<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/NCT03811223</url>
  </required_header>
  <id_info>
    <org_study_id>UMCU-VASC-CO-002</org_study_id>
    <nct_id>NCT03811223</nct_id>
  </id_info>
  <brief_title>Effects of Evolocumab Versus Placebo Added to Standard Lipid-lowering Therapy on Fasting and Post Fat Load Lipids in Patients With Familial Dysbetalipoproteinemia</brief_title>
  <acronym>EVOLVE-FD</acronym>
  <official_title>A Multicenter, Randomized, Double-blind, Placebo-controlled, Crossover Trial to Evaluate the Effects of Evolocumab Added to Standard Lipid-lowering Therapy on Fasting and Post Fat Load Lipids in Patients With Familial Dysbetalipoproteinemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>UMC Utrecht</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Erasmus Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Medical Center Nijmegen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>UMC Utrecht</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Patients with familial dysbetalipoproteinemia (FD) have increased triglycerides,&#xD;
      non-high-density lipoprotein cholesterol (non-HDL-C), beta VLDL, premature atherosclerosis&#xD;
      and cardiovascular disease. They also have a delayed postprandial triglyceride and&#xD;
      chylomicron (CM) remnant clearance. Postprandial hypertriglyceridemia is associated with&#xD;
      increased vascular risk. Although combination therapy with statin and fibrate is recommended&#xD;
      in the treatment of patients with FD, there is still a substantial amount of patient who do&#xD;
      not reach their treatment target with this medication. Furthermore no information is&#xD;
      available about the postprandial effects of adding evocolumab to standard lipid lowering&#xD;
      therapy in FD patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      See brief summary&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">August 2019</start_date>
  <completion_date type="Anticipated">March 2021</completion_date>
  <primary_completion_date type="Anticipated">January 2021</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>AUC (area under the curve) non-HDL-cholesterol</measure>
    <time_frame>12 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Fasting levels, AUC and iAUC of total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and ApoB, as well as fasting non-HDL-cholesterol.</measure>
    <time_frame>12 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage change from baseline and absolute difference in fasting and post fat load non-HDL-cholesterol, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and ApoB.</measure>
    <time_frame>12 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fasting and post fat load lipoprotein (VLDL1, VLDL2, IDL, LDL, HDL) concentrations and composition (triglycerides, cholesterol, ApoB and apolipoproteins).</measure>
    <time_frame>12 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Post fat load ApoB 48-containing lipoprotein concentrations (chylomicrons and chylomicron remnants) and proteins involved in postprandial lipid metabolism.</measure>
    <time_frame>12 weeks</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Familial Dysbetalipoproteinemia</condition>
  <condition>Hyperlipoproteinemia Type III</condition>
  <arm_group>
    <arm_group_label>Evolocumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo injection once every 2 weeks for 12 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Evolocumab Auto-Injector [Repatha]</intervention_name>
    <description>Evolocumab 140 mg every 2 weeks for 12 weeks</description>
    <arm_group_label>Evolocumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebos</intervention_name>
    <description>Placebo subcutaneous injection every 2 weeks for 12 weeks</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          1. Patients diagnosed with Familial Dysbetalipoproteinemia;&#xD;
&#xD;
               -  ε2ε2 genotype or dominant APOE mutation genotype (confirmed by genotyping or&#xD;
                  isoelectric focusing) with any lipid-lowering treatment at a stable dose for at&#xD;
                  least three months and non-HDL-C &gt;1.6 mmol/L or;&#xD;
&#xD;
               -  Patients with ε2ε2 genotype or dominant APOE mutation (confirmed by genotyping or&#xD;
                  isoelectric focusing) without lipid-lowering treatment and with an ApoB/TC ratio&#xD;
                  &lt; 0.15.&#xD;
&#xD;
          2. &gt;18 years old (on the day of signing informed consent).&#xD;
