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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


Phase 1/Phase 2
10 Years
N/A
Not Enrolling
Both
Chronic Granulomatous Disease, Crohn'S-like IBD, Inflammatory Bowel Disease (IBD)

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Trial Information

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


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.

Inclusion Criteria


- 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.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine whether treatment with infliximab is safe in CGD patients and does not cause a significant increase in serious infections.

Safety Issue:

Yes

Principal Investigator

Caryn G Morse, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Institutes of Health Clinical Center (CC)

Authority:

United States: Federal Government

Study ID:

060160

NCT ID:

NCT00325078

Start Date:

May 2006

Completion Date:

June 2012

Related Keywords:

  • Chronic Granulomatous Disease
  • Crohn'S-like IBD
  • Inflammatory Bowel Disease (IBD)
  • Remicade
  • Crohn's Disease
  • IBD
  • CGD Infection
  • Infliximab
  • Chorionic Granulomatous Disease
  • CGD
  • Inflammatory Bowel Disease
  • Crohn Disease
  • Granulomatous Disease, Chronic
  • Inflammatory Bowel Diseases
  • Intestinal Diseases
  • Granuloma

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892