Infliximab to Treat Crohn'S-like Inflammatory Bowel Disease in Chronic Granulomatous Disease
| Status: | Terminated |
|---|---|
| Conditions: | Irritable Bowel Syndrome (IBS), Gastrointestinal |
| Therapuetic Areas: | Gastroenterology |
| Healthy: | No |
| Age Range: | 10 - Any |
| Updated: | 4/21/2016 |
| Start Date: | May 2006 |
| End Date: | June 2012 |
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.
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.
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.
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:
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.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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