<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/NCT02199496</url>
  </required_header>
  <id_info>
    <org_study_id>140153</org_study_id>
    <secondary_id>14-I-0153</secondary_id>
    <nct_id>NCT02199496</nct_id>
  </id_info>
  <brief_title>Study of Safety, Tolerability, and Efficacy of Ustekinumab for Symptomatic Gastrointestinal Inflammation Associated With Common Variable Immunodeficiency</brief_title>
  <official_title>An Open-Label Phase I/II Pilot Study to Assess the Safety/Tolerability and Efficacy of Ustekinumab for Symptomatic Gastrointestinal Inflammation Associated With Common Variable Immunodeficiency</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      - Some people with Common Variable Immunodeficiency Disease (CVID) have gastrointestinal&#xD;
      inflammation. This can cause diarrhea, weight loss, and not being able to absorb nutrition&#xD;
      from food. Researchers want to see if the drug ustekinumab can help these problems. This drug&#xD;
      blocks some proteins that cause inflammation.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      - To test the safety and efficacy of the drug ustekinumab for people with CVID with&#xD;
      gastrointestinal inflammation.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - Adults ages 18-75 with CVID. They must have chronic diarrhea, have unintentionally lost&#xD;
      weight in the last year, and/or need to use nutritional supplements to maintain their weight.&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will undergo the following screening studies to make sure that this study is a&#xD;
      good fit for your medical situation, and to make sure it is safe for you to receive the study&#xD;
      medications tests, including tests for HIV and hepatitis . This will be done as an inpatient&#xD;
      at the NIH Clinical Center and takes about 5-6 days:&#xD;
&#xD;
        -  Participants will be screened with:&#xD;
&#xD;
        -  Medical history&#xD;
&#xD;
        -  Physical exam&#xD;
&#xD;
        -  Blood tests, including tests for HIV and hepatitis.&#xD;
&#xD;
        -  Stool tests, including a timed 48 hour collection for fat malabsorption and a 24 hour&#xD;
           collection for protein malabsorption&#xD;
&#xD;
        -  Urine tests, including a pregnancy test for any women with the ability to have a child&#xD;
&#xD;
        -  Chest CT scan to look for infection&#xD;
&#xD;
        -  D-xylose testing, which involves drinking a sugary solution and then having a blood&#xD;
           sample drawn to test carbohydrate (sugar) malabsorption&#xD;
&#xD;
        -  Hydrogen breath testing for test for small intestinal bacterial overgrowth (SIBO) this&#xD;
           test also involves drinking a sugary solution and then collecting breath samples&#xD;
&#xD;
        -  Upper endoscopy (EGD) and/or colonoscopy to look at the lining of the GI tract and take&#xD;
           biopsies for testing. This will be done under sedation by a qualified&#xD;
           gastroenterologist.&#xD;
&#xD;
      Participants who complete screening and meet all criteria will then return to the NIH&#xD;
      Clinical Center for the following visits:&#xD;
&#xD;
        -  First Treatment Visit (1 clinic day): Medical history, physical exam, measurement of&#xD;
           vital signs and weight, review of medications, and an assessment of number and&#xD;
           consistency of stools each day. A pregnancy test for women of childbearing potential. A&#xD;
           nurse will give you three shots of 90 mg ustekinumab (270 mg total dose) by very small&#xD;
           needles injected under the skin, and then observe you for 1 hour.&#xD;
&#xD;
        -  Week 8 Treatment Visit (1 clinic day): Medical history, physical exam, measurement of&#xD;
           vital signs and weight, review of medications, and an assessment of number and&#xD;
           consistency of stools each day. Blood, urine and stool samples will be collected. A&#xD;
           pregnancy test for women of childbearing potential. A nurse will give you one 90 mg dose&#xD;
           of ustekinumab by a very small needle injected under the skin, and then observe you for&#xD;
           1 hour.&#xD;
&#xD;
        -  Week 16 Treatment Visit (1 clinic day): Medical history, physical exam, measurement of&#xD;
           vital signs and weight, review of medications, and an assessment of number and&#xD;
           consistency of stools each day. Blood, urine and stool samples will be collected. A&#xD;
           pregnancy test for women of childbearing potential. A nurse will give you one 90 mg dose&#xD;
           of ustekinumab by a very small needle injected under the skin, and then observe you for&#xD;
           1 hour.&#xD;
&#xD;
        -  Week 24 Treatment and Mid-point Evaluation Visit (4-6 inpatient days): Medical history,&#xD;
           physical exam, measurement of vital signs and weight, review of medications, and an&#xD;
           assessment of number and consistency of stools each day. Blood, urine and stool samples&#xD;
           will be collected, including repeating the d-xylose carbohydrate malabsorption testing,&#xD;
           the 24 hour stool collection for protein malabsorption and the 48 hour stool collection&#xD;
           for fat malabsorption. A pregnancy test for women of childbearing potential. A nurse&#xD;
           will give you one 90 mg dose of ustekinumab by a very small needle injected under the&#xD;
           skin, and then observe you for 1 hour.&#xD;
&#xD;
        -  Week 32 Treatment Visit: Medical history, physical exam, measurement of vital signs and&#xD;
           weight, review of medications, and an assessment of number and consistency of stools&#xD;
           each day. Blood, urine and stool samples will be collected. A pregnancy test for women&#xD;
           of childbearing potential. A nurse will give you one 90 mg dose of ustekinumab by a very&#xD;
