<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/NCT01683656</url>
  </required_header>
  <id_info>
    <org_study_id>NILACH 2012DR4097</org_study_id>
    <nct_id>NCT01683656</nct_id>
  </id_info>
  <brief_title>ER Niacin/Laropiprant Impact on Cardiovascular Markers and Atheroprogression in HIV-infected Individuals on cART</brief_title>
  <acronym>NILACH</acronym>
  <official_title>ER Niacin/Laropiprant Impact on Cardiovascular Markers and Atheroprogression in HIV-infected Individuals on cART</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Calmy Alexandra</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University Hospital, Geneva</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Swiss National Science Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Fondation Ernest Boninchi</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Swiss Heart Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital, Geneva</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      HIV-infected patients are at increased risk for cardiovascular disease. Large investigations&#xD;
      support an inverse correlation between HDL-C levels and coronary heart disease. Therefore a&#xD;
      treatment lowering HDL-C such as niacin could reduce the risk of atheroprogression not only&#xD;
      through its benefit in terms of lipid profile, but also by reducing atherosclerotic&#xD;
      inflammation.&#xD;
&#xD;
      The study aims at showing that a therapy targeting HDL-C increase in HIV-infected patients on&#xD;
      suppressive cART has the potential for reducing subclinical atherosclerotic inflammation&#xD;
      associated with HIV itself in HIV-individuals on cART.&#xD;
&#xD;
      NILACH is a randomised, multicenter, double blind, placebo controlled, 48 weeks trial to test&#xD;
      the effect of the newly marketed niacin/laropiprant on carotid intima-media thickness (IMT)&#xD;
      in 90 subjects.&#xD;
&#xD;
        -  Regimen 1: ER niacin/laropiprant 1g/20 mg for the first 4 weeks and 2g/40mg from week 5&#xD;
           to the end of the study (the titration aims to reduce adverse reactions)&#xD;
&#xD;
        -  Regimen 2: ER niacin/laropiprant placebo p.m.&#xD;
&#xD;
      The primary end point is the change in mean common carotid intima-media thickness from&#xD;
      baseline and 48 weeks, compared between the niacin/laropiprant group and the placebo group.&#xD;
&#xD;
      The proposed in vivo experiments should provide insights on the potential benefits of niacin&#xD;
      treatment of cardiovascular disease in HIV patients. In addition, we will be able to further&#xD;
      clarify the role of systemic inflammatory mediators in the development of early&#xD;
      atherosclerosis of HIV-infected patients on antiretroviral therapy. Detection and treatment&#xD;
      of non-infectious co-morbidities such as cardiovascular diseases have become essential for&#xD;
      HIV-infected individuals exposed to lifelong antiretroviral therapy and go beyond mere&#xD;
      management of opportunistic infections or virologic suppression.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Withdrawal of IMP from the market. Data on risk-benefit ratio pending.&#xD;
  </why_stopped>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">July 2014</completion_date>
  <primary_completion_date type="Actual">July 2014</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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>change in mean common carotid intima-media thickness</measure>
    <time_frame>48 weeks</time_frame>
    <description>mean of maximal IMT value will be calculated over three cardiac cycles and for left and right carotid artery at baseline and week 48. The primary endpoint will be assessed by a single investigator in a blinded and anonymized fashion at cIMT Core Facility, Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada Responsible: Pr Jean-Claude Tardif.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Mean hs-CRP plasma concentration changes</measure>
    <time_frame>12, 24, 48 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Total Cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, apolipoprotein, triglycerides, and apolipoprotein (apo) Al, B and E levels</measure>
    <time_frame>12, 24, 48 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean biomarkers of inflammatory process (fibrinogen, S-VCAM-1, adiponectin, CCL2, CCL3, d-dimer, IL-6, TNF-alpha, Lp-PLA2) changes</measure>
    <time_frame>12, 24, 48 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical MACE: cardiovascular mortality, stroke, acute coronary syndromes, any cardiac arrhythmias, hospitalisation for cardiovascular causes, peripheral artery disease, revascularization.</measure>
    <time_frame>one year</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">4</enrollment>
  <condition>HIV</condition>
  <condition>Atherosclerosis</condition>
  <arm_group>
    <arm_group_label>ER Niacin/laropipant</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>ER niacin/laropiprant 1g/20 mg for the first 4 weeks and 2g/40mg from week 5 to the end of the study.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ER Niacin/laropipant Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>ER niacin/laropiprant placebo p.m.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>niacin/laropiprant</intervention_name>
    <arm_group_label>ER Niacin/laropipant</arm_group_label>
    <other_name>Tredaptive</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Procedures for the manufacturing and testing of the placebo are compiled in the IMP/study drug dossier and comply with local regulatory requirements (by GMP certified manufacturer).</description>
    <arm_group_label>ER Niacin/laropipant Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult patients &gt; 40 years;&#xD;
&#xD;
          -  Women of childbearing potential must use two reliable contraceptive methods during the&#xD;
             entire trial, from day 1 to one month after the end of the trial.&#xD;
&#xD;
          -  Signing the study consent form;&#xD;
&#xD;
          -  Stable cART since at least 3 months (ie no recent drug change);&#xD;
&#xD;
          -  HIV-RNA below 100 copies for at least 6 months;&#xD;
&#xD;
          -  HDL-cholesterol &lt;1.29 mmol/l for men; &lt;1.42 mmol/l for women&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnancy or lactation;&#xD;
&#xD;
          -  Congestive Heart Failure;&#xD;
&#xD;
          -  Malignant Hypertension;&#xD;
&#xD;
          -  Acute or chronic coronary artery diseases;&#xD;
&#xD;
          -  Any known cardiac arrhythmias;&#xD;
&#xD;
          -  Diabetes;&#xD;
&#xD;
          -  Concomitant cancer, rheumatologic disease or inflammatory bowel diseases;&#xD;
&#xD;
          -  Concomitant renal or hepatic disease:&#xD;
&#xD;
               -  Creatinine above 150 micromol/L&#xD;
&#xD;
               -  Transaminases above 5 times upper normal limit&#xD;
&#xD;
               -  Prothrombin time (Quick) value below 50%;&#xD;
&#xD;
          -  Prior intolerance to niacin therapy (reported in a medical report);&#xD;
&#xD;
          -  Cyclosporine, anti-inflammatory drugs (other than aspirin) or cytokine therapy in&#xD;
             concomitant intake;&#xD;
&#xD;
          -  Abnormal thyroid function;&#xD;
&#xD;
          -  Excessive consumption of alcohol;&#xD;
&#xD;
          -  Known severe lactose intolerance.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Alexandra Calmy, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospital, Geneva</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Hospital Berne Inselspital</name>
      <address>
        <city>Berne</city>
        <state>BE</state>
        <zip>3010</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Basel</name>
      <address>
        <city>Basel</city>
        <state>BS</state>
        <zip>4031</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospitals Genève</name>
      <address>
        <city>Geneva</city>
        <state>GE</state>
        <zip>1211</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kantonsspital St Gallen</name>
      <address>
        <city>St Gallen</city>
        <state>SG</state>
        <zip>9007</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>EOC Ente Ospedaliero Cantonale, civico</name>
      <address>
        <city>Lugano</city>
        <state>TI</state>
        <zip>6903</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHUV Cantonal University Hospital Vaud</name>
      <address>
        <city>Lausanne</city>
        <state>VD</state>
        <zip>1011</zip>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Zurich</name>
      <address>
        <city>Zurich</city>
        <state>ZH</state>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
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    <citation>Gotto AM Jr. High-density lipoprotein cholesterol and triglycerides as therapeutic targets for preventing and treating coronary artery disease. Am Heart J. 2002 Dec;144(6 Suppl):S33-42. doi: 10.1067/mhj.2002.130301.</citation>
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    <citation>Thoenes M, Oguchi A, Nagamia S, Vaccari CS, Hammoud R, Umpierrez GE, Khan BV. The effects of extended-release niacin on carotid intimal media thickness, endothelial function and inflammatory markers in patients with the metabolic syndrome. Int J Clin Pract. 2007 Nov;61(11):1942-8. doi: 10.1111/j.1742-1241.2007.01597.x.</citation>
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    <PMID>19031552</PMID>
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    <citation>Kush D, Hu DY, Ye P, Kim HS, Chen E, Sirah W, McCrary Sisk C, Paolini JF, Maccubbin D. Flushing profile of extended-release niacin/laropiprant at initiation of therapy in Asian lipid clinic patients. Cardiology. 2009;114(3):192-8. doi: 10.1159/000228585. Epub 2009 Jul 15.</citation>
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    <citation>Dube MP, Wu JW, Aberg JA, Deeg MA, Alston-Smith BL, McGovern ME, Lee D, Shriver SL, Martinez AI, Greenwald M, Stein JH; AIDS Clinical Trials Group A5148 Study Team. Safety and efficacy of extended-release niacin for the treatment of dyslipidaemia in patients with HIV infection: AIDS Clinical Trials Group Study A5148. Antivir Ther. 2006;11(8):1081-9.</citation>
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    <citation>Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M, Weissman NJ, Turco M. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009 Nov 26;361(22):2113-22. doi: 10.1056/NEJMoa0907569. Epub 2009 Nov 15.</citation>
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    <citation>Stein EA. Additional lipid lowering trials using surrogate measurements of atherosclerosis by carotid intima-media thickness: more clarity or confusion? J Am Coll Cardiol. 2008 Dec 16;52(25):2206-9. doi: 10.1016/j.jacc.2008.11.002. No abstract available.</citation>
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    <citation>Maggi P, Serio G, Epifani G, Fiorentino G, Saracino A, Fico C, Perilli F, Lillo A, Ferraro S, Gargiulo M, Chirianni A, Angarano G, Regina G, Pastore G. Premature lesions of the carotid vessels in HIV-1-infected patients treated with protease inhibitors. AIDS. 2000 Nov 10;14(16):F123-8. doi: 10.1097/00002030-200011100-00001.</citation>
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    <citation>de Saint Martin L, Vandhuick O, Guillo P, Bellein V, Bressollette L, Roudaut N, Amaral A, Pasquier E. Premature atherosclerosis in HIV positive patients and cumulated time of exposure to antiretroviral therapy (SHIVA study). Atherosclerosis. 2006 Apr;185(2):361-7. doi: 10.1016/j.atherosclerosis.2005.06.049. Epub 2005 Aug 30.</citation>
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    <citation>Mercie P, Thiebaut R, Lavignolle V, Pellegrin JL, Yvorra-Vives MC, Morlat P, Ragnaud JM, Dupon M, Malvy D, Bellet H, Lawson-Ayayi S, Roudaut R, Dabis F. Evaluation of cardiovascular risk factors in HIV-1 infected patients using carotid intima-media thickness measurement. Ann Med. 2002;34(1):55-63. doi: 10.1080/078538902317338652.</citation>
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    <citation>Currier JS, Kendall MA, Henry WK, Alston-Smith B, Torriani FJ, Tebas P, Li Y, Hodis HN. Progression of carotid artery intima-media thickening in HIV-infected and uninfected adults. AIDS. 2007 May 31;21(9):1137-45. doi: 10.1097/QAD.0b013e32811ebf79.</citation>
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    <citation>Chow DC, Stein JH, Seto TB, Mitchell C, Sriratanaviriyakul N, Grandinetti A, Gerschenson M, Shiramizu B, Souza S, Shikuma C. Short-term effects of extended-release niacin on endothelial function in HIV-infected patients on stable antiretroviral therapy. AIDS. 2010 Apr 24;24(7):1019-23. doi: 10.1097/QAD.0b013e3283383016.</citation>
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    <citation>Ross AC, Rizk N, O'Riordan MA, Dogra V, El-Bejjani D, Storer N, Harrill D, Tungsiripat M, Adell J, McComsey GA. Relationship between inflammatory markers, endothelial activation markers, and carotid intima-media thickness in HIV-infected patients receiving antiretroviral therapy. Clin Infect Dis. 2009 Oct 1;49(7):1119-27. doi: 10.1086/605578.</citation>
    <PMID>19712036</PMID>
  </reference>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>August 31, 2012</study_first_submitted>
  <study_first_submitted_qc>September 7, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 12, 2012</study_first_posted>
  <last_update_submitted>October 7, 2019</last_update_submitted>
  <last_update_submitted_qc>October 7, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 8, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital, Geneva</investigator_affiliation>
    <investigator_full_name>Calmy Alexandra</investigator_full_name>
    <investigator_title>Head of HIV Unit</investigator_title>
  </responsible_party>
  <keyword>HIV</keyword>
  <keyword>Atherosclerosis</keyword>
  <keyword>Niacin/laropiprant</keyword>
  <keyword>HDL</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Atherosclerosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Niacin</mesh_term>
  </intervention_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/NCT01683656
org study id: NILACH 2012DR4097
nct id: NCT01683656
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
HIV-infected patients are at increased risk for cardiovascular disease. Large investigations
      support an inverse correlation between HDL-C levels and coronary heart disease. Therefore a
      treatment lowering HDL-C such as niacin could reduce the risk of atheroprogression not only
      through its benefit in terms of lipid profile, but also by reducing atherosclerotic
      inflammation.

