Effect of Ranitidine on Hyper-IgE Recurrent Infection (Job's) Syndrome

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00527878
• Collaborator: (none)
• Enrollment: 16
• Location: 1
• Arms: 2
• Duration (Months): 45
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This study will examine the safety and effectiveness of ranitidine (Zantac) in patients with Hyper-IgE recurrent infection syndrome, a disease characterized by recurrent infections of the ears, sinuses, lungs and skin, and abnormal levels of the antibody immunoglobulin E (IgE).

Patients age 2 and older who have Hyper-IgE recurrent infection syndrome and who have had chronic or frequent infections in the last 12 months may be eligible for this study.

Participants are randomly assigned to take ranitidine or placebo in pill or liquid form twice a day for 12 months. In addition to treatment, patients undergo the following procedures during visits scheduled on day 0 of the study (baseline) and at 3, 12, 15 and 24 months. Evaluations at 6, 9, 18 and 21 months are by telephone.

• Medical history and physical examination - baseline and 3 and 24 months.

• Clinical severity score - baseline and 3, 6, 9, 12, 15, 18, 21 and 24 months.

• Dermatology exam - baseline and 3, 12, 15 and 24 months.

• Pulmonary function test - baseline and 12 and 24 months.

• Chest CT - baseline and 12 and 24 months.

• Quality of life assessment - baseline and 3, 12, 15 and 24 months.

• Pregnancy testing - baseline and 3, 12, 15 and 24 months.

• HIV test - baseline and 12 and 24 months.

• Contraception evaluation - baseline and 3, 6, 9, 12, 15, 18, 21 and 24 months.

• Missed school/work days assessment - baseline and 3, 12, 15 and 24 months.

• Medication adherence - baseline and 3, 6, 9, 12, 15, 18, 21 and 24 months.

In addition to the above procedures, participants who are not enrolled in study 00-I-0159 have a baseline scoliosis series and genetic consult.

Condition or Disease	Intervention/Treatment	Phase
JOB's Syndrome; Hyper-IgE Recurrent Infection Syndrome; Immune Deficiency	Drug: Ranitidine; Drug: Placebo	Phase 2

Detailed Description

Hyper-immunoglobulin E (IgE) syndrome (HIES) is a rare primary immunodeficiency characterized by eczema, recurrent skin and lung infections, elevated serum IgE, and multiple connective tissue and skeletal abnormalities. The autosomal dominant form of HIES is caused primarily by a mutation in the STAT3 gene. Patients with HIES produce IgE antibodies specific for Candida albicans and Staphylococcus aureus, two of the common pathogens in this population. We hypothesize that the presence of pathogen-specific IgE, combined with continuous exposure to these ubiquitous agents, leads to chronic IgE-mediated histamine release from basophils and mast cells, with subsequent pathogen-specific immune tolerance and an increase in pathogen-specific T regulatory cells. We plan to test this hypothesis through clinical and immunologic evaluation of HIES patients before, during, and after histamine-2 receptor (H2) blocker therapy with ranitidine through a prospective, placebo-controlled crossover study. We chose this therapy because histamine has been shown to stimulate interleukin-10 (IL-10), a major down regulatory cytokine, through the H2 receptor, and clinical improvement has been observed in several patients treated with H2 blockers. Laboratory studies will include determinations of pathogen-specific immunoglobulin G4 (IgG4):IgE ratios, basophil activation, IL-10 producing regulatory T-cells, cellular proliferative responses to staphylococcal and candidal antigens, and functional testing of regulatory T-cells. Clinical evaluations will include comprehensive history and physical examination, dermatologic evaluation, genetic evaluation for clinical severity scoring of HIES, pulmonary function tests, and chest computerized tomography (CT) examination. Through this study, we will further our understanding of the immunologic abnormalities of HIES and determine whether a larger prospective, double-blind trial of H2 blockade as adjunctive therapy for HIES is indicated.