           small needle injected under the skin, and then observe you for 1 hour.&#xD;
&#xD;
        -  Week 40 Treatment Visit: Medical history, physical exam, measurement of vital signs and&#xD;
           weight, review of medications, and an assessment of number and consistency of stools&#xD;
           each day. Blood, urine and stool samples will be collected. A pregnancy test for women&#xD;
           of childbearing potential. A nurse will give you one 90 mg dose of ustekinumab by a very&#xD;
           small needle injected under the skin, and then observe you for 1 hour.&#xD;
&#xD;
        -  Week 48 ...&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The purpose of this study is to assess the safety/tolerability and efficacy of using&#xD;
      ustekinumab in subjects with common variable immunodeficiency CVID or selective IgG subclass&#xD;
      deficiency (functional agammaglobulinemia) who have associated symptomatic gastrointestinal&#xD;
      inflammation (CVID enteropathy). Ustekinumab (a Food and Drug Administration [FDA] approved&#xD;
      drug) is a monoclonal antibody to interleukin (IL)-12/23p40. CVID is a clinically&#xD;
      heterogeneous disorder characterized by decreased serum immunoglobulin IgG and IgA levels. In&#xD;
      addition to chronic or recurrent pyogenic sino-pulmonary infections, many patients develop&#xD;
      non-infectious gastrointestinal manifestations that can be disabling or fatal. Currently&#xD;
      there is no standard therapy for the associated gastrointestinal disease outside of empiric&#xD;
      nutritional intervention for weight loss, anti-diarrheal agents, and non-specific&#xD;
      anti-inflammatory agents.&#xD;
&#xD;
      Recently, gut inflammation complicating functional hypogammaglobulinemia due to CVID and&#xD;
      selective IgG subclass deficiency has been characterized as a T helper type 1 (Th1)&#xD;
      inflammatory response, with excess IL-12 cytokine production associated with diarrhea and&#xD;
      weight loss as well as reduced D-xylose absorption and steatorrhea. This protocol aims to&#xD;
      test specific anti-IL-12 therapy in this patient group. It has been previously shown that&#xD;
      therapy targeted to IL-12 successfully treated the Th1 gut inflammation of Crohn s disease&#xD;
      (CD). Ustekinumab, a monoclonal antibody to the p40 subunit of IL-12 and IL-23, is FDA&#xD;
      approved for the treatment of moderate to severe plaque psoriasis, active psoriatic&#xD;
      arthritis, and more recently, moderately to severely active CD. This protocol is designed to&#xD;
      measure the safety of ustekinumab in patients with functional hypogammaglobulinemia and CVID&#xD;
      enteropathy, as well as measure effects on symptoms, gut function, expression of immune cell&#xD;
      surface markers, production of cytokines and global gene expression from blood and gut&#xD;
      mucosal mononuclear cells, and the gut microbiota.&#xD;
&#xD;
      Patients with CVID and selective IgG subclass deficiency with gastrointestinal symptoms of&#xD;
      malabsorption, maldigestion, and chronic diarrhea will be enrolled into this study. Subjects&#xD;
      (up to a total of 10 individuals) will receive a treatment dose of 270 mg (3 doses of 90 mg&#xD;
      either single-use prefilled syringe or single-use vial, depending on availability) will be&#xD;
      injected subcutaneously in subjects by qualified nursing staff on the Day 0 study visit.&#xD;
      Subjects will then receive a follow up treatment dose of 90 mg at Week 8, Week 16, Week 24,&#xD;
      Week 32 and Week 40 and be followed for a total of 48 weeks.&#xD;
&#xD;
      Subjects will have study procedures prior to treatment and 48 weeks post-treatment, these&#xD;
      include upper and/or lower endoscopies, to measure changes in immune responses and studies to&#xD;
      evaluate physiologic measures of gut function at 48 weeks, as well as routine safety&#xD;
      monitoring throughout the study. Gut absorption tests will be performed at the Week 24 visit.&#xD;
      Variables will include safety (adverse event rate), clinical (weight, stool frequency,&#xD;
      results of gut absorption tests), and laboratory (lymphocyte and cytokine assays) parameters&#xD;
      for descriptive summary statistical analysis (n, mean, median, standard deviation, minimum&#xD;
      and maximum range).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 19, 2015</start_date>
  <completion_date type="Actual">July 10, 2020</completion_date>
  <primary_completion_date type="Actual">August 16, 2019</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Increase in Infection or Serious Adverse Events (SAEs) Related to Single Dose Administration of Ustekinumab</measure>
    <time_frame>6 months</time_frame>
    <description>Whether treatment with ustekinumab is safe and tolerated in patients with common variable immunodeficiency (CVID) enteropathy as determined by no significant increase in infection or serious adverse events</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With Increase in Infection or Serious Adverse Events (SAEs) Related to Multi-dose Administration of Ustekinumab (Cohort 1)</measure>
    <time_frame>48 weeks</time_frame>
    <description>Whether treatment with ustekinumab is safe and tolerated in patients with common variable immunodeficiency (CVID) enteropathy as determined by no significant increase in infection or serious adverse events</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With Increase in Infection or Serious Adverse Events (SAEs) Related to Multi-dose Administration of Ustekinumab (Cohort 2)</measure>
    <time_frame>48 weeks</time_frame>
    <description>Whether treatment with ustekinumab is safe and tolerated in patients with common variable immunodeficiency (CVID) enteropathy as determined by no significant increase in infection or serious adverse events</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>Gastrointestinal Inflammation Associated With CVID</condition>
