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

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

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.

Study Overview

• Status: Completed
• Conditions: Hypotension; Angioedema; Anaphylaxis; Bronchospasm
• Intervention / Treatment: Drug: Placebos; Drug: Epinephrine; Drug: Omalizumab (Xolair)

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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:

Volunteers must satisfy 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 agent (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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Omalizumab; Subjects will receive two doses of Omalizumab while hospitalized, followed by continued outpatient therapy, every 2 to 4 weeks, for up to 6 months.	Drug: Epinephrine; Drug: Omalizumab (Xolair)
Placebo Comparator: Placebo; Subjects will receive two doses of placebo while hospitalized, followed by continued outpatient therapy, every 2 to 4 weeks, for up to 6 months.	Drug: Placebos; Drug: Epinephrine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in the Number and Timing of Anaphylactic Events in Subjects With a History of Frequent Idiopathic Anaphylaxis.	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. Ordinal outcome of participants based on number of events in 6 months after baseline and timing of first event. Events were calculated based on detailed event logs maintained by the patients and collected every 2-4 weeks based on injection schedule. Mean percent change in number of events experienced while on study agent for each subject and results presented as a group.	6 months

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Webb LM, Lieberman P. Anaphylaxis: a review of 601 cases. Ann Allergy Asthma Immunol. 2006 Jul;97(1):39-43. doi: 10.1016/S1081-1206(10)61367-1.
• Thong BY, Cheng YK, Leong KP, Tang CY, Chng HH. Anaphylaxis in adults referred to a clinical immunology/allergy centre in Singapore. Singapore Med J. 2005 Oct;46(10):529-34.
• Neugut AI, Ghatak AT, Miller RL. Anaphylaxis in the United States: an investigation into its epidemiology. Arch Intern Med. 2001 Jan 8;161(1):15-21. doi: 10.1001/archinte.161.1.15.
• Carter MC, Robyn JA, Bressler PB, Walker JC, Shapiro GG, Metcalfe DD. Omalizumab for the treatment of unprovoked anaphylaxis in patients with systemic mastocytosis. J Allergy Clin Immunol. 2007 Jun;119(6):1550-1. doi: 10.1016/j.jaci.2007.03.032. Epub 2007 May 3. No abstract available.
• Constantine GM, Bressler PB, Petroni D, Metcalfe DD, Carter MC. Twelve-year follow-up of omalizumab therapy for anaphylaxis in 2 patients with systemic mastocytosis. J Allergy Clin Immunol Pract. 2019 Apr;7(4):1314-1316. doi: 10.1016/j.jaip.2018.07.041. Epub 2018 Aug 24. No abstract available.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start: April 27, 2009
• Primary Completion (Actual): July 31, 2018
• Study Completion (Actual): May 31, 2019

Study Registration Dates

• First Submitted: April 28, 2009
• First Submitted That Met QC Criteria: April 28, 2009
• First Posted (Estimate): April 29, 2009

Study Record Updates

• Last Update Posted (Actual): July 1, 2019
• Last Update Submitted That Met QC Criteria: June 12, 2019
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Adult; Anaphylaxis; Placebo-Controlled; Allergic Reaction; Omalizumab; Idiopathic Anaphylaxis; Serum Tryptase
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Respiratory Tract Diseases; Immune System Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Shock; Hypotension; Angioedema; Bronchial Spasm; Anaphylaxis; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic alpha-Agonists; Adrenergic Agonists; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Anti-Allergic Agents; Adrenergic beta-Agonists; Sympathomimetics; Vasoconstrictor Agents; Mydriatics; Omalizumab; Epinephrine
• Other Study ID Numbers: 090129; 09-I-0129

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes