Infliximab to Treat Crohn'S-like Inflammatory Bowel Disease in Chronic Granulomatous Disease

Tumor Necrosis Factor Alpha Inhibitor (Lnfliximab, Adalimumab) Treatment for Crohn'S-like Inflammatory Bowel Disease in Chronic Granulomatous Disease: A Phase I/II Study Assessing Clinical and Immune Responses to Treatment and Genetic Influences

This study will determine if the drug infliximab is safe for treating inflammatory bowel disease (IBD) in patients with chronic granulomatous disease (CGD). IBD is an inflammation or irritation of the gut that leads to symptoms such as diarrhea, bloating and stomach cramps. CGD is an inherited disease affecting white blood cells called neutrophils in which patients are susceptible to repeated bacterial and fungal infections. They also have a higher incidence of some autoimmune diseases, such as IBD. Infliximab is approved to treat Crohn's disease, an IBD similar to that seen in patients with CGD.

Patients 10 years of age and older with CGD and IBD may be eligible for this study. Candidates are screened with a medical history, physical examination, blood and urine tests, electrocardiogram (EKG), tuberculosis skin test (PPD skin testing), and stool test for the presence of infections. Additional tests may be done, including colonoscopy (procedure using a flexible tube through the rectum to examine the lining of the gut) and imaging studies such as an x-ray, chest CT scan (test using a special x-ray machine), MRI (test using a magnetic field and radio waves), and barium studies (study using a drinkable solution of barium to help enhance the x-ray pictures of the gut).

Participants are divided into patients with IBD symptoms (Group 1) and patients without IBD symptoms (Group 2) for the following procedures:

Group 1

Patients are evaluated every 6 months with a medical history and physical examination for signs and symptoms of IBD. Patients who are taking moderate to high doses of steroid medications have their medication slowly lowered (tapered) and are evaluated every 3 months for a total of 2 years. Patients in this group who start to develop IBD symptoms are moved to Group 2 for treatment with infliximab (see below).

Group 2

Patients in Group 2 receive infliximab infusions at 2-week intervals for three doses. The drug is given over a 2-hour period through a catheter placed in a vein. Patients are evaluated with a medical history, physical exam, and blood tests the day of each dose. One week after the last dose, they have another evaluation, including a colonoscopy. Patients who respond well to infliximab may continue to receive the drug every 2 months for a total of 1 year, with evaluations at every dosing visit. At the end of the first year of receiving infliximab, all patients have follow-up evaluations every 6 months for a total of 2 years.

Group 3

Subjects who volunteer to undergo colonoscopy and research biopsies that serve as controls for evaluation of the patient gut samples.

Study Overview

• Status: Terminated
• Conditions: Chronic Granulomatous Disease; Inflammatory Bowel Disease (IBD); Crohn'S-like IBD
• Intervention / Treatment: Drug: Infliximab

Detailed Description

Chronic Granulomatous Disease (CGD) is an inherited immune disorder involving decreased phagocytic superoxide oxygen radical production, resulting in increased susceptibility to infections. Furthermore, there is a predominance of immune-related inflammatory problems in a subset of CGD patients, such as the inflammatory bowel disease (CGD-IBD). CGD-IBD is often complicated by obstruction, strictures, fissures, fistulae, and extra-intestinal problems. In fact, it is clinically and histologically indistinguishable from Crohn's Disease (CD), another inflammatory bowel disease that affects the general population. Crohn's disease (CD) is a prototypic T helper cell type 1 (Th1) immune disease. Since CGD-IBD bears such close resemblance to CD, it is possible that CGD-IBD is also immune-based. Furthermore, mice studies also support a primarily immune basis for CGD-IBD. However, currently there is little data on this Crohn's-like CGD-IBD in human patients. Treatment for the Crohn's-like CGD-IBD has been primarily oral or topical corticosteroids. Antibiotics have been ineffective and stool cultures typically do not identify clear pathogens. Many patients with the Crohn's-like CGD-IBD disease remain steroid-dependent, thus new therapeutic regimens are needed.