  <condition>CVID Enteropathy</condition>
  <arm_group>
    <arm_group_label>Cohort 1: Ustekinumab-Single-dose Phase 1, Multi-dose Phase 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects given an induction dose of 270 mg Stelara (ustekinumab) subcutaneously then re-enrolled into the multi-dose phase. In multi-dose phase, subjects given an induction dose of 270 mg Stelara (ustekinumab) subcutaneously followed by every 8 week maintenance doses of 90 mg Stelara (ustekinumab) subcutaneously at week 8, week 16, week 24, week 32, and week 40</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2: Ustekinumab-Multi-dose Phase 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects given an induction dose of 270 mg Stelara (ustekinumab) subcutaneously followed by every 8 week maintenance doses of 90 mg Stelara (ustekinumab) subcutaneously at week 8, week 16, week 24, week 32, and week 40</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Stelara (ustekinumab)</intervention_name>
    <description>In the single-phase part of the study, subjects receive a single dose of Stelara (ustekinumab) 270 mg subcutaneously on Day 0 study visit.&#xD;
In the multi-phase part of the study, subjects receive single dose of Stelara (ustekinumab) 270 mg subcutaneously on Day 0 study visit with follow up dose of Stelara (ustekinumab) 90 mg subcutaneously at Week 8, Week 16, Week 24, Week 32 and Week 40</description>
    <arm_group_label>Cohort 1: Ustekinumab-Single-dose Phase 1, Multi-dose Phase 2</arm_group_label>
    <arm_group_label>Cohort 2: Ustekinumab-Multi-dose Phase 2</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  DIAGNOSIS AND CRITERIA FOR INCLUSION:&#xD;
&#xD;
        A subject is eligible for the study if all of the following criteria are met:&#xD;
&#xD;
          -  Has given written informed consent.&#xD;
&#xD;
          -  Is male or female aged 18 through 75 years.&#xD;
&#xD;
          -  Has CVID or selective IgG subclass deficiency of either one or concomitant IgG&#xD;
             subclasses comprising IgG1, IgG2, IgG3 or IgG4 (functional hypogammaglobulinemia)&#xD;
             diagnosed prior to screening as based on the International Union of Immunological&#xD;
             Societies (IUIS) criteria.&#xD;
&#xD;
          -  Has a documented, unintended loss of &gt;5% of their body weight over the last year or&#xD;
             requires nutritional supplements to maintain his/her body weight and/or has chronic&#xD;
             diarrhea defined as a complaint of at &gt;/= 50% of stools are non-formed for at least 4&#xD;
             consecutive weeks per patient history. Alternately, must be dependent on a therapeutic&#xD;
             dose of antidiarrheals (e.g., loperamide or diphenoxylate with atropine) for control&#xD;
             of chronic diarrhea.&#xD;
&#xD;
          -  If taking oral antibiotics chronically, must have used a stable dose of the antibiotic&#xD;
             continuously for at least 2 weeks prior to start of screening period.&#xD;
&#xD;
          -  Is willing to have samples stored.&#xD;
&#xD;
          -  Be willing to consistently take appropriate measures to avoid pregnancy through the&#xD;
             Week 48 study point. All subjects will be informed of the potential risks of&#xD;
             ustekinumab during pregnancy and counseled on pregnancy avoidance appropriate to the&#xD;
             subject s circumstances (e.g. fertility status, medical contraindications to hormonal&#xD;
             birth control, and/or personal or religious beliefs regarding pregnancy avoidance).&#xD;
             Subject to the judgment and discretion of the PI, some subjects may not need to take&#xD;
             pregnancy&#xD;
&#xD;
        avoidance measures. Patient handout on pregnancy avoidance will be provided to patients at&#xD;
        the time of consent and discussion regarding pregnancy avoidance during the study.&#xD;
&#xD;
        -Subjects who have previously been treated with a single 270 mg dose of ustekinumab on this&#xD;
        study must be greater than 6 months from their treatment dose and have had recurrence of&#xD;
        enteropathy symptoms.&#xD;
&#xD;
        CRITERIA FOR EXCLUSION:&#xD;
&#xD;
        A subject is excluded from the study if any of the following criteria are met:&#xD;
&#xD;
        GENERAL CRITERIA:&#xD;
&#xD;
          -  Has any clinically significant disease or condition (e.g., renal, hepatic,&#xD;
             neurological, cardiovascular, pulmonary, endocrinologic, psychiatric, hematologic,&#xD;
             urologic, or other acute or chronic illness) that in the opinion of the investigator&#xD;
             would make the subject an unsuitable candidate for this trial, or put the subject at&#xD;
             undue risk by participating in this study.&#xD;
&#xD;
          -  Is a woman who has a positive pregnancy test or who is breast-feeding&#xD;
&#xD;
          -  Is a woman who does not agree to abide by the contraceptive measures required to&#xD;
             prevent pregnancy during participation in the study, or meets exemption criteria for&#xD;
             contraceptive measures, as outlined in the protocol.&#xD;
&#xD;
          -  Has any of the following clinical chemistry values:&#xD;
&#xD;
               -  AST &gt;2.5 times upper limit of normal (ULN).&#xD;
&#xD;
               -  ALT &gt;2.5 times ULN.&#xD;
&#xD;
               -  Serum bilirubin &gt;1.5 times ULN.&#xD;
&#xD;
               -  Serum creatinine &gt;1.5 times ULN.&#xD;
&#xD;
               -  Alkaline phosphatase &gt;2.5 times ULN.&#xD;
&#xD;
          -  Has a hemoglobin level &lt;9 g/dL or hematocrit &lt;30%.&#xD;
&#xD;
          -  Has an International Normalized Ratio (INR) &gt;1.3 or a Partial Thromboplastin Time&#xD;
             (PTT) &gt;3 sec of ULN.&#xD;
&#xD;
          -  Has the following cell counts (cells/microL):&#xD;
