A Randomized, Double-Blind, Placebo-Controlled Study of Omalizumab for Idiopathic Anaphylaxis

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2013 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier:
NCT00890162
First received: April 28, 2009
Last updated: March 14, 2014
Last verified: October 2013
  Purpose

Background:

  • Omalizumab is an approved drug for the treatment of asthma by the Food and Drug Administration.
  • Researchers are now studying this drug in a double-blind placebo-controlled manner to assess efficacy in patients with idiopathic anaphylaxis (recurrent hypersensitive allergic episodes for which a cause is not identified).
  • The study will improve understanding of the mechanisms involved in anaphylactic reactions as a response to the downregulation (a decrease in the number of receptors on the surface of cells) in mast cell (a resident cell with several types of tissues) activation, and lead to the development of strategies to better prevent or treat anaphylaxis.

Objectives:

  • To determine whether treatment with omalizumab will reduce or prevent episodes of unprovoked anaphylaxis (an acute allergic reaction) in subjects with a history of idiopathic anaphylaxis.
  • To assess pharmacodynamics (physiological effects of a drug) and identify patients with undiagnosed mastocytosis (rare disorders caused by too many mast cells).
  • To investigate cellular and molecular mechanisms of signaling and the effect of omalizumab on mast cells or basophils (a cell in the leukocyte family that releases histamine, which affects allergic response) and explore other regulatory pathways that may be involved with modulation of mast cell degranulation.

Eligibility:

  • Patients between 18 and 70 years of age who have been diagnosed with idiopathic anaphylaxis, a diagnosis that is made only after other causes of anaphylaxis have been considered.
  • Patients with documented anaphylaxis episodes (mild to severe) at least six times within the past 1 year period, at least once within the last 4 months, and with at least one of the following:

    • Elevated serum tryptase above baseline within 2 hours of the event.
    • Emergency room visit with documented anaphylaxis without a known cause established by the acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (generalized hives, itching or flushing, swollen lips-tongue-throat) and at least one of the following: (1) respiratory compromise or gastrointestinal involvement (shortness of breath, wheeze-bronchospasm, throat tightness, low oxygen levels, nausea, vomiting, or abdominal pain); or (2) reduced blood pressure or associated symptoms of end-organ dysfunction (collapse, loss of consciousness, or loss of bladder or bowel control).
    • Hospitalization for anaphylaxis.
  • Patients must provide a letter of referral, with copies of pertinent medical history and laboratory tests, from the prospective participant s local physician, and have the ability to give informed consent.
  • Women with childbearing potential must have a negative pregnancy test, and must agree to practice abstinence or effective birth control from the start of the protocol and for 3 months following the last injection of the study drug.

Design:

  • Participants will undergo a clinical evaluation, blood tests, and a bone marrow biopsy and aspirate.
  • Participants will be randomized to either drug or placebo and will receive two doses of omalizumab or a matched placebo while hospitalized, followed by continued outpatient therapy, every 2 to 4 weeks, for up to 6 months.
  • Participants will remain on the assigned regimen for 6 months or until they have experienced new onset of severe adverse event on one occasion within 24 hours of study medication that are related to the study drug, whichever comes first. At that time, the participant will be discontinued from drug administration.

Condition Intervention Phase
Anaphylaxis
Hypotension
Bronchospasm
Angioedema
Drug: Epinephrine
Procedure: Bone Marrow Apsiration
Drug: Omalizumab (Xolair)
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: A Randomized Double-Blinded, Placebo-Controlled Study of Omalizumab for Idiopathic Anaphylaxis

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • The primary objective of this study is to determine if treatment with omalizumab over 6 months will produce a reduction in the number and timing of anaphylactic events in subjects with a history of frequent idiopathic anaphylaxis. [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Assess the pharmacodynamics of omalizumab in subjects with anaphylaxis. Examine the effects of omalizumab in the immunopathogenesis of anaphylaxis. Identify subjects with the D816V mutation. [ Designated as safety issue: Yes ]

Estimated Enrollment: 30
Study Start Date: April 2009
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Epinephrine
    N/A
    Procedure: Bone Marrow Apsiration
    N/A
    Drug: Omalizumab (Xolair)
    N/A
Detailed Description:

Anaphylaxis is a severe systemic reaction caused by release of mediators from mast cells and basophils. Manifestations include cutaneous, respiratory, cardiovascular, or gastrointestinal signs and symptoms. Although anaphylaxis is frequently attributed to exposure to specific foods, drugs, and insect venoms in sensitive individuals, a causative factor is not identified in 30% to 50% of patients with recurrent anaphylactic episodes (idiopathic anaphylaxis).

Currently, therapeutic options for the treatment of idiopathic anaphylaxis are limited with variable efficacy. This pilot study will examine the hypothesis that omalizumab (Xolair ) will decrease episodes of unexplained anaphylaxis in patients with idiopathic anaphylaxis. Omalizumab is approved for use in asthma. We will examine the safety profile and efficacy of omalizumab in patients with anaphylaxis. In addition, the study will investigate whether patients with anaphylaxis have unique molecular and cellular defects in mast cells that result in these cells being more susceptible to degranulation.