This is a Phase I/II study that will evaluate the safety and efficacy of Tumor Necrosis Factor Alpha Inhibitor (Infliximab or Adalimumab) in CGD patients with symptomatic Crohn's-like IBD. Infliximab and Adalimumab are standard-of-care treatments for moderate to severe CD, with extensive experience using these agents being well documented in terms of safety and efficacy. Preliminary reports from ongoing studies of CD at NIH are encouraging in inducing remission. We will also evaluate changes in immunophenotype and cytokine profiles of peripheral blood and colonic lamina propria lymphocytes following treatment. In addition, we will evaluate the immunophenotype and cytokine profile of blood and mucosal cells in CGD patients, with or without IBD, to determine the CGD-specific cytokine profile. Specific cytokine profiles have been observed in different genetic immunodeficiencies, despite similar IBD clinical manifestation.

Documentation of clinical status will be performed using the Crohn's Disease Activity Index (CDAI). Potential effects of genetic variation (including CGD mutation type) on the expression of IBD in patients with CGD, and their responses to treatment will also be assessed. The long-term goal of this study is to establish better or alternative treatment modalities with low risk profiles for CGD patients with Crohn's-like IBD.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:

Group One

• Must have a confirmed CGD diagnosis
• Must have IBD documented by medical history or documented IBD endoscopically.
• Must not be pregnant or breastfeeding
• Must have a home physician
• Must be willing to submit samples for storage.

Group Two:

• Must have a confirmed CGD diagnosis
• Must have IBD documented by medical history or documented IBD endoscopically.
• Must be symptomatic
• Must have negative results on stool examination for culture of enteric pathogens, such as Salmonella, Shigella, Yersinia, Campylobacter, E. coli O157/H7, Clostridium difficile toxin assay, enteric parasites and their ova such as Cryptosporidia, Cyclospora, Microsporidia and Giardia (by stool enzyme immunoassay [EIA]) prior to the start of receiving TNF? inhibitors.
• Must not be pregnant or breastfeeding
• If of childbearing potential, one must agree to consistently use contraception, while on the study medication.
• Must have a recent chest CT (within 3 months) to confirm absence of tuberculosis (TB) infection
• Must have a home physician
• Must be willing to submit samples for storage.

Group Three:

• Must be willing to undergo upper and lower endoscopy and mucosal biopsies for research purpose
• Must be greater than or equal to 18 years old and weigh greater than or equal to 15 kg.
• Must not be pregnant
• Must be willing to submit samples for storage.

EXCLUSION CRITERIA:

Group One:

- Any condition that, in the investigator's opinion, places the patient at undue risk by participating in the study.

Group Two:

• Any condition that, in the investigator's opinion, places the patient at undue risk by participating in the study
• Positive TB diagnosis
• Patients who are in the at-risk group for treatment such as history of tuberculosis, congestive cardiac failure or myocardial infarction within the last 12 months unstable angina, thrombocytopenia (platelet < 100, 000), uncontrolled hypertension
• Acute systemic or intestinal infection(s)
• Evidence of Hepatitis B or C infection
• Signs and symptoms of hepatotoxicity
• Pregnant or breastfeeding
• History of cancer within the last 10 years
• The presence of certain types of acquired abnormalities of immunity such as HIV, cytotoxic chemotherapy for malignancy could be grounds for possible exclusion if, in the opinion of the investigator, the presence of such disease process interferes with evaluation of a co-existing abnormality of immunity that is a subject of study under this protocol.
• Co-existing Th2-type inflammatory disease
• Current active bowel obstruction, intestinal perforation, or significant GI hemorrhage.
• Live vaccine within 4 weeks prior to therapy or potential need for a live vaccine during the study.
• Unwillingness to undergo testing or procedures associated with this protocol.

Group Three:

• Acute systemic or intestinal infection requiring antibiotics
• Any condition that, in the investigator's opinion, places the patient at undue risk by participating in the study
• The presence of certain types of acquired abnormalities of immunity such as HIV, cytotoxic chemotherapy for malignancy could be grounds for possible exclusion if, in the opinion of the investigator, the presence of such disease process interferes with evaluation of a co-existing abnormality of immunity that is a subject of study under this protocol.
• Unwillingness to undergo testing or procedures associated with this protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment; Study drug (TNFa inhibitor-infliximab or adalimumab) treated group.	Drug: Infliximab
NO_INTERVENTION: Observation; Subjects with IBD without TNFa inhibitor treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety of Study Drug	Number of Infections from Baseline to 1 year	Baseline to 1 year
Efficacy of Treatment With Study Drug	Measured participant Crohn's disease Activity Index (CDAI) values. The CDAI is a tool comprised of clinical and laboratory factors such as stool frequency, consistency, abdominal pain, general well being, weight and blood profile as an objective measure of disease activity. A higher score corresponds to greater severity of inflammatory bowel disease; severe disease conventionally defined as >450, a remission as <150, and a response to treatment as a fall of CDAI of >70 points. Infections and IBD are not expected in healthy control subjects. The greater the score, the more severe the disease, and a score of less than 5 represents clinical remission.	Baseline, 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gut Immune Cell Types and Their Cytokine Profile	Gut Immune cell types and their cytokine profile	1 year

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Winkelstein JA, Marino MC, Johnston RB Jr, Boyle J, Curnutte J, Gallin JI, Malech HL, Holland SM, Ochs H, Quie P, Buckley RH, Foster CB, Chanock SJ, Dickler H. Chronic granulomatous disease. Report on a national registry of 368 patients. Medicine (Baltimore). 2000 May;79(3):155-69. doi: 10.1097/00005792-200005000-00003.
• Vignais PV. The superoxide-generating NADPH oxidase: structural aspects and activation mechanism. Cell Mol Life Sci. 2002 Sep;59(9):1428-59. doi: 10.1007/s00018-002-8520-9.
• Segal BH, Leto TL, Gallin JI, Malech HL, Holland SM. Genetic, biochemical, and clinical features of chronic granulomatous disease. Medicine (Baltimore). 2000 May;79(3):170-200. doi: 10.1097/00005792-200005000-00004.
• Buckner CM, Moir S, Kardava L, Ho J, Santich BH, Kim LJ, Funk EK, Nelson AK, Winckler B, Chairez CL, Theobald-Whiting NL, Anaya-O'Brien S, Alimchandani M, Quezado MM, Yao MD, Kovacs JA, Chun TW, Fauci AS, Malech HL, De Ravin SS. CXCR4/IgG-expressing plasma cells are associated with human gastrointestinal tissue inflammation. J Allergy Clin Immunol. 2014 Jun;133(6):1676-85.e5. doi: 10.1016/j.jaci.2013.10.050. Epub 2013 Dec 25.

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (ACTUAL): June 1, 2012
• Study Completion (ACTUAL): June 1, 2012

Study Registration Dates

• First Submitted: May 11, 2006
• First Submitted That Met QC Criteria: May 11, 2006
• First Posted (ESTIMATE): May 12, 2006

Study Record Updates

• Last Update Posted (ESTIMATE): December 29, 2015
• Last Update Submitted That Met QC Criteria: November 19, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: Inflammatory Bowel Disease; CGD; IBD; Crohn's Disease; Infliximab; Remicade; CGD Infection; Chorionic Granulomatous Disease
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Immunologic Deficiency Syndromes; Immune System Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Hematologic Diseases; Gastrointestinal Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Gastroenteritis; Leukocyte Disorders; Phagocyte Bactericidal Dysfunction; Inflammatory Bowel Diseases; Intestinal Diseases; Granuloma; Granulomatous Disease, Chronic; Antirheumatic Agents; Gastrointestinal Agents; Dermatologic Agents; Infliximab
• Other Study ID Numbers: 060160; 06-I-0160