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-Blind, Randomized, Placebo-Controlled Cross-Over Study Assessing the Role of Pathogen-Specific IgE and Histamine Release in the Hyper-IgE Syndrome and the Effect of Ranitidine on Laboratory and Clinical Manifestations
• Study Start Date: Sep 1, 2007
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Placebo/Ranitidine crossover Patients took placebo for 12 months and then ranitidine for 12 months	Drug: Ranitidine; Double blinded, randomized placebo controlled crossover study. Patients received 12 months of placebo and 12 months of treatment medication (ranitidine).; Drug: Placebo
Experimental: Ranitidine/placebo crossover Ranitidine for one year followed by placebo for one year	Drug: Ranitidine; Double blinded, randomized placebo controlled crossover study. Patients received 12 months of placebo and 12 months of treatment medication (ranitidine).; Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Number of Infections in Subjects With HIES. [1 year on intervention]

   Patients received one year of treatment medication and one year of placebo. New infections (bacterial, fungal, viral or parasitic) were defined as those requiring an addition or change of an antimicrobial (including topical, oral or intravenous therapies) or those requiring a medical procedure (i.e., incision and drainage of a skin abscess, warm soaks to aid abscess drainage or sinus drainage).

Secondary Outcome Measures

1. New Skin Infections [12 months placebo/12 months ranitidine]

   Patients reported the number of new skin infections

2. New Lung Infections [12 months placebo and 12 months ranitidine]

   Number of new infection while on placebo or study drug

3. Clinical Severity Score [one year on ranitidine and one year on placebo]

   Scoring that was completed every 3 months. Clinical severity scored had outcomes that could range from 0 to 121 with 0 being the least severe and 121 being the most severe.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 2 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

1. Male and female patients with the diagnosis of Hyper IgE Recurrent Infection (Job) syndrome. Mutations in the STAT3 gene account for the majority, if not all cases of HIES. However as the full genetics of HIES remains unknown, we will use clinical criteria, including the expert opinion of the investigators, as well as a score greater than 40 by the diagnostic scoring system used in protocol 00-I-0159.

2. A chronic (greater than 4 weeks duration) infection or greater than 2 acute infections within the last 12 months. Acute infections can include but are not limited to: pneumonia, abscesses, sinusitis, skin infections, mucocutaneous candidiasis and ear infections. Chronic infections include continuous or intermittent symptoms despite appropriate therapeutic interventions for at least 4 weeks, including but not limited to chronic lung infiltrates with productive cough, chronic ear drainage despite topical therapy, chronic or intermittent drainage from a single abscess site, and/or chronic signs of sinusitis on sinus CT scan.

3. Patients aged 2 years and above. There is no upper age limit. We are excluding children less than 2 years of age, as we do not expect them to meet the first inclusion criterion, having a score high enough to be diagnosed with HIES.

4. Patients have to be at their own personal clinical baseline for at least 2 weeks duration. Patients will not start the study medication during an acute exacerbation of and infection.

5. The patient or the patient's guardian will be willing and capable of providing informed consent after initial counseling by clinical staff. Separate consent forms for all interventional procedures will be obtained after explanation of the specific procedure.

6. Patients must agree to have blood stored for future studies of the immune system and/or other medical conditions.

7. Women of childbearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation.

8. Patients may be concurrently enrolled on other protocols as long as the Principal Investigator (PI) is informed.

EXCLUSION CRITERIA:

1. Pregnancy. Ranitidine is pregnancy class B, and likely safe in pregnancy, but as this has not been studied, pregnant patients will be excluded. In addition, hormonal changes that occur during pregnancy may affect the skin manifestations and frequency of infection.

2. Hypersensitivity to ranitidine or any of the ingredients in ranitidine.

3. Pre-existing medications or conditions for which the investigators judge that ranitidine should not be given.

4. Patient or investigators unwilling to stop baseline H2 receptor antagonist therapy (over the counter or prescription) such as Tagamet (Cimetidine), Pepcid (Famotidine), and Axid (Nizatidine). H2 receptor antagonist therapy must be stopped for 3 months prior to study initiation. Patients who are receiving H2 receptor antagonist therapy for gastritis, acid reflux, or peptic ulcer disease will be offered changing their regimen to a proton pump inhibitor or other non-H2 receptor antagonist therapy to allow for study enrollment (3 months after stopping the H2 receptor antagonist).

5. Patients under the age of 2 years

6. Patients with HIV, receiving chemotherapy or who have a malignancy.

7. Any condition that in the judgment of the investigator would place the subject at undue risk or compromise the results or interpretation of the study.

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

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Buckley RH, Wray BB, Belmaker EZ. Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics. 1972 Jan;49(1):59-70.
• Davis SD, Schaller J, Wedgwood RJ. Job's Syndrome. Recurrent, "cold", staphylococcal abscesses. Lancet. 1966 May 7;1(7445):1013-5.
• Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, Miller JA, O'Connell AC, Puck JM. Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder. N Engl J Med. 1999 Mar 4;340(9):692-702.

