Study of Safety, Tolerability, and Efficacy of Ustekinumab for Symptomatic Gastrointestinal Inflammation Associated With Common Variable Immunodeficiency

NCT02199496 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 14015314-I-0153
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief 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 ...

Conditions

Gastrointestinal Inflammation Associated With CVID; CVID Enteropathy

Keywords

Malabsorption; Enteropathy; Diarrhea; IL-12

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Increase in Infection or Serious Adverse Events (SAEs) Related to Single Dose Administration of Ustekinumab

  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

  6 months

• Number of Participants With Increase in Infection or Serious Adverse Events (SAEs) Related to Multi-dose Administration of Ustekinumab (Cohort 1)

  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

  48 weeks

• Number of Participants With Increase in Infection or Serious Adverse Events (SAEs) Related to Multi-dose Administration of Ustekinumab (Cohort 2)

  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

  48 weeks

Study Arms (2)

Cohort 1: Ustekinumab-Single-dose Phase 1, Multi-dose Phase 2

EXPERIMENTAL

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

Biological: Stelara (ustekinumab)

Cohort 2: Ustekinumab-Multi-dose Phase 2

EXPERIMENTAL

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

Biological: Stelara (ustekinumab)

Interventions

Stelara (ustekinumab) BIOLOGICAL

* 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

Cohort 1: Ustekinumab-Single-dose Phase 1, Multi-dose Phase 2; Cohort 2: Ustekinumab-Multi-dose Phase 2

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Malabsorption Syndromes; Intestinal Diseases; Diarrhea

Interventions

Ustekinumab

Condition Hierarchy (Ancestors)

Gastrointestinal Diseases; Digestive System Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Signs and Symptoms, Digestive; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Fuss, Ivan
• Organization: NIAID - LCIM

ifuss@niaid.nih.gov

+1 301 496 9663

Study Officials

• Ivan J Fuss, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 23, 2014
• First Posted: July 24, 2014
• Study Start: October 19, 2015
• Primary Completion: August 16, 2019
• Study Completion: July 10, 2020
• Last Updated: August 24, 2020
• Results First Posted: August 24, 2020

Record last verified: 2020-07

Locations

US (1)