Patients with Chronic Kidney disease (CKD) stages 4 and 5 treated with statins.&#xD;
&#xD;
        2. Despite achieving LDL-C and non-HDL-C targets, a significant number of statin-treated&#xD;
           patients have residual cardiovascular risk related to raised hsCRP. The relationship&#xD;
           between hsCRP and Lp-PLA2 (markers of inflammation) and LDL particle number measured by&#xD;
           apoB100 is stronger than that of measured and calculated LDL and non-HDL. In statin&#xD;
           treated patients there will be higher levels of hs-CRP and Lp-PLA2 in patients achieving&#xD;
           LDL targets but not apo B targets.&#xD;
&#xD;
        3. We hypothesise that non-diabetic patients with severe hypertriglyceridaemia (fasting&#xD;
           serum triglyceride &gt;5.5 mmol/l) have evidence of greater nerve damage compared with&#xD;
           matched controls.&#xD;
&#xD;
        4. LAL deficiency is underdiagnosed in patients with severe hypertriglyceridaemia, low&#xD;
           HDL-C, hyperlipidaemias, non alcoholic fatty liver disease and idiopathic high liver&#xD;
           enzymes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Fats are present in the body in the form of lipid particles containing cholesterol and&#xD;
      triglycerides. Lipid particles can deposit in blood vessels, forming atheromas, blocking&#xD;
      blood vessels and leading to heart attacks and strokes. These harmful particles are termed&#xD;
      'atherogenic' particles. Low density lipoprotein (LDL) is the major atherogenic particle.&#xD;
      Each atherogenic particle has a protein associated with it called apolipoprotein B (apoB).&#xD;
      Cholesterol, triglycerides, and apoB levels can be measured in the laboratory. In this study&#xD;
      we focus on patients with raised levels of triglycerides (hypertriglyceridaemia).&#xD;
&#xD;
      We will recruit patients with hypertriglyceridaemia to look at (1) therapeutic targets, (2)&#xD;
      genetic causes, and (3) associated neuropathy in these patients.&#xD;
&#xD;
        1. Therapeutic target arm:&#xD;
&#xD;
           LDL-cholesterol (LDL-C) is the primary target for lipid-lowering drugs. A drug (commonly&#xD;
           a statin) is effective when it lowers LDL-C. Patients with diabetes, chronic kidney&#xD;
           disease and hypertriglyceridaemia on statins may have normal levels of LDL-C; but&#xD;
           because the size of LDL particles in these patients is smaller, they may in fact have&#xD;
           raised levels of apoB and therefore remain at cardiovascular risk. Thus, measurement of&#xD;
           apoB may be a better target for treatment because it measures 'atherogenic' particle&#xD;
           numbers. Since atheromatous disease is an inflammatory disease, we will also investigate&#xD;
           if residual risk may be correlated with inflammatory markers, such as hsCRP and Lp-PLA2.&#xD;
&#xD;
        2. Hypertriglyceridaemia and nerve function arm:&#xD;
&#xD;
           We aim to demonstrate that severe hypertriglyceridaemia is associated with more&#xD;
           significant nerve damage.&#xD;
&#xD;
        3. Genetic screening arm:&#xD;
&#xD;
      Several genetic mutations have been identified to cause hypertriglyceridaemia. Deficiency of&#xD;
      the enzyme lysosomal acid lipase (LAL) results in Cholesterol Ester Storage Disease (CESD)&#xD;
      and hypercholesterolaemia, hypertriglyceridaemia, and abnormal lipid deposition in organs. We&#xD;
      wish to identify genetic mutations associated with severe hypertriglyceridemia and the&#xD;
      prevalence of LAL deficiency in patients attending our tertiary referral centre.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 23, 2014</start_date>
  <completion_date type="Anticipated">December 2030</completion_date>
  <primary_completion_date type="Anticipated">December 2030</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>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Measurement of ApoB in specified patient populations to gauge cardiovascular risk.</measure>
    <time_frame>1 day.</time_frame>
    <description>Residual risk due to the presence of sd-LDL and reflected in a discrepancy between apoB and cholesterol indices is correlated with hs-CRP.</description>
  </primary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">1396</enrollment>
  <condition>Hypertriglyceridaemia</condition>
  <arm_group>
    <arm_group_label>Therapeutic target arm</arm_group_label>
