JOB's SyndromePhase 2NCT00527878
Effect of Ranitidine on Hyper-IgE Recurrent Infection (Job's) Syndrome
A Phase 2 study testing Ranitidine in people with JOB's Syndrome and Hyper-IgE Recurrent Infection Syndrome, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 2 years and older
- Conditions the study is for
- JOB's Syndrome, Hyper-IgE Recurrent Infection Syndrome, Immune Deficiency
- What is being tested?
- Ranitidine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 16 participants
- Where
- 1 siteUnited States
- Study dates
- Sep 2007to Jun 2011
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
- 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.
- 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.
- 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.
- 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.
- Patients must agree to have blood stored for future studies of the immune system and/or other medical conditions.
- 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.
- Patients may be concurrently enrolled on other protocols as long as the Principal Investigator (PI) is informed.
Who cannot join
- 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.
- Hypersensitivity to ranitidine or any of the ingredients in ranitidine.
- Pre-existing medications or conditions for which the investigators judge that ranitidine should not be given.
- 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).
- Patients under the age of 2 years
- Patients with HIV, receiving chemotherapy or who have a malignancy.
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
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
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.
Read more
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.
Read the 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.
- Being tested
- Ranitidine, Placebo
- Keywords
- Hyper-IgE Recurrent Infection Syndrome, Ranitidine Therapy, Job's Syndrome, Cross-Over Study, Double-Blind Placebo Controlled, Hyper-IgE Syndrome, Job Syndrome, Immune Deficiency
- Medical subject headings
- Job Syndrome, Immunologic Deficiency Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RanitidineDrug
Double blinded, randomized placebo controlled crossover study. Patients received 12 months of placebo and 12 months of treatment medication (ranitidine).
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| Placebo/Ranitidine crossover | Experimental | Patients took placebo for 12 months and then ranitidine for 12 months Receives: Drug: Ranitidine; Drug: Placebo |
| Ranitidine/placebo crossover | Experimental | Ranitidine for one year followed by placebo for one year Receives: Drug: Ranitidine; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Infections in Subjects With HIES.
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).
Measured: 1 year on intervention
Secondary outcomes (3)
New Skin Infections
Patients reported the number of new skin infections
Measured: 12 months placebo/12 months ranitidine
New Lung Infections
Number of new infection while on placebo or study drug
Measured: 12 months placebo and 12 months ranitidine
Clinical Severity Score
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.
Measured: one year on ranitidine and one year on placebo
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Sep 2007 (estimated)
- Study startSep 2007
- Primary completionJun 2011
- Study completionJun 2011
Why it stopped: Failure to enroll adequate patient numbers due to small number of eligible patients
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for JOB's SyndromeStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 16 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00527878
- Sponsor's protocol ID
- 070218
- Other IDs
- 07-I-0218
- Status last verified
- Feb 2013
- First submitted
- 8 Sep 2007
- Last updated
- 4 Feb 2013
- Results posted
- Yes, on ClinicalTrials.gov
Publications
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. doi: 10.1056/NEJM199903043400904.
PubMed 10053178Davis SD, Schaller J, Wedgwood RJ. Job's Syndrome. Recurrent, "cold", staphylococcal abscesses. Lancet. 1966 May 7;1(7445):1013-5. doi: 10.1016/s0140-6736(66)90119-x. No abstract available.
PubMed 4161105Buckley RH, Wray BB, Belmaker EZ. Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics. 1972 Jan;49(1):59-70. No abstract available.
PubMed 5059313
Study at a glance
From the registry record, last updated by the sponsor on 4 Feb 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00527878
- Acronym / sponsor ID
- 070218
- Keywords
- Hyper-IgE Recurrent Infection Syndrome, Ranitidine Therapy, Job's Syndrome, Cross-Over Study, Double-Blind Placebo Controlled, Hyper-IgE Syndrome, Job Syndrome, Immune Deficiency
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Failure to enroll adequate patient numbers due to small number of eligible patients
- Enrolment
- 16 participants (actual)
- Lead sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)US National Institutes of Health
- Study start
- Sep 2007
- Primary completion
- Jun 2011 (actual)
- Study completion
- Jun 2011 (actual)
- First posted
- 11 Sep 2007 (estimated)
- Results
- Posted 4 Feb 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo/Ranitidine crossover | Experimental | Drug: Ranitidine, Drug: PlaceboPatients took placebo for 12 months and then ranitidine for 12 months |
| Ranitidine/placebo crossover | Experimental | Drug: Ranitidine, Drug: PlaceboRanitidine for one year followed by placebo for one year |
Who may qualify
- Ages
- 2 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (8 listed)
Key exclusion criteria (7 listed)
- 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.
- Hypersensitivity to ranitidine or any of the ingredients in ranitidine.
- Pre-existing medications or conditions for which the investigators judge that ranitidine should not be given.
- 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).
- Patients under the age of 2 years
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RanitidineDouble blinded, randomized placebo controlled crossover study. Patients received 12 months of placebo and 12 months of treatment medication (ranitidine). | Drug | Placebo/Ranitidine crossover, Ranitidine/placebo crossover |
| Placebo | Drug | Placebo/Ranitidine crossover, Ranitidine/placebo crossover |
Primary outcome
Number of Infections in Subjects With HIES.
Time frame: 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).
3 secondary outcomes
New Skin Infections
Time frame: 12 months placebo/12 months ranitidine
New Lung Infections
Time frame: 12 months placebo and 12 months ranitidine
Clinical Severity Score
Time frame: one year on ranitidine and one year on placebo
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Feb 2013.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 10053178Grimbacher 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. doi: 10.1056/NEJM199903043400904.
- Background: PubMed 4161105Davis SD, Schaller J, Wedgwood RJ. Job's Syndrome. Recurrent, "cold", staphylococcal abscesses. Lancet. 1966 May 7;1(7445):1013-5. doi: 10.1016/s0140-6736(66)90119-x. No abstract available.
- Background: PubMed 5059313Buckley RH, Wray BB, Belmaker EZ. Extreme hyperimmunoglobulinemia E and undue susceptibility to infection. Pediatrics. 1972 Jan;49(1):59-70. No abstract available.
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RecruitingObservational study
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Enrolling by invitationPhase 1/2
Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Ranitidine in people with JOB's Syndrome and Hyper-IgE Recurrent Infection Syndrome, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 4 Feb 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 4 Feb 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Infections in Subjects With HIES. (time frame: 1 year on intervention). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00527878, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Feb 2013.