&#xD;
          3. Women are postmenopausal and not receiving hormone therapy (including cyclic and&#xD;
             non-cyclical hormone replacement therapy or any estrogen antagonist/agonist).&#xD;
             Postmenopausal status is defined as:&#xD;
&#xD;
               -  no menses for ≥3 years or;&#xD;
&#xD;
               -  no menses for ≥1 year but &lt;3 years and confirmed by FSH levels elevated into the&#xD;
                  postmenopausal range (15-150 IU/L).&#xD;
&#xD;
          4. Willingness to maintain a stable diet for the duration of the study.&#xD;
&#xD;
          5. Understanding of the study procedures, alternative treatments available, and risks&#xD;
             involved with the study and voluntarily agreement to participate by giving written&#xD;
             informed consent.&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          1. Intolerance, known allergy or hypersensitivity to evolocumab (or other PCSK-9&#xD;
             monoclonal antibodies), latex or any of the components of the medication.&#xD;
&#xD;
          2. Current or prior exposure to evolocumab or another PCSK9-inhibitor mAb in the past 12&#xD;
             weeks.&#xD;
&#xD;
          3. Unable or unwilling to drink an oral fat load.&#xD;
&#xD;
          4. Premenopausal women.&#xD;
&#xD;
          5. Uncontrolled diabetes as defined by a HbA1c &gt;69 mmol/mol.&#xD;
&#xD;
          6. BMI &gt;40 kg/m2.&#xD;
&#xD;
          7. Uncontrolled blood pressure with systolic blood pressure &gt;180 mmHg or diastolic blood&#xD;
             pressure &gt;110 mmHg.&#xD;
&#xD;
          8. Increased hepatic enzymes, defined as alanine transaminase (ALAT) or aspartate&#xD;
             transaminase (ASAT) &gt;3 times the ULN, or active liver disease defined as non alcoholic&#xD;
             steatohepatitis (NASH), cirrhosis or Child Pugh B and C, or history of chronic active&#xD;
             hepatitis B or C; subjects with documented resolution after treatment are permitted.&#xD;
&#xD;
          9. Impaired renal function, defined by an estimated glomerular filtration rate (eGFR) &lt;30&#xD;
             mL/min/1.73m2, and/or need of renal placement therapy or other clinically significant&#xD;
             renal disease.&#xD;
&#xD;
         10. (Sub)clinical hypothyroidism defined as TSH &gt;5.0 mcl/U/mL or (sub)clinical&#xD;
             hyperthyroidism defined as TSH &lt; 0.35 mcl/U/ml.&#xD;
&#xD;
         11. Increased levels of creatinine kinase defined as &gt;3 times the ULN.&#xD;
&#xD;
         12. Increased fasting levels of triglycerides defined as &gt;10 mmol/L.&#xD;
&#xD;
         13. History of organ transplantation and/or use of immunosuppressive medication.&#xD;
&#xD;
         14. Use of fish oil or red yeast rice, bempedoic acid, niacin, CETP inhibitors,&#xD;
             lomitapide, mipomersen &lt; 6 weeks prior to the study or the use of siRNA targeting&#xD;
             PCSK9 inhibitors &lt; 36 weeks prior to the study.&#xD;
&#xD;
         15. Active malignancy (&lt;2 year prior to informed consent), except non-melanoma skin cancer&#xD;
             or carcinoma in situ of the cervix.&#xD;
&#xD;
         16. Known infection with Human Immunodeficiency Virus (HIV) or AIDS.&#xD;
&#xD;
         17. Known celiac disease or other disorder associated with significant intestinal&#xD;
             malabsorption.&#xD;
&#xD;
         18. Known galactose-intolerance, Lapp-lactase deficiency or glucose-galactose&#xD;
             malabsorption.&#xD;
&#xD;
         19. Alcohol use, defined as &gt;14 alcoholic consumptions per week for women and &gt;21 alcohol&#xD;
             consumptions per week for men. One alcohol consumption unit is defined as follows: 350&#xD;
             mL beer, 150 mL wine or 45 mL alcohol for mixed drinks.&#xD;
&#xD;
         20. Current participation or participation in a study with an investigational compound or&#xD;
             device within 30 days of signing informed consent.&#xD;
&#xD;
         21. Any medical, social or physiological circumstance which interferes the study, based on&#xD;
             judgement by the principal investigator.&#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>Frank LJ Visseren, prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>UMC Utrecht</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Frank LJ Visseren, prof</last_name>
    <phone>+31 88 7557324</phone>
    <email>f.l.j.visseren@umcutrecht.nl</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Britt E Heidemann, MD</last_name>