&#xD;
               -  Platelet count &lt;75,000 or &gt;800,000.&#xD;
&#xD;
               -  White blood cell count &lt;2,000.&#xD;
&#xD;
               -  Neutrophil count &lt;1,000.&#xD;
&#xD;
          -  Has a current infection requiring intravenous antibiotics, a serious local infection&#xD;
             (e.g., cellulitis, abscess) or systemic infection (e.g., pneumonia, septicemia).&#xD;
&#xD;
          -  Has a history of cancer within the past 5 years, with the exception of excised basal&#xD;
             cell carcinoma, squamous cell carcinoma of the skin, or cervical carcinoma in situ.&#xD;
&#xD;
          -  Had a dependency for any illicit drug, chemical, or alcohol within the past 5 years.&#xD;
&#xD;
          -  Has a history of active tuberculosis (TB) (or a chest x-ray (CXR) with findings&#xD;
             suggestive of old TB infection including calcified nodular lesions, apical fibrosis,&#xD;
             or pleural scarring), acute or chronic hepatitis B, hepatitis C, human&#xD;
             immunodeficiency virus (HIV) or opportunistic infections.&#xD;
&#xD;
        GASTROINTESTINAL CRITERIA&#xD;
&#xD;
        -Has a stool sample determined positive for acute gastrointestinal infection with impact of&#xD;
        occurrence on gastrointestinal inflammation as determined by principal investigator during&#xD;
        screening. In addition, stool samples positive for GI pathogens will be discussed with an&#xD;
        infectious disease physician to determine impact of occurrence on gastrointestinal&#xD;
        inflammation. If organism thought to be pathogenic, the subject will be treated with&#xD;
        appropriate therapy. This will be documented in the subject s medical record.&#xD;
&#xD;
        PRIOR MEDICATION CRITERIA&#xD;
&#xD;
          -  Received daily corticosteroids within 1 month prior to receiving study agent. The use&#xD;
             of short-term or single-dose corticosteroids as a pretreatment regimen for IVIG is&#xD;
             acceptable.&#xD;
&#xD;
          -  Received any investigational drug within 3 months prior to receiving study agent.&#xD;
&#xD;
          -  Received certolizumab or natalizumab within 3 months prior to receiving study agent&#xD;
&#xD;
          -  Received vedolizumab, infliximab, etanercept, or adalimumab within 2 months prior to&#xD;
             receiving study agent.&#xD;
&#xD;
          -  Received cyclosporine, tacrolimus, sirolimus, pimecrolimus, mycophenolate mofetil or&#xD;
             any other systemic immunosuppressants within 1 month prior to receiving study agent.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ivan J Fuss, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute of Allergy and Infectious Diseases (NIAID)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center, 9000 Rockville Pike</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-I-0153.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <reference>
    <citation>Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999 Jul;92(1):34-48. doi: 10.1006/clim.1999.4725.</citation>
    <PMID>10413651</PMID>
  </reference>
  <reference>
    <citation>Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, Guzzo C, Sands BE, Hanauer SB, Targan S, Rutgeerts P, Ghosh S, de Villiers WJ, Panaccione R, Greenberg G, Schreiber S, Lichtiger S, Feagan BG; CERTIFI Study Group. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N Engl J Med. 2012 Oct 18;367(16):1519-28. doi: 10.1056/NEJMoa1203572.</citation>
    <PMID>23075178</PMID>
  </reference>
  <reference>
    <citation>Mannon PJ, Fuss IJ, Dill S, Friend J, Groden C, Hornung R, Yang Z, Yi C, Quezado M, Brown M, Strober W. Excess IL-12 but not IL-23 accompanies the inflammatory bowel disease associated with common variable immunodeficiency. Gastroenterology. 2006 Sep;131(3):748-56. doi: 10.1053/j.gastro.2006.06.022.</citation>
    <PMID>16952544</PMID>
  </reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 23, 2014</study_first_submitted>
  <study_first_submitted_qc>July 23, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 24, 2014</study_first_posted>
  <results_first_submitted>August 10, 2020</results_first_submitted>
  <results_first_submitted_qc>August 10, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">August 24, 2020</results_first_posted>
  <last_update_submitted>August 10, 2020</last_update_submitted>
  <last_update_submitted_qc>August 10, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 24, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Malabsorption</keyword>
  <keyword>Enteropathy</keyword>
  <keyword>Diarrhea</keyword>
  <keyword>IL-12</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Intestinal Diseases</mesh_term>
    <mesh_term>Common Variable Immunodeficiency</mesh_term>
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ustekinumab</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 17, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/96/NCT02199496/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Cohort 1: Single-dose Phase 1, Multi-dose Phase 2</title>
          <description>Subjects given single dose of 270mg Ustekinumab subcutaneously then re-enrolled into the multi-dose phase. In multi-dose phase subjects given single dose of 270mg Ustekinumab subcutaneously with follow up treatment doses of 90 mg (1 dose of 90 mg) at week 8, week 16, week 24, week 32, and week 40</description>
        </group>
        <group group_id="P2">
          <title>Cohort 2: Multi-Dose Ustekinumab Phase 2</title>
          <description>Subjects given single dose of 270mg Ustekinumab subcutaneously then follow up treatment doses of 90 mg (1 dose of 90 mg) at week 8, week 16, week 24, week 32, and week 40</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Ustekinumab-Single Dose</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Ustekinumab-Multi-dose</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="2">Cohort 2 only participated in multi-dose phase 2</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Cohort 1: Ustekinumab-Single-dose Phase 1, Multi-dose Phase 2</title>
