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| Sponsored by: |
National Institute of Allergy and Infectious Diseases (NIAID) |
|---|---|
| Information provided by: | National Institutes of Health Clinical Center (CC) |
| ClinicalTrials.gov Identifier: | NCT00325078 |
Purpose
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 o...
| Condition | Intervention | Phase |
|---|---|---|
|
Chronic Granulomatous Disease Crohn's-Like IBD Inflammatory Bowel Disease (IBD) |
Drug: Infliximab |
Phase I |
| Study Type: | Interventional |
| Study Design: | Treatment, Safety/Efficacy Study |
| Official Title: | Infliximab 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 |
| Estimated Enrollment: | 35 |
| Study Start Date: | May 2006 |
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 infliximab (Remicade® (Registered Trademark)) in CGD patients with symptomatic Crohn's-like IBD. Infliximab is a standard-of-care treatment for CD, with extensive experience using this agent 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.
Eligibility| Ages Eligible for Study: | 10 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Group One:
Must have a confirmed CGD diagnosis by the absence of respiratory oxidative burst by a dihydrorhodamine release assay (DHR) or mutations of one of the four components of phagocytic oxidative system
Must have IBD documented by medical history or documented IBD endoscopically.
Must be asymptomatic
Must be 3 years old or older and weigh greater than or equal to 15 kg.
Must have negative results on stool examination for culture of enteric pathogens (Salmonella, Shigella, Yersinia, Campylobacter, Vibrio, E. coli O157/H7), Clostridium difficile toxin assay, enteric parasites and their ova (including Cryptosporidia, Cyclospora, Microsporidia and Giardia (by stool enzyme immunoassay [EIA]).
Must not be pregnant or breastfeeding
If of child-bearing potential, must agree to consistently use contraception throughout study participation. Acceptable forms of contraception are:
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 Two:
Must have a confirmed CGD diagnosis by the absence of respiratory oxidative burst by DHR or mutations of one of the four components of phagocytic oxidative system.
Must have IBD documented by medical history or documented IBD endoscopically.
Must have symptomatic IBD.
Must be 3 years old or older and weigh greater than or equal to 15 kg.
Must have negative results on stool examination for culture of enteric pathogens (Salmonella, Shigella, Yersinia, Campylobacter, Vibrio, E. coli O157/H7), Clostridium difficile toxin assay, enteric parasites and their ova (including Cryptosporidia, Cyclospora, Microsporidia and Giardia (by stool EIA).
Must not be pregnant or breastfeeding
If of child-bearing potential, must agree to consistently use contraception throughout study participation. Acceptable forms of contraception are:
Must have a recent chest CT (within 3 months) to confirm absence of TB infection.
Must have a home physician
Must be willing to submit samples for storage
Group Three:
Must have a confirmed CGD diagnosis by the absence of respiratory oxidative burst by a dihydrorhodamine release assay (DHR) or mutations of one of the four components of phagocytic oxidative system.
Must be greater than or equal to 18 years old and greater than or equal to 15 kg.
Must not be pregnant.
Must be willing to submit samples for storage.
EXCLUSION CRITERIA:
Group One:
Patients with positive test for HIV or signs and symptoms consistent with HIV infection
CGD patients with symptomatic IBD
Patient less than 3 years old
Weight less than 15 kg
Non-CGD patients
Pregnancy or breastfeeding
Positive TB diagnosis per CT scan
CGD patients without a history of IBD
Patients who are in the at-risk group for treatment with infliximab such as history of tuberculosis, congestive cardiac failure or unstable angina, thrombocytopenia (platelet less than 100, 000), uncontrolled hypertension
Any of the following abnormalities on an electrocardiogram: QTC greater than 0.48sec, Mobitz type II second or third degree atrioventricular block, left bundle branch block or right bundle branch block with any fascicular block, changes consistent with acute ischemia.