• ClinicalTrials.gov Identifier: NCT00527878
• Other Study ID Numbers: 070218; 07-I-0218
• First Posted: Sep 11, 2007
• Last Update Posted: Feb 4, 2013
• Last Verified: Feb 1, 2013

• Keywords provided by , ,: Hyper-IgE Recurrent Infection Syndrome; Ranitidine Therapy; Job's Syndrome; Cross-Over Study; Double-Blind Placebo Controlled; Hyper-IgE Syndrome; Job Syndrome; Immune Deficiency
• Additional relevant MeSH terms: Infections; Job Syndrome; Immunologic Deficiency Syndromes; Syndrome; Recurrence; Reinfection; Ranitidine; Ranitidine bismuth citrate

Study Results

Participant Flow

Pre-assignment Detail	16 participants were screened but only 14 participants were randomized. Two individuals decided not to participate.

Arm/Group Title	Placebo/Ranitidine	Ranitidine/Placebo
Arm/Group Description	Ranitidine will be dosed orally at 150 mg twice daily for adults, and at 2-4 mg/kg/dose twice daily for children with a maximum dose of 150 mg twice daily. Liquid formulations will be provided for individuals unable to swallow pills. Subjects will be randomized to receive placebo for 12 months followed by 12 months of the ranitidine.	Ranitidine will be dosed orally at 150 mg twice daily for adults, and at 2-4 mg/kg/dose twice daily for children with a maximum dose of 150 mg twice daily. Liquid formulations will be provided for individuals unable to swallow pills. Subjects will be randomized to receive ranitidine for 12 months followed by 12 months of the ranitidine.
Period Title: Intervention 1
STARTED	7	7
COMPLETED	5	4
NOT COMPLETED	2	3
Period Title: Intervention 1
STARTED	5	4
COMPLETED	5	4
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Patients
Arm/Group Description
Overall Participants	16
Age (Count of Participants)
<=18 years	6 37.5%
Between 18 and 65 years	10 62.5%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	25.2 (13.6)
Sex: Female, Male (Count of Participants)
Female	8 50%
Male	8 50%
Region of Enrollment (participants) [Number]
United States	16 100%

Outcome Measures

1. Primary Outcome

Title	Number of Infections in Subjects With HIES.
Description	Patients received one year of treatment medication and one year of placebo. New infections (bacterial, fungal, viral or parasitic) were defined as those requiring an addition or change of an antimicrobial (including topical, oral or intravenous therapies) or those requiring a medical procedure (i.e., incision and drainage of a skin abscess, warm soaks to aid abscess drainage or sinus drainage).
Time Frame	1 year on intervention

Outcome Measure Data

Analysis Population Description

Patients that completed both arms of the study (24 months)

Arm/Group Title	Placebo	Ranitidine
Arm/Group Description	Crossover study in which patients received one year of placebo and one year of ranitidine. This analysis will include the placebo for both arms.	Crossover study in which patients received one year of placebo and one year of ranitidine. This analysis will include the treatment for both arms.
Measure Participants	9	9
Median (Full Range) [infections]	4	4

2. Secondary Outcome

Title	New Skin Infections
Description	Patients reported the number of new skin infections
Time Frame	12 months placebo/12 months ranitidine

Outcome Measure Data

Analysis Population Description

Patients that completed the study

Arm/Group Title	Placebo	Ranitidine
Arm/Group Description	Crossover study in which patients received one year of placebo and one year of ranitidine. This analysis will include the placebo for both arms.	Crossover study in which patients received one year of placebo and one year of ranitidine. This analysis will include the treatment for both arms.
Measure Participants	9	9
Median (Full Range) [skin infections]	1	0

3. Secondary Outcome

Title	New Lung Infections
Description	Number of new infection while on placebo or study drug
Time Frame	12 months placebo and 12 months ranitidine

Outcome Measure Data

Analysis Population Description

Patients who completed the study

Arm/Group Title	Placebo	Ranitidine
Arm/Group Description	Crossover study in which patients received one year of placebo and one year of ranitidine. This analysis will include the placebo for both arms.	Crossover study in which patients received one year of placebo and one year of ranitidine. This analysis will include the treatment for both arms.
Measure Participants	9	9
Median (Full Range) [new lung infections]	1	0