          <description>Subjects given an induction dose of 270 mg Stelara (ustekinumab) subcutaneously then re-enrolled into the multi-dose phase. In multi-dose phase, subjects given an induction dose of 270 mg Stelara (ustekinumab) subcutaneously followed by every 8 week maintenance doses of 90 mg Stelara (ustekinumab) subcutaneously at week 8, week 16, week 24, week 32, and week 40</description>
        </group>
        <group group_id="B2">
          <title>Cohort 2: Ustekinumab-Multi-dose Phase 2</title>
          <description>Subjects given an induction dose of 270 mg Stelara (ustekinumab) subcutaneously followed by every 8 week maintenance doses of 90 mg Stelara (ustekinumab) subcutaneously at week 8, week 16, week 24, week 32, and week 40</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="3"/>
            <count group_id="B2" value="2"/>
            <count group_id="B3" value="5"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Increase in Infection or Serious Adverse Events (SAEs) Related to Single Dose Administration of Ustekinumab</title>
        <description>Whether treatment with ustekinumab is safe and tolerated in patients with common variable immunodeficiency (CVID) enteropathy as determined by no significant increase in infection or serious adverse events</description>
        <time_frame>6 months</time_frame>
        <population>Participants who received ustekinumab</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1: Ustekinumab-Single Dose Phase 1</title>
            <description>Single dose of 270mg ustekinumab subcutaneously</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Increase in Infection or Serious Adverse Events (SAEs) Related to Single Dose Administration of Ustekinumab</title>
          <description>Whether treatment with ustekinumab is safe and tolerated in patients with common variable immunodeficiency (CVID) enteropathy as determined by no significant increase in infection or serious adverse events</description>
          <population>Participants who received ustekinumab</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Increase in Infection or Serious Adverse Events (SAEs) Related to Multi-dose Administration of Ustekinumab (Cohort 1)</title>
        <description>Whether treatment with ustekinumab is safe and tolerated in patients with common variable immunodeficiency (CVID) enteropathy as determined by no significant increase in infection or serious adverse events</description>
        <time_frame>48 weeks</time_frame>
        <population>Participants who received ustekinumab</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1: Ustekinumab-Multi-dose Phase 2</title>
            <description>Single dose of 270mg ustekinumab subcutaneously then follow up doses of 90 mg ustekinumab subcutaneously at week 8, week 16, week 24, week 32, and week 40</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Increase in Infection or Serious Adverse Events (SAEs) Related to Multi-dose Administration of Ustekinumab (Cohort 1)</title>
          <description>Whether treatment with ustekinumab is safe and tolerated in patients with common variable immunodeficiency (CVID) enteropathy as determined by no significant increase in infection or serious adverse events</description>
          <population>Participants who received ustekinumab</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Increase in Infection or Serious Adverse Events (SAEs) Related to Multi-dose Administration of Ustekinumab (Cohort 2)</title>
        <description>Whether treatment with ustekinumab is safe and tolerated in patients with common variable immunodeficiency (CVID) enteropathy as determined by no significant increase in infection or serious adverse events</description>
        <time_frame>48 weeks</time_frame>
        <population>Participants who received ustekinumab</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 2: Ustekinumab-Multi-dose Phase 2</title>
            <description>Single dose of 270mg ustekinumab subcutaneously then follow up doses of 90 mg ustekinumab subcutaneously at week 8, week 16, week 24, week 32, and week 40</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Increase in Infection or Serious Adverse Events (SAEs) Related to Multi-dose Administration of Ustekinumab (Cohort 2)</title>
          <description>Whether treatment with ustekinumab is safe and tolerated in patients with common variable immunodeficiency (CVID) enteropathy as determined by no significant increase in infection or serious adverse events</description>
          <population>Participants who received ustekinumab</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>6 months for Phase 1 and 48 Weeks for Phase 2</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Cohort 1: Ustekinumab-Single Dose Phase 1</title>
          <description>Single dose of 270mg ustekinumab subcutaneously</description>
        </group>
        <group group_id="E2">
          <title>Cohort 1: Ustekinumab-Multi-dose Phase 2</title>
          <description>Single dose of 270mg ustekinumab subcutaneously then follow up doses of 90 mg ustekinumab subcutaneously at week 8, week 16, week 24, week 32, and week 40</description>
        </group>
        <group group_id="E3">
          <title>Cohort 2: Ustekinumab-Multi-dose Phase 2</title>
