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

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00325078
• Collaborator: (none)
• Enrollment: 40
• Location: 1
• Arms: 2
• Duration (Months): 73
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Granulomatous Disease; Crohn'S-like IBD; Inflammatory Bowel Disease (IBD)	Drug: Infliximab	Phase 1/Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: May 1, 2006
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Safety of Study Drug [Baseline to 1 year]

   Number of Infections from Baseline to 1 year

2. Efficacy of Treatment With Study Drug [Baseline, 1 year]

   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.

Other Outcome Measures

1. Gut Immune Cell Types and Their Cytokine Profile [1 year]

   Gut Immune cell types and their cytokine profile

Eligibility Criteria

Criteria

• Ages Eligible for Study: 10 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Suk S De Ravin, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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. Review.
• Vignais PV. The superoxide-generating NADPH oxidase: structural aspects and activation mechanism. Cell Mol Life Sci. 2002 Sep;59(9):1428-59. Review.
• 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.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00325078
• Other Study ID Numbers: 060160; 06-I-0160
• First Posted: May 12, 2006
• Last Update Posted: Dec 29, 2015
• Last Verified: Nov 1, 2015

• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Remicade; Crohn's Disease; IBD; CGD Infection; Infliximab; Chorionic Granulomatous Disease; CGD; Inflammatory Bowel Disease
• Additional relevant MeSH terms: Intestinal Diseases; Inflammatory Bowel Diseases; Granuloma; Granulomatous Disease, Chronic; Infliximab

Study Results

Participant Flow

Arm/Group Title	Treatment Group	Observation Group	Control Volunteer
Arm/Group Description	This group comprises patients with Chronic granulomatous disease (CGD) complicated by significant inflammatory bowel disease (IBD). The subjects are treated with a TNFa inhibitor at standard recommended doses for treatment of Crohn's disease. Infliximab is administered as intravenous infusions at 5mg/kg on weeks 0, 2 and 6 for induction and every 6-8 weeks at 5-10mg/kg for maintenance. Adalimumab is administered at 160mg, 60mg, 40mg, 40mg on weeks 0, 2, 4 and 6 via subcutaneous injection. Endoscopies and gastrointestinal mucosal biopsies are obtained before treatment, following induction, and again at completion of treatment.	CGD patients with IBD who are not treated with any study medication and are monitored for rate of infections.	Subjects who volunteer to participate in endoscopy and GI mucosal biopsies to provide controls for the study. The subjects in this arm may be healthy subjects, CGD subjects without GI symptoms, or subjects with Crohn's disease (CD). The rate of infections in the CGD patients without IBD are monitored.
Period Title: Overall Study
STARTED	8	7	25
COMPLETED	3	2	23
NOT COMPLETED	5	5	2

Baseline Characteristics

Arm/Group Title	Treatment Group	Observation Group	Control Volunteer	Total
Arm/Group Description	This group comprises patients with Chronic granulomatous disease (CGD) complicated by significant inflammatory bowel disease (IBD). The subjects are treated with a TNFa inhibitor at standard recommended doses for treatment of Crohn's disease. Infliximab is administered as intravenous infusions at 5mg/kg on weeks 0, 2 and 6 for induction and every 6-8 weeks at 5-10mg/kg for maintenance. Adalimumab is administered at 160mg, 60mg, 40mg, 40mg on weeks 0, 2, 4 and 6 via subcutaneous injection. Endoscopies and gastrointestinal mucosal biopsies are obtained before treatment, following induction, and again at completion of treatment.	CGD patients with IBD who are not treated with any study medication and are monitored for rate of infections.	Subjects who volunteer to participate in endoscopy and GI mucosal biopsies to provide controls for the study. The subjects in this arm may be healthy subjects, CGD subjects without GI symptoms, or subjects with Crohn's disease (CD). The rate of infections in the CGD patients without IBD are monitored.	Total of all reporting groups
Overall Participants	8	7	25	40
Age (Count of Participants)
<=18 years	1 12.5%	3 42.9%	0 0%	4 10%
Between 18 and 65 years	7 87.5%	4 57.1%	25 100%	36 90%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	1 12.5%	0 0%	6 24%	7 17.5%
Male	7 87.5%	7 100%	19 76%	33 82.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 14.3%	2 8%	3 7.5%
Not Hispanic or Latino	8 100%	6 85.7%	22 88%	36 90%
Unknown or Not Reported	0 0%	0 0%	1 4%	1 2.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	1 4%	1 2.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	6 24%	6 15%
White	8 100%	6 85.7%	15 60%	29 72.5%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	1 14.3%	3 12%	4 10%

Outcome Measures

1. Primary Outcome

Title	Safety of Study Drug
Description	Number of Infections from Baseline to 1 year
Time Frame	Baseline to 1 year

Outcome Measure Data

Analysis Population Description

The volunteer group includes patients with chronic granulomatous disease as well as healthy normal volunteers as controls. Infection rates only pertain to and are counted in subjects with underlying immunodeficiency (chronic granulomatous disease).

Arm/Group Title	Treatment	Observation	Control Volunteers
Arm/Group Description	This group comprises patients with Chronic granulomatous disease (CGD) complicated by significant inflammatory bowel disease (IBD). The subjects are treated with a TNFa inhibitor at standard recommended doses for treatment of Crohn's disease. Infliximab is administered as intravenous infusions at 5mg/kg on weeks 0, 2 and 6 for induction and every 6-8 weeks at 5-10mg/kg for maintenance. Adalimumab is administered at 160mg, 60mg, 40mg, 40mg on weeks 0, 2, 4 and 6 via subcutaneous injection. Endoscopies and gastrointestinal mucosal biopsies are obtained before treatment, following induction, and again at completion of treatment.	Subjects with IBD without TNFa inhibitor treatment	Subjects who volunteer to participate in endoscopy and GI mucosal biopsies to provide controls for the study. The subjects in this arm may be healthy subjects, CGD subjects without GI symptoms, or subjects with Crohn's disease (CD). The rate of infections in the CGD patients without IBD are monitored.
Measure Participants	8	7	8
Number [infections]	5	4	13

2. Primary Outcome

Title	Efficacy of Treatment With Study Drug
Description	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.
Time Frame	Baseline, 1 year

Outcome Measure Data

Analysis Population Description

All participants in the Treatment and Observation Arms with collected CDAI data. The CDAI, a tool validated for Crohn's disease is not applicable to healthy donors or CGD patients without IBD, and therefore not measured in the Control participants.

Arm/Group Title	Treatment	Observation
Arm/Group Description	This group comprises patients with Chronic granulomatous disease (CGD) complicated by significant inflammatory bowel disease (IBD). The subjects are treated with a TNFa inhibitor at standard recommended doses for treatment of Crohn's disease. Infliximab is administered as intravenous infusions at 5mg/kg on weeks 0, 2 and 6 for induction and every 6-8 weeks at 5-10mg/kg for maintenance. Adalimumab is administered at 160mg, 60mg, 40mg, 40mg on weeks 0, 2, 4 and 6 via subcutaneous injection. Endoscopies and gastrointestinal mucosal biopsies are obtained before treatment, following induction, and again at completion of treatment.	CGD patients with IBD who are not treated with any study medication and are monitored for rate of infections.
Measure Participants	5	5
CDAI Value #1 at Baseline	114.4	17.5
CDAI Value #2 at Baseline	191	22.5
CDAI Value #3 at Baseline	329.8	53
CDAI Value #4 at Baseline	505.2	159
CDAI Value #5 at Baseline	516	266.7
CDAI Value #1 at 1 year	95.5	NA
CDAI Value #2 at 1 year	138	NA
CDAI Value #3 at 1 year	185.4	NA
CDAI Value #4 at 1 year	259.2	NA
CDAI Value #5 at 1 year	295.2	NA

3. Other Pre-specified Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Adverse Event Reporting Description	The adverse events reported only relate to events occurring following study drug (TNFa inhibitors) treatment. Group 3 subjects who volunteered for endoscopy/gut biopsies are terminated at completion of the procedure. Baseline infections in endoscopy volunteers are not reported as adverse events.
Arm/Group Title	Treatment Group		Observation Group		Control Volunteer
Arm/Group Description	This group comprises patients with Chronic granulomatous disease (CGD) complicated by significant inflammatory bowel disease (IBD). The subjects are treated with a TNFa inhibitor at standard recommended doses for treatment of Crohn's disease. Infliximab is administered as intravenous infusions at 5mg/kg on weeks 0, 2 and 6 for induction and every 6-8 weeks at 5-10mg/kg for maintenance. Adalimumab is administered at 160mg, 60mg, 40mg, 40mg on weeks 0, 2, 4 and 6 via subcutaneous injection. Endoscopies and gastrointestinal mucosal biopsies are obtained before treatment, following induction, and again at completion of treatment.		CGD patients with IBD who are not treated with any study medication and are monitored for rate of infections.		Subjects who volunteer to participate in endoscopy and GI mucosal biopsies to provide controls for the study. The subjects in this arm may be healthy subjects, CGD subjects without GI symptoms, or subjects with Crohn's disease (CD). The rate of infections in the CGD patients without IBD are monitored.
All Cause Mortality
	Treatment Group		Observation Group		Control Volunteer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Treatment Group		Observation Group		Control Volunteer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/8 (25%)		0/7 (0%)		0/25 (0%)
Infections and infestations
lung infection	1/8 (12.5%)		0/7 (0%)		0/25 (0%)
Nervous system disorders
Nervous system disorders - drug overdose	1/8 (12.5%)		0/7 (0%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	Treatment Group		Observation Group		Control Volunteer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/8 (37.5%)		1/7 (14.3%)		0/25 (0%)
Gastrointestinal disorders
diarrhea (clostridium diff)	1/8 (12.5%)		0/7 (0%)		0/25 (0%)
General disorders
Infusion related reaction	2/8 (25%)		0/7 (0%)		0/25 (0%)
Surgical and medical procedures
Infections and infestations, IV line infection	0/8 (0%)		1/7 (14.3%)		0/25 (0%)

Limitations/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.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.