Study of Safety, Tolerability, and Efficacy of Ustekinumab for Symptomatic Gastrointestinal Inflammation Associated With Common Variable Immunodeficiency
Condition: Gastrointestinal Inflammation Associated With CVID; CVID Enteropathy
MeSH terms: Intestinal Diseases; Common Variable Immunodeficiency; Inflammation
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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 ...
    

Detailed description: 
      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).
    

Intervention name(s): Stelara (ustekinumab)
Intervention type(s): Biological
Intervention description(s): 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
Intervention MeSH terms: Ustekinumab
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Malabsorption; Enteropathy; Diarrhea; IL-12