          <description>Single dose of 270mg ustekinumab subcutaneously then follow up doses of 90 mg ustekinumab subcutaneously at week 8, week 16, week 24, week 32, and week 40</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Gastritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Respiratory syncytial virus infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Neuropathy peripheral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Iron deficiency anaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Lymph node pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Splenomegaly</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Ear pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eye irritation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Haematochezia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Haemorrhoids</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Parotid gland enlargement</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Portal hypertensive gastropathy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Rectal tenesmus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Varices oesophageal</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Injection site pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Oedema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Peripheral swelling</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Swelling</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Tenderness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Acute sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Bacterial vaginosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Campylobacter infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Clostridium difficile infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Enterovirus infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Gastroenteritis Escherichia coli</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Gastroenteritis salmonella</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Gastrointestinal bacterial overgrowth</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Oral herpes</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Respiratory syncytial virus infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Arthropod bite</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Injury</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Muscle strain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Alpha-1 anti-trypsin increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Blood 1,25-dihydroxycholecalciferol increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Blood alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Blood chloride increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Blood copper decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Blood glucose decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Blood glucose increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Blood iron decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Blood lactate dehydrogenase</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Blood urea increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Blood zinc decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Body temperature increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>C-reactive protein increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Clostridium test positive</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Electrocardiogram abnormal</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Epstein-Barr virus test positive</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Faecal calprotectin increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Faecal fat increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>False positive investigation result</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Gamma-glutamyltransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Haematocrit decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>International normalised ratio increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Norovirus test positive</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Prothrombin time prolonged</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Prothrombin time shortened</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Red blood cell count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Vitamin B6 increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>White blood cells urine positive</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Gout</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Hyperphosphataemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Hyperuricaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Hypoalbuminaemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Hypocalcaemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Hypomagnesaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Hypoproteinaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Vitamin B6 deficiency</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Vitamin E deficiency</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Carpal tunnel syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Hemiparesis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Neuropathy peripheral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Radiculopathy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Nightmare</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Breast mass</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Pelvic pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Rhinorrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Sinus pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Throat irritation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Upper-airway cough syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash pruritic</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Skin disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Fuss, Ivan</name_or_title>
      <organization>NIAID - LCIM</organization>
      <phone>+1 301 496 9663</phone>
      <email>ifuss@niaid.nih.gov</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02199496
org study id: 140153
secondary id: 14-I-0153
nct id: NCT02199496
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
Background:

      - Some people with Common Variable Immunodeficiency Disease (CVID) have gastrointestinal
      inflammation. This can cause diarrhea, weight loss, and not being able to absorb nutrition
      from food. Researchers want to see if the drug ustekinumab can help these problems. This drug
      blocks some proteins that cause inflammation.

      Objective:

      - To test the safety and efficacy of the drug ustekinumab for people with CVID with
      gastrointestinal inflammation.

      Eligibility:

      - Adults ages 18-75 with CVID. They must have chronic diarrhea, have unintentionally lost
      weight in the last year, and/or need to use nutritional supplements to maintain their weight.

      Design:

      Participants will undergo the following screening studies to make sure that this study is a
      good fit for your medical situation, and to make sure it is safe for you to receive the study
      medications tests, including tests for HIV and hepatitis . This will be done as an inpatient
      at the NIH Clinical Center and takes about 5-6 days:

        -  Participants will be screened with:

        -  Medical history

        -  Physical exam

        -  Blood tests, including tests for HIV and hepatitis.

        -  Stool tests, including a timed 48 hour collection for fat malabsorption and a 24 hour
           collection for protein malabsorption

        -  Urine tests, including a pregnancy test for any women with the ability to have a child

        -  Chest CT scan to look for infection

        -  D-xylose testing, which involves drinking a sugary solution and then having a blood
           sample drawn to test carbohydrate (sugar) malabsorption

        -  Hydrogen breath testing for test for small intestinal bacterial overgrowth (SIBO) this
           test also involves drinking a sugary solution and then collecting breath samples

        -  Upper endoscopy (EGD) and/or colonoscopy to look at the lining of the GI tract and take
           biopsies for testing. This will be done under sedation by a qualified
           gastroenterologist.

      Participants who complete screening and meet all criteria will then return to the NIH
      Clinical Center for the following visits:

        -  First Treatment Visit (1 clinic day): Medical history, physical exam, measurement of
           vital signs and weight, review of medications, and an assessment of number and
           consistency of stools each day. A pregnancy test for women of childbearing potential. A
           nurse will give you three shots of 90 mg ustekinumab (270 mg total dose) by very small
           needles injected under the skin, and then observe you for 1 hour.

        -  Week 8 Treatment Visit (1 clinic day): Medical history, physical exam, measurement of
           vital signs and weight, review of medications, and an assessment of number and
           consistency of stools each day. Blood, urine and stool samples will be collected. A
           pregnancy test for women of childbearing potential. A nurse will give you one 90 mg dose
           of ustekinumab by a very small needle injected under the skin, and then observe you for
           1 hour.

        -  Week 16 Treatment Visit (1 clinic day): Medical history, physical exam, measurement of
           vital signs and weight, review of medications, and an assessment of number and
           consistency of stools each day. Blood, urine and stool samples will be collected. A
           pregnancy test for women of childbearing potential. A nurse will give you one 90 mg dose
           of ustekinumab by a very small needle injected under the skin, and then observe you for
           1 hour.

        -  Week 24 Treatment and Mid-point Evaluation Visit (4-6 inpatient days): Medical history,
           physical exam, measurement of vital signs and weight, review of medications, and an
           assessment of number and consistency of stools each day. Blood, urine and stool samples
           will be collected, including repeating the d-xylose carbohydrate malabsorption testing,
           the 24 hour stool collection for protein malabsorption and the 48 hour stool collection
           for fat malabsorption. A pregnancy test for women of childbearing potential. A nurse
           will give you one 90 mg dose of ustekinumab by a very small needle injected under the
           skin, and then observe you for 1 hour.

        -  Week 32 Treatment Visit: Medical history, physical exam, measurement of vital signs and
           weight, review of medications, and an assessment of number and consistency of stools
           each day. Blood, urine and stool samples will be collected. A pregnancy test for women
           of childbearing potential. A nurse will give you one 90 mg dose of ustekinumab by a very
           small needle injected under the skin, and then observe you for 1 hour.

        -  Week 40 Treatment Visit: Medical history, physical exam, measurement of vital signs and
           weight, review of medications, and an assessment of number and consistency of stools
           each day. Blood, urine and stool samples will be collected. A pregnancy test for women
           of childbearing potential. A nurse will give you one 90 mg dose of ustekinumab by a very
           small needle injected under the skin, and then observe you for 1 hour.

        -  Week 48 ...
The purpose of this study is to assess the safety/tolerability and efficacy of using
      ustekinumab in subjects with common variable immunodeficiency CVID or selective IgG subclass
      deficiency (functional agammaglobulinemia) who have associated symptomatic gastrointestinal
      inflammation (CVID enteropathy). Ustekinumab (a Food and Drug Administration [FDA] approved
      drug) is a monoclonal antibody to interleukin (IL)-12/23p40. CVID is a clinically
      heterogeneous disorder characterized by decreased serum immunoglobulin IgG and IgA levels. In
      addition to chronic or recurrent pyogenic sino-pulmonary infections, many patients develop
      non-infectious gastrointestinal manifestations that can be disabling or fatal. Currently
      there is no standard therapy for the associated gastrointestinal disease outside of empiric
      nutritional intervention for weight loss, anti-diarrheal agents, and non-specific
      anti-inflammatory agents.

      Recently, gut inflammation complicating functional hypogammaglobulinemia due to CVID and
      selective IgG subclass deficiency has been characterized as a T helper type 1 (Th1)
      inflammatory response, with excess IL-12 cytokine production associated with diarrhea and
      weight loss as well as reduced D-xylose absorption and steatorrhea. This protocol aims to
      test specific anti-IL-12 therapy in this patient group. It has been previously shown that
      therapy targeted to IL-12 successfully treated the Th1 gut inflammation of Crohn s disease
      (CD). Ustekinumab, a monoclonal antibody to the p40 subunit of IL-12 and IL-23, is FDA
      approved for the treatment of moderate to severe plaque psoriasis, active psoriatic
      arthritis, and more recently, moderately to severely active CD. This protocol is designed to
      measure the safety of ustekinumab in patients with functional hypogammaglobulinemia and CVID
      enteropathy, as well as measure effects on symptoms, gut function, expression of immune cell
      surface markers, production of cytokines and global gene expression from blood and gut
      mucosal mononuclear cells, and the gut microbiota.

