Study of Safety, Tolerability, and Efficacy of Ustekinumab for Symptomatic Gastrointestinal Inflammation Associated With Common Variable Immunodeficiency
Study of Safety, Tolerability, and Efficacy of Ustekinumab for Symptomatic Gastrointestinal Inflammation Associated With Common Variable Immunodeficiency
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).
-  DIAGNOSIS AND CRITERIA FOR INCLUSION:

 A subject is eligible for the study if all of the following criteria are met:

 -  Has given written informed consent.

 -  Is male or female aged 18 through 75 years.

 -  Has CVID or selective IgG subclass deficiency of either one or concomitant IgG
 subclasses comprising IgG1, IgG2, IgG3 or IgG4 (functional hypogammaglobulinemia)
 diagnosed prior to screening as based on the International Union of Immunological
 Societies (IUIS) criteria.

 -  Has a documented, unintended loss of >5% of their body weight over the last year or
 requires nutritional supplements to maintain his/her body weight and/or has chronic
 diarrhea defined as a complaint of at >/= 50% of stools are non-formed for at least 4
 consecutive weeks per patient history. Alternately, must be dependent on a therapeutic
 dose of antidiarrheals (e.g., loperamide or diphenoxylate with atropine) for control
 of chronic diarrhea.

 -  If taking oral antibiotics chronically, must have used a stable dose of the antibiotic
 continuously for at least 2 weeks prior to start of screening period.

 -  Is willing to have samples stored.

 -  Be willing to consistently take appropriate measures to avoid pregnancy through the
 Week 48 study point. All subjects will be informed of the potential risks of
 ustekinumab during pregnancy and counseled on pregnancy avoidance appropriate to the
 subject s circumstances (e.g. fertility status, medical contraindications to hormonal
 birth control, and/or personal or religious beliefs regarding pregnancy avoidance).
 Subject to the judgment and discretion of the PI, some subjects may not need to take
 pregnancy

 avoidance measures. Patient handout on pregnancy avoidance will be provided to patients at
 the time of consent and discussion regarding pregnancy avoidance during the study.

 -Subjects who have previously been treated with a single 270 mg dose of ustekinumab on this
 study must be greater than 6 months from their treatment dose and have had recurrence of
 enteropathy symptoms.

 CRITERIA FOR EXCLUSION:

 A subject is excluded from the study if any of the following criteria are met:

 GENERAL CRITERIA:

 -  Has any clinically significant disease or condition (e.g., renal, hepatic,
 neurological, cardiovascular, pulmonary, endocrinologic, psychiatric, hematologic,
 urologic, or other acute or chronic illness) that in the opinion of the investigator
 would make the subject an unsuitable candidate for this trial, or put the subject at
 undue risk by participating in this study.

 -  Is a woman who has a positive pregnancy test or who is breast-feeding

 -  Is a woman who does not agree to abide by the contraceptive measures required to
 prevent pregnancy during participation in the study, or meets exemption criteria for
 contraceptive measures, as outlined in the protocol.

 -  Has any of the following clinical chemistry values:

 -  AST >2.5 times upper limit of normal (ULN).

 -  ALT >2.5 times ULN.

 -  Serum bilirubin >1.5 times ULN.

 -  Serum creatinine >1.5 times ULN.

 -  Alkaline phosphatase >2.5 times ULN.

 -  Has a hemoglobin level <9 g/dL or hematocrit <30%.

 -  Has an International Normalized Ratio (INR) >1.3 or a Partial Thromboplastin Time
 (PTT) >3 sec of ULN.

 -  Has the following cell counts (cells/microL):

 -  Platelet count <75,000 or >800,000.

 -  White blood cell count <2,000.

 -  Neutrophil count <1,000.

 -  Has a current infection requiring intravenous antibiotics, a serious local infection
 (e.g., cellulitis, abscess) or systemic infection (e.g., pneumonia, septicemia).

 -  Has a history of cancer within the past 5 years, with the exception of excised basal
 cell carcinoma, squamous cell carcinoma of the skin, or cervical carcinoma in situ.

 -  Had a dependency for any illicit drug, chemical, or alcohol within the past 5 years.

 -  Has a history of active tuberculosis (TB) (or a chest x-ray (CXR) with findings
 suggestive of old TB infection including calcified nodular lesions, apical fibrosis,
 or pleural scarring), acute or chronic hepatitis B, hepatitis C, human
 immunodeficiency virus (HIV) or opportunistic infections.

 GASTROINTESTINAL CRITERIA

 -Has a stool sample determined positive for acute gastrointestinal infection with impact of
 occurrence on gastrointestinal inflammation as determined by principal investigator during
 screening. In addition, stool samples positive for GI pathogens will be discussed with an
 infectious disease physician to determine impact of occurrence on gastrointestinal
 inflammation. If organism thought to be pathogenic, the subject will be treated with
 appropriate therapy. This will be documented in the subject s medical record.

 PRIOR MEDICATION CRITERIA

 -  Received daily corticosteroids within 1 month prior to receiving study agent. The use
 of short-term or single-dose corticosteroids as a pretreatment regimen for IVIG is
 acceptable.

 -  Received any investigational drug within 3 months prior to receiving study agent.

 -  Received certolizumab or natalizumab within 3 months prior to receiving study agent

 -  Received vedolizumab, infliximab, etanercept, or adalimumab within 2 months prior to
 receiving study agent.

 -  Received cyclosporine, tacrolimus, sirolimus, pimecrolimus, mycophenolate mofetil or
 any other systemic immunosuppressants within 1 month prior to receiving study agent.