      The study aims at showing that a therapy targeting HDL-C increase in HIV-infected patients on
      suppressive cART has the potential for reducing subclinical atherosclerotic inflammation
      associated with HIV itself in HIV-individuals on cART.

      NILACH is a randomised, multicenter, double blind, placebo controlled, 48 weeks trial to test
      the effect of the newly marketed niacin/laropiprant on carotid intima-media thickness (IMT)
      in 90 subjects.

        -  Regimen 1: ER niacin/laropiprant 1g/20 mg for the first 4 weeks and 2g/40mg from week 5
           to the end of the study (the titration aims to reduce adverse reactions)

        -  Regimen 2: ER niacin/laropiprant placebo p.m.

      The primary end point is the change in mean common carotid intima-media thickness from
      baseline and 48 weeks, compared between the niacin/laropiprant group and the placebo group.

      The proposed in vivo experiments should provide insights on the potential benefits of niacin
      treatment of cardiovascular disease in HIV patients. In addition, we will be able to further
      clarify the role of systemic inflammatory mediators in the development of early
      atherosclerosis of HIV-infected patients on antiretroviral therapy. Detection and treatment
      of non-infectious co-morbidities such as cardiovascular diseases have become essential for
      HIV-infected individuals exposed to lifelong antiretroviral therapy and go beyond mere
      management of opportunistic infections or virologic suppression.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: change in mean common carotid intima-media thickness
time frame: 48 weeks
description: mean of maximal IMT value will be calculated over three cardiac cycles and for left and right carotid artery at baseline and week 48. The primary endpoint will be assessed by a single investigator in a blinded and anonymized fashion at cIMT Core Facility, Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada Responsible: Pr Jean-Claude Tardif.
measure: Mean hs-CRP plasma concentration changes
time frame: 12, 24, 48 weeks
measure: Mean Total Cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, apolipoprotein, triglycerides, and apolipoprotein (apo) Al, B and E levels
time frame: 12, 24, 48 weeks
measure: Mean biomarkers of inflammatory process (fibrinogen, S-VCAM-1, adiponectin, CCL2, CCL3, d-dimer, IL-6, TNF-alpha, Lp-PLA2) changes
time frame: 12, 24, 48 weeks
measure: Clinical MACE: cardiovascular mortality, stroke, acute coronary syndromes, any cardiac arrhythmias, hospitalisation for cardiovascular causes, peripheral artery disease, revascularization.
time frame: one year
arm group label: ER Niacin/laropipant
arm group type: Active Comparator
description: ER niacin/laropiprant 1g/20 mg for the first 4 weeks and 2g/40mg from week 5 to the end of the study.
arm group label: ER Niacin/laropipant Placebo
arm group type: Placebo Comparator
description: ER niacin/laropiprant placebo p.m.
intervention type: Drug
intervention name: niacin/laropiprant
arm group label: ER Niacin/laropipant
other name: Tredaptive
intervention type: Drug
intervention name: Placebo
description: Procedures for the manufacturing and testing of the placebo are compiled in the IMP/study drug dossier and comply with local regulatory requirements (by GMP certified manufacturer).
arm group label: ER Niacin/laropipant Placebo
criteria: 
gender: All
minimum age: 40 Years
maximum age: N/A
healthy volunteers: No
last name: Alexandra Calmy, MD
role: Principal Investigator
affiliation: University Hospital, Geneva
facility: 
facility: 
facility: 
facility: 
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country: Switzerland
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responsible party type: Sponsor-Investigator
investigator affiliation: University Hospital, Geneva
investigator full name: Calmy Alexandra
investigator title: Head of HIV Unit
mesh term: Atherosclerosis
mesh term: Niacin