The study will enroll patients with idiopathic anaphylaxis. Patients will undergo a clinical evaluation, blood tests, and a bone marrow biopsy and aspirate. Patients will be randomized to either drug or placebo and will receive, in a double-blind placebo-controlled approach, 2 doses of omalizumab or a matched placebo while hospitalized, followed by continued outpatient therapy, every 2 to 4 weeks, for up to 6 months. Patients will remain on the assigned regimen if they have experienced anaphylactic events (post 24-hr window) determined to be unrelated to study drug or have been followed for 6 months, whichever comes first. These unrelated events would be determined by the PI not to jeopardize patient safety or restrict the use of additional therapy such as corticosteroids to control symptoms. After this point, the patient may be discontinued from drug administration until unblinding. This design ensures that no patient will have anaphylactic episodes while on placebo if other therapy is medically indicated. Research studies will be conducted to elucidate other markers or pathways of mast cell regulation.

The primary outcome will be a reduction in the number and timing of anaphylactic events during the randomized phase. Secondary outcomes will include a reduction in surface IgE receptors on basophils, identification of mutations in c-kit, and evaluation of the efficacy of omalizumab on other mediator-induced symptoms associated with anaphylaxis. The study will improve the understanding of the mechanisms involved in anaphylactic reactions as a response to the downregulation of mechanisms involved in mast cell activation that could, in turn, lead to development of strategies to better prevent or treat anaphylaxis.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Volunteers must satify all of the following inclusion criteria to be eligible for this study.

Subject must be at least 18 years of age and no older than 70 years of age.

Diagnosis of idiopathic anaphylaxis, a diagnosis of exclusion, assigned after other causes of anaphylaxis and other diseases in the differential diagnoses have been considered.

Anaphylaxis episodes (mild-severe) at least 6 times within the past 1 year period, documented according to medical records physician report, or patient report and 1 episode within the last 4 months, and with at least 1 of the following:

  1. Elevated serum tryptase above baseline within 2 hours of the event.
  2. Emergency room visit with documented anaphylaxis without an etiology established by the acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) [Grade 1]* and at least 1 of the following:

    1. Respiratory compromise or gastrointestinal involvement (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia, nausea, vomiting, or abdominal pain [Grade 2]*).
    2. Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, or incontinence [Grade 3]*).
  3. Hospitalization for anaphylaxis: hospital records with documented anaphylaxis without known cause established by the acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) [Grade 1]*) and at least one of the following:

    1. Respiratory compromise or gastrointestinal involvement (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow, hypoxemia, nausea, vomiting, or abdominal pain [Grade 2]*).
    2. Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, or incontinence [Grade 3]*).
  4. Letter of referral, with copies of pertinent medical history and laboratory tests, from prospective study participant s local physician.
  5. Ability to give informed consent.
  6. Women of childbearing potential must have a negative beta-HCG serum or urine pregnancy test prior to each injection, and must agree to practice abstinence or effective contraception from initiation of the protocol and for 3 months following the last infusion of the study drug (effective contraception methods include abstinence; surgical sterilization of either partner, barrier methods such as diaphragm, condom, cap, or sponge; or hormonal contraception).

    • Severity grading of anaphylaxis

EXCLUSION CRITERIA:

A volunteer who satisfies any of the following exclusion criteria will be ineligible to participate in this study.

  1. Presence of conditions which, in the judgment of the investigator or the referring physician, may put the subject at undue risk for study participation or travel (such as an acute infection, severe thrombocytopenia, coronary artery disease, uncontrolled hypertension, congestive heart failure, chronic beta blocker therapy such as atenolol or metoprolol, or myeloproliferative disease).
  2. History of malignancy
  3. Known cause for anaphylaxis or flushing
  4. Diagnosis of mastocytosis
  5. Inability to provide informed consent
  6. Inability or refusal to undergo a bone marrow biopsy and aspirate
  7. HIV positive or other known immunodeficiency
  8. Active or chronic hepatitis
  9. Use of any other investigational agent within 30 days of the study
  10. Current use of chronic-oral corticosteroids or other immunosuppressant medications
  11. Pregnant or nursing women
  12. Positive pregnancy test
  13. IgE levels and subject s weight that cause dosing to be above dosing guidelines.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00890162

Contacts
Contact: Hyejeong Root (301) 594-1233 roothy@niaid.nih.gov
Contact: Melody C Carter, M.D. (301) 496-8772 mc396j@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Melody C Carter, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
ClinicalTrials.gov Identifier: NCT00890162     History of Changes
Other Study ID Numbers: 090129, 09-I-0129
Study First Received: April 28, 2009
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Omalizumab
Idiopathic Anaphylaxis
Serum Tryptase
Placebo-Controlled
Adult
Anaphylaxis
Allergic Reaction

Additional relevant MeSH terms:
Anaphylaxis
Angioedema
Bronchial Spasm
Hypotension
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Vascular Diseases
Cardiovascular Diseases
Urticaria
Skin Diseases, Vascular
Skin Diseases
Bronchial Diseases
Respiratory Tract Diseases
Epinephrine
Racepinephrine
Epinephryl borate
Omalizumab
Adrenergic alpha-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Adrenergic beta-Agonists
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Anti-Asthmatic Agents

ClinicalTrials.gov processed this record on August 18, 2014