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

NCT00325078 | Terminated Phase 1 Results DMC

• 2 other identifiers: 06016006-I-0160
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Chronic Granulomatous Disease; Crohn'S-like IBD; Inflammatory Bowel Disease (IBD)

Keywords

Remicade; Crohn's Disease; IBD; CGD Infection; Infliximab; Chorionic Granulomatous Disease; CGD; Inflammatory Bowel Disease

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (1)

• Gut Immune Cell Types and Their Cytokine Profile

  1 year

Study Arms (2)

Treatment

EXPERIMENTAL

Study drug (TNFa inhibitor-infliximab or adalimumab) treated group.

Drug: Infliximab

Observation

NO INTERVENTION

Subjects with IBD without TNFa inhibitor treatment

Interventions

Infliximab DRUG

Treatment

Eligibility Criteria

• Age: 10 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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.

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 (4)

• 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.

  PMID: 12440767 BACKGROUND

• 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.

  PMID: 10844936 BACKGROUND

• 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.

  PMID: 10844935 BACKGROUND

• 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.

  PMID: 24373354 BACKGROUND

MeSH Terms

Conditions

Granulomatous Disease, Chronic; Inflammatory Bowel Diseases; Crohn Disease

Interventions

Infliximab

Condition Hierarchy (Ancestors)

Phagocyte Bactericidal Dysfunction; Leukocyte Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Immunologic Deficiency Syndromes; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

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

Limitations and Caveats

Due to limited subject participation and lack of sustained clinical benefits (1 year), there is insufficient complete data to generate meaningful statistics for the outcome measures. Instead, this data are reported as a case series.

Results Point of Contact

• Title: De Ravin, SukSee
• Organization: National Institute of Allergy and Infectious Diseases

sderavin@mail.nih.gov

+1 301 496 6772

Study Officials

• Suk S De Ravin, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

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

Study Record Dates

• First Submitted: May 11, 2006
• First Posted: May 12, 2006
• Study Start: May 1, 2006
• Primary Completion: June 1, 2012
• Study Completion: June 1, 2012
• Last Updated: December 29, 2015
• Results First Posted: December 29, 2015

Record last verified: 2015-11

Locations

US (1)