Severe persistent asthma defined as the presence of one of the features listed below:
Peak expiratory flow rate (PEF) or forced expiratory volume 1 (FEV1) less than 60% predicted, variability greater than 30%
Daily medications required to maintain control such as high-dose corticosteroids, long-acting bronchodilators or oral corticosteroids
Acute systemic or intestinal infection requiring antibiotics
Evidence of Hepatitis B or C infection
Signs and symptoms of hepatotoxicity
Pregnant or breastfeeding
History of cancer within the last 10 years
History of myocardial infarction within the last 12 months
Any condition that, in the investigator's opinion, places the patient at undue risk by participating in the study
History of anaphylactic reaction or hypersensitivity to Infliximab or proteins derived from E. coli.
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.
Positive TB diagnosis per CT scan
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 Two:
Patients with positive test for HIV or signs and symptoms consistent with HIV infection
Non-CGD patients
Patient less than 3 years old
Weight less than 15 kg
CGD patients with no symptoms of IBD
Patients who are in the at-risk group for treatment with infliximab such as history of tuberculosis, congestive cardiac failure or unstable angina, thrombocytopenia (platelet less than 100, 000), uncontrolled hypertension
Any of the following abnormalities on an electrocardiogram: QTC greater than 0.48sec, Mobitz type II second or third degree atrioventricular block, left bundle branch block or right bundle branch block with any fascicular block, changes consistent with acute ischemia.
Severe persistent asthma defined as the presence of one of the features listed below:
Daily medications required to maintain control such as high-dose corticosteroids, long-acting bronchodilators or oral corticosteroids
Acute systemic or intestinal infection requiring antibiotics
Evidence of Hepatitis B or C infection
Signs and symptoms of hepatotoxicity
Pregnant or breastfeeding
History of cancer within the last 10 years
History of myocardial infarction within the last 12 months
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.
Co-existing Th2-type inflammatory disease
Current active bowel obstruction, intestinal perforation, or significant GI hemorrhage.
Positive TB diagnosis per CT scan
Live vaccine within 4 weeks prior to therapy or potential need for a live vaccine during the study.
Inability or unwillingness to undergo testing or procedures associated with this protocol.
Group Three:
Patients with positive test for HIV or signs and symptoms consistent with HIV infection
Patients less than 18 years old, or weighs less than 15 kg
Pregnancy
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 of procedures associated with this protocol.
Contacts and Locations| Contact: Patient Recruitment and Public Liaison Office | (800) 411-1222 | prpl@mail.cc.nih.gov |
| Contact: TTY | 1-866-411-1010 |
| United States, Maryland | |
| National Institutes of Health Clinical Center, 9000 Rockville Pike | Recruiting |
| Bethesda, Maryland, United States, 20892 | |
More Information
| Study ID Numbers: | 060160, 06-I-0160 |
| Study First Received: | May 11, 2006 |
| Last Updated: | July 18, 2008 |
| ClinicalTrials.gov Identifier: | NCT00325078 |
| Health Authority: | United States: Federal Government |
|
Remicade Crohn's Disease IBD CGD Infection Infliximab |
Chorionic Granulomatous Disease CGD Inflammatory Bowel Disease IBD |
|
Infliximab Hematologic Diseases Gastrointestinal Diseases Inflammatory Bowel Diseases Leukocyte Disorders Intestinal Diseases Granuloma Immunologic Deficiency Syndromes Lymphatic Diseases |
Digestive System Diseases Genetic Diseases, Inborn Granulomatous Disease, Chronic Crohn Disease Genetic Diseases, X-Linked Chronic granulomatous disease Lymphoproliferative Disorders Gastroenteritis |
|
Anti-Inflammatory Agents Phagocyte Bactericidal Dysfunction Pathologic Processes Immune System Diseases Therapeutic Uses |
Gastrointestinal Agents Antirheumatic Agents Dermatologic Agents Pharmacologic Actions |