4. Secondary Outcome

Title	Clinical Severity Score
Description	Scoring that was completed every 3 months. Clinical severity scored had outcomes that could range from 0 to 121 with 0 being the least severe and 121 being the most severe.
Time Frame	one year on ranitidine and one year on placebo

Outcome Measure Data

Analysis Population Description

Patients who completed the study

Arm/Group Title	Placebo	Ranitidine
Arm/Group Description	Crossover study in which patients received one year of placebo and one year of ranitidine. This analysis will include the placebo for both arms.	Crossover study in which patients received one year of placebo and one year of ranitidine. This analysis will include the treatment for both arms.
Measure Participants	9	9
Mean (Full Range) [score on a scale]	9.8	8.5

Adverse Events

Adverse Event Reporting Description	Adverse events were not analyzed for each participant as 7 participants did not complete the study and so we were not able to evaluate for adverse events for both placebo and study medication.
Arm/Group Title	Placebo		Ranitidine
Arm/Group Description	this was a crossover study and patients received both placebo and study drug (ranitidine), both of which for 12 months, unless they terminated the study.		This was a crossover study and patients received 12 months of ranitidine and 12 months of placebo, unless they terminated the study.
All Cause Mortality
	Placebo		Ranitidine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Ranitidine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/11 (36.4%)		4/12 (33.3%)
Cardiac disorders
hypotension	1/11 (9.1%)		0/12 (0%)
Infections and infestations
pneumonia	1/11 (9.1%)		0/12 (0%)
pneumonia	0/11 (0%)		1/12 (8.3%)
skin abscess	1/11 (9.1%)		0/12 (0%)
groin abscess	0/11 (0%)		1/12 (8.3%)
central line infection	1/11 (9.1%)		0/12 (0%)
Respiratory, thoracic and mediastinal disorders
asthma	0/11 (0%)	1	1/12 (8.3%)	1
death from respiratory failure	0/11 (0%)		1/12 (8.3%)
Other (Not Including Serious) Adverse Events
	Placebo		Ranitidine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/11 (90.9%)		11/12 (91.7%)
Blood and lymphatic system disorders
anemia	3/11 (27.3%)		1/12 (8.3%)
neutropenia	3/11 (27.3%)		4/12 (33.3%)
Eye disorders
eyelid stye	1/11 (9.1%)		1/12 (8.3%)
Gastrointestinal disorders
gastric ulcer	1/11 (9.1%)		0/12 (0%)
vomiting	1/11 (9.1%)		2/12 (16.7%)
nausea	2/11 (18.2%)		1/12 (8.3%)
abdominal pain	1/11 (9.1%)		1/12 (8.3%)
occult blood in stool	1/11 (9.1%)		0/12 (0%)
General disorders
Dental problems	1/11 (9.1%)		1/12 (8.3%)
pain	0/11 (0%)		1/12 (8.3%)
tongue ulcer	1/11 (9.1%)		0/12 (0%)
Hepatobiliary disorders
elevated alkaline phosphatase	2/11 (18.2%)		0/12 (0%)
elevated Liver function tests	1/11 (9.1%)		1/12 (8.3%)
Immune system disorders
pruritus	1/11 (9.1%)		2/12 (16.7%)
Infections and infestations
sinusitis	4/11 (36.4%)		6/12 (50%)
otitis	4/11 (36.4%)		4/12 (33.3%)
upper respiratory tract infection	4/11 (36.4%)		5/12 (41.7%)
abscess	4/11 (36.4%)		5/12 (41.7%)
Streptococcal sore throat	0/11 (0%)		1/12 (8.3%)
candidiasis	2/11 (18.2%)		2/12 (16.7%)
fever	2/11 (18.2%)		1/12 (8.3%)
pneumonia	2/11 (18.2%)		0/12 (0%)
infection	1/11 (9.1%)		0/12 (0%)
urinary tract infection	0/11 (0%)		1/12 (8.3%)
Musculoskeletal and connective tissue disorders
fracture	0/11 (0%)		1/12 (8.3%)
arthralgias	0/11 (0%)		1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
cough	3/11 (27.3%)		2/12 (16.7%)
chest pain	0/11 (0%)		1/12 (8.3%)
dyspnea	1/11 (9.1%)		0/12 (0%)
Skin and subcutaneous tissue disorders
rash	2/11 (18.2%)		3/12 (25%)
folliculitis	0/11 (0%)		1/12 (8.3%)

Limitations/Caveats

[Not Specified]

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.