      Patients with CVID and selective IgG subclass deficiency with gastrointestinal symptoms of
      malabsorption, maldigestion, and chronic diarrhea will be enrolled into this study. Subjects
      (up to a total of 10 individuals) will receive a treatment dose of 270 mg (3 doses of 90 mg
      either single-use prefilled syringe or single-use vial, depending on availability) will be
      injected subcutaneously in subjects by qualified nursing staff on the Day 0 study visit.
      Subjects will then receive a follow up treatment dose of 90 mg at Week 8, Week 16, Week 24,
      Week 32 and Week 40 and be followed for a total of 48 weeks.

      Subjects will have study procedures prior to treatment and 48 weeks post-treatment, these
      include upper and/or lower endoscopies, to measure changes in immune responses and studies to
      evaluate physiologic measures of gut function at 48 weeks, as well as routine safety
      monitoring throughout the study. Gut absorption tests will be performed at the Week 24 visit.
      Variables will include safety (adverse event rate), clinical (weight, stool frequency,
      results of gut absorption tests), and laboratory (lymphocyte and cytokine assays) parameters
      for descriptive summary statistical analysis (n, mean, median, standard deviation, minimum
      and maximum range).
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Increase in Infection or Serious Adverse Events (SAEs) Related to Single Dose Administration of Ustekinumab
time frame: 6 months
description: Whether treatment with ustekinumab is safe and tolerated in patients with common variable immunodeficiency (CVID) enteropathy as determined by no significant increase in infection or serious adverse events
measure: Number of Participants With Increase in Infection or Serious Adverse Events (SAEs) Related to Multi-dose Administration of Ustekinumab (Cohort 1)
time frame: 48 weeks
description: Whether treatment with ustekinumab is safe and tolerated in patients with common variable immunodeficiency (CVID) enteropathy as determined by no significant increase in infection or serious adverse events
measure: Number of Participants With Increase in Infection or Serious Adverse Events (SAEs) Related to Multi-dose Administration of Ustekinumab (Cohort 2)
time frame: 48 weeks
description: Whether treatment with ustekinumab is safe and tolerated in patients with common variable immunodeficiency (CVID) enteropathy as determined by no significant increase in infection or serious adverse events
arm group label: Cohort 1: Ustekinumab-Single-dose Phase 1, Multi-dose Phase 2
arm group type: Experimental
description: Subjects given an induction dose of 270 mg Stelara (ustekinumab) subcutaneously then re-enrolled into the multi-dose phase. In multi-dose phase, subjects given an induction dose of 270 mg Stelara (ustekinumab) subcutaneously followed by every 8 week maintenance doses of 90 mg Stelara (ustekinumab) subcutaneously at week 8, week 16, week 24, week 32, and week 40
arm group label: Cohort 2: Ustekinumab-Multi-dose Phase 2
arm group type: Experimental
description: Subjects given an induction dose of 270 mg Stelara (ustekinumab) subcutaneously followed by every 8 week maintenance doses of 90 mg Stelara (ustekinumab) subcutaneously at week 8, week 16, week 24, week 32, and week 40
intervention type: Biological
intervention name: Stelara (ustekinumab)
description: In the single-phase part of the study, subjects receive a single dose of Stelara (ustekinumab) 270 mg subcutaneously on Day 0 study visit.
In the multi-phase part of the study, subjects receive single dose of Stelara (ustekinumab) 270 mg subcutaneously on Day 0 study visit with follow up dose of Stelara (ustekinumab) 90 mg subcutaneously at Week 8, Week 16, Week 24, Week 32 and Week 40
arm group label: Cohort 1: Ustekinumab-Single-dose Phase 1, Multi-dose Phase 2
arm group label: Cohort 2: Ustekinumab-Multi-dose Phase 2
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Ivan J Fuss, M.D.
role: Principal Investigator
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-I-0153.html
description: NIH Clinical Center Detailed Web Page
citation: Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999 Jul;92(1):34-48. doi: 10.1006/clim.1999.4725.
PMID: 10413651
citation: Sandborn WJ, Gasink C, Gao LL, Blank MA, Johanns J, Guzzo C, Sands BE, Hanauer SB, Targan S, Rutgeerts P, Ghosh S, de Villiers WJ, Panaccione R, Greenberg G, Schreiber S, Lichtiger S, Feagan BG; CERTIFI Study Group. Ustekinumab induction and maintenance therapy in refractory Crohn's disease. N Engl J Med. 2012 Oct 18;367(16):1519-28. doi: 10.1056/NEJMoa1203572.
PMID: 23075178
citation: Mannon PJ, Fuss IJ, Dill S, Friend J, Groden C, Hornung R, Yang Z, Yi C, Quezado M, Brown M, Strober W. Excess IL-12 but not IL-23 accompanies the inflammatory bowel disease associated with common variable immunodeficiency. Gastroenterology. 2006 Sep;131(3):748-56. doi: 10.1053/j.gastro.2006.06.022.
PMID: 16952544
responsible party type: Sponsor
mesh term: Intestinal Diseases
mesh term: Common Variable Immunodeficiency
mesh term: Inflammation
mesh term: Ustekinumab
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 