    <description>Statin treated patients with and without raised triglycerides who do not have diabetes or dysglycemia. Statin treated patients with type 2 diabetes.Statin treated patients with CKD stages 4 and 5 (eGFR ≤30mL/min).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nerve function arm</arm_group_label>
    <description>Patients with severe hypertriglyceridaemia (fasting TG &gt; 5.5mmol/l.) are recruited for nerve function assessment and corneal confocal microscopy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Genetic screening arm</arm_group_label>
    <description>For LAL deficiency screening, patients will be recruited over a 5 year period with a documented triglyceride level of more than 10 mmol/l at any time, low HDLC, raised ALT, combined hyperlipidaemia, or non-alcoholic fatty liver disease. Patients recruited from Manchester will be offered additional genetic testing for familial hypercholesterolaemia.</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Serum &amp; plasma samples will be stored for further studies.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients are recruited from secondary and tertiary care hospital clinics.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Therapeutic target arm&#xD;
&#xD;
               -  Statin treated patients with and without hypertriglyceridemia.&#xD;
&#xD;
               -  Statin treated patients with type 2 diabetes.&#xD;
&#xD;
               -  Statin treated patients with CKD stages 4 and 5.&#xD;
&#xD;
          -  Nerve function arm&#xD;
&#xD;
             •Patients known to have severe hypertriglyceridaemia (defined as triglyceride &gt;5.5&#xD;
             mmol/l) but not known to have diabetes and matched controls.&#xD;
&#xD;
          -  Genetic screening arm&#xD;
&#xD;
               -  Patients with a documented triglyceride level of more than 10 mmol/l at any time.&#xD;
&#xD;
               -  Criteria for screening for FH and LAL deficiency include non-obese patients (BMI&#xD;
                  &lt;30) with low HDL-C (&lt;1.0 mmol/l male and &lt;1.3 mmol female), high triglycerides&#xD;
                  &gt;1.7 mmol/l, high total cholesterol &gt;6.2 or LDL cholesterol &gt;4.7 mmol/l; patients&#xD;
                  with raised liver alanine aminotransferase (ALT) (1.5 x above ULN) but no&#xD;
                  metabolic or viral disease or alcohol excess and patients diagnosed with NAFLD&#xD;
                  with or without hyperlipidaemia.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant and/or breast-feeding women.&#xD;
&#xD;
          -  Significant liver impairment.&#xD;
&#xD;
          -  Patients known to have active malignant disease.&#xD;
&#xD;
          -  Patients treated with medications that could affect lipoprotein metabolism&#xD;
             significantly (like atypical antipsychotics, chemotherapy).&#xD;
&#xD;
          -  Untreated hypothyroid and hyperthyroidism (if treated and TFT normal could be&#xD;
             recruited).&#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>Handrean Soran, MD FRCP</last_name>
    <role>Principal Investigator</role>
    <affiliation>Manchester University NHS Foundation Trust</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>See Kwok, MD FRCGP</last_name>
    <phone>01612768863</phone>
    <email>sk7@doctors.org.uk</email>
  </overall_contact>
  <location>
    <facility>
      <name>Cardiovascular Trials Unit</name>
      <address>
        <city>Manchester</city>
        <zip>M13 9WL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>See Kwok, MD FRCGP</last_name>
      <phone>01612768863</phone>
      <email>sk7@doctors.org.uk</email>
    </contact>
    <investigator>
      <last_name>See Kwok, MD FRCGP</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>July 10, 2014</study_first_submitted>
  <study_first_submitted_qc>July 17, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 21, 2014</study_first_posted>
  <last_update_submitted>May 30, 2023</last_update_submitted>
  <last_update_submitted_qc>May 30, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 31, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertriglyceridemia</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/NCT02195050
org study id: APOB2012
secondary id: R03301
nct id: NCT02195050
lead sponsor: 
has dmc: No
1. At target LDL-C levels, apoB100 concentrations will be higher than recommended levels in
           the following populations:

             1. Tertiary centre lipid clinic patients with raised TG treated with statins.

             2. Patients with type 2 diabetes treated with statins.

             3. Patients with Chronic Kidney disease (CKD) stages 4 and 5 treated with statins.

        2. Despite achieving LDL-C and non-HDL-C targets, a significant number of statin-treated
           patients have residual cardiovascular risk related to raised hsCRP. The relationship
           between hsCRP and Lp-PLA2 (markers of inflammation) and LDL particle number measured by
           apoB100 is stronger than that of measured and calculated LDL and non-HDL. In statin
           treated patients there will be higher levels of hs-CRP and Lp-PLA2 in patients achieving
           LDL targets but not apo B targets.

        3. We hypothesise that non-diabetic patients with severe hypertriglyceridaemia (fasting
           serum triglyceride >5.5 mmol/l) have evidence of greater nerve damage compared with
           matched controls.

        4. LAL deficiency is underdiagnosed in patients with severe hypertriglyceridaemia, low
           HDL-C, hyperlipidaemias, non alcoholic fatty liver disease and idiopathic high liver
           enzymes.
Fats are present in the body in the form of lipid particles containing cholesterol and
      triglycerides. Lipid particles can deposit in blood vessels, forming atheromas, blocking
      blood vessels and leading to heart attacks and strokes. These harmful particles are termed
      'atherogenic' particles. Low density lipoprotein (LDL) is the major atherogenic particle.
      Each atherogenic particle has a protein associated with it called apolipoprotein B (apoB).
      Cholesterol, triglycerides, and apoB levels can be measured in the laboratory. In this study
      we focus on patients with raised levels of triglycerides (hypertriglyceridaemia).

      We will recruit patients with hypertriglyceridaemia to look at (1) therapeutic targets, (2)
      genetic causes, and (3) associated neuropathy in these patients.

        1. Therapeutic target arm:

           LDL-cholesterol (LDL-C) is the primary target for lipid-lowering drugs. A drug (commonly
           a statin) is effective when it lowers LDL-C. Patients with diabetes, chronic kidney
           disease and hypertriglyceridaemia on statins may have normal levels of LDL-C; but
           because the size of LDL particles in these patients is smaller, they may in fact have
           raised levels of apoB and therefore remain at cardiovascular risk. Thus, measurement of
           apoB may be a better target for treatment because it measures 'atherogenic' particle
           numbers. Since atheromatous disease is an inflammatory disease, we will also investigate
           if residual risk may be correlated with inflammatory markers, such as hsCRP and Lp-PLA2.

        2. Hypertriglyceridaemia and nerve function arm:

           We aim to demonstrate that severe hypertriglyceridaemia is associated with more
           significant nerve damage.

        3. Genetic screening arm:

      Several genetic mutations have been identified to cause hypertriglyceridaemia. Deficiency of
      the enzyme lysosomal acid lipase (LAL) results in Cholesterol Ester Storage Disease (CESD)
      and hypercholesterolaemia, hypertriglyceridaemia, and abnormal lipid deposition in organs. We
      wish to identify genetic mutations associated with severe hypertriglyceridemia and the
      prevalence of LAL deficiency in patients attending our tertiary referral centre.
observational model: Cohort
time perspective: Cross-Sectional
measure: Measurement of ApoB in specified patient populations to gauge cardiovascular risk.
time frame: 1 day.
description: Residual risk due to the presence of sd-LDL and reflected in a discrepancy between apoB and cholesterol indices is correlated with hs-CRP.
arm group label: Therapeutic target arm
description: Statin treated patients with and without raised triglycerides who do not have diabetes or dysglycemia. Statin treated patients with type 2 diabetes.Statin treated patients with CKD stages 4 and 5 (eGFR ≤30mL/min).
arm group label: Nerve function arm
description: Patients with severe hypertriglyceridaemia (fasting TG > 5.5mmol/l.) are recruited for nerve function assessment and corneal confocal microscopy.
arm group label: Genetic screening arm
description: For LAL deficiency screening, patients will be recruited over a 5 year period with a documented triglyceride level of more than 10 mmol/l at any time, low HDLC, raised ALT, combined hyperlipidaemia, or non-alcoholic fatty liver disease. Patients recruited from Manchester will be offered additional genetic testing for familial hypercholesterolaemia.
Serum & plasma samples will be stored for further studies.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Handrean Soran, MD FRCP
role: Principal Investigator
affiliation: Manchester University NHS Foundation Trust
last name: See Kwok, MD FRCGP
phone: 01612768863
email: sk7@doctors.org.uk
facility: 
status: Recruiting
contact: 
investigator: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Hypertriglyceridemia