    <phone>+31 88 75 579 94</phone>
    <email>b.e.heidemann@umcutrecht.nl</email>
  </overall_contact_backup>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>January 17, 2019</study_first_submitted>
  <study_first_submitted_qc>January 17, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 22, 2019</study_first_posted>
  <last_update_submitted>January 17, 2019</last_update_submitted>
  <last_update_submitted_qc>January 17, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 22, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>UMC Utrecht</investigator_affiliation>
    <investigator_full_name>dr.Frank L.J. Visseren</investigator_full_name>
    <investigator_title>prof. dr. F.L.J. Visseren</investigator_title>
  </responsible_party>
  <keyword>Postprandial hyperlipidemia</keyword>
  <keyword>Evolocumab</keyword>
  <keyword>PCSK9 monoclonal antibody</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hyperlipoproteinemia Type III</mesh_term>
    <mesh_term>Hyperlipoproteinemias</mesh_term>
    <mesh_term>Hyperlipidemias</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Evolocumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>Currently, there is no plan to make individual participant data available to other researchers, but this is possible in the future.</ipd_description>
  </patient_data>
  <!-- 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/NCT03811223
org study id: UMCU-VASC-CO-002
nct id: NCT03811223
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Patients with familial dysbetalipoproteinemia (FD) have increased triglycerides,
      non-high-density lipoprotein cholesterol (non-HDL-C), beta VLDL, premature atherosclerosis
      and cardiovascular disease. They also have a delayed postprandial triglyceride and
      chylomicron (CM) remnant clearance. Postprandial hypertriglyceridemia is associated with
      increased vascular risk. Although combination therapy with statin and fibrate is recommended
      in the treatment of patients with FD, there is still a substantial amount of patient who do
      not reach their treatment target with this medication. Furthermore no information is
      available about the postprandial effects of adding evocolumab to standard lipid lowering
      therapy in FD patients.
See brief summary
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: AUC (area under the curve) non-HDL-cholesterol
time frame: 12 weeks
measure: Fasting levels, AUC and iAUC of total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and ApoB, as well as fasting non-HDL-cholesterol.
time frame: 12 weeks
measure: Percentage change from baseline and absolute difference in fasting and post fat load non-HDL-cholesterol, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and ApoB.
time frame: 12 weeks
measure: Fasting and post fat load lipoprotein (VLDL1, VLDL2, IDL, LDL, HDL) concentrations and composition (triglycerides, cholesterol, ApoB and apolipoproteins).
time frame: 12 weeks
measure: Post fat load ApoB 48-containing lipoprotein concentrations (chylomicrons and chylomicron remnants) and proteins involved in postprandial lipid metabolism.
time frame: 12 weeks
arm group label: Evolocumab
arm group type: Experimental
description: Evolocumab 140 mg subcutaneous injection once every 2 weeks for 12 weeks
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo injection once every 2 weeks for 12 weeks
intervention type: Drug
intervention name: Evolocumab Auto-Injector [Repatha]
description: Evolocumab 140 mg every 2 weeks for 12 weeks
arm group label: Evolocumab
intervention type: Drug
intervention name: Placebos
description: Placebo subcutaneous injection every 2 weeks for 12 weeks
arm group label: Placebo
other name: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Frank LJ Visseren, prof
role: Principal Investigator
affiliation: UMC Utrecht
last name: Frank LJ Visseren, prof
phone: +31 88 7557324
email: f.l.j.visseren@umcutrecht.nl
last name: Britt E Heidemann, MD
phone: +31 88 75 579 94
email: b.e.heidemann@umcutrecht.nl
responsible party type: Principal Investigator
investigator affiliation: UMC Utrecht
investigator full name: dr.Frank L.J. Visseren
investigator title: prof. dr. F.L.J. Visseren
mesh term: Hyperlipoproteinemia Type III
mesh term: Hyperlipoproteinemias
mesh term: Hyperlipidemias
mesh term: Evolocumab
sharing ipd: Undecided
ipd description: Currently, there is no plan to make individual participant data available to other researchers, but this is possible in the future.