Early Phase Administration of Anakinra as a Rescue Treatment for Inhaled Allergen Challenge-Induced Airway Inflammation

Study Overview
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Brief Summary
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Purpose: The primary objective of this study is to examine the effectiveness of anakinra as a rescue treatment for allergic airway inflammation. Utilizing an inhaled allergen challenge model, the investigators will determine the effectiveness of a single 1 mg/kg dose of anakinra administered after inhaled allergen challenge for mitigating features of airway inflammation. Participants: 12 mild allergic asthmatics sensitized to Dermatophagoides farinae (D. farinae) Procedures (methods): Eligible subjects will participate in a double blind cross-over study. Following randomization to the placebo or anakinra treatment group, subjects will undergo inhalation of D. farinae, and their early and late phase asthmatic responses will be measured. Subjects will undergo induced sputum sampling, methacholine challenge, and mucociliary clearance measures. After completion of period 1, subjects will cross over to the alternate study arm.

Detailed Description
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Asthma is an increasingly common chronic illness with higher rates of hospitalization for exacerbation than many other chronic conditions. In 2009, total asthma costs in the U.S. were estimated at $56 billion per year, and over half the overall asthma-related costs were attributed to inpatient hospitalization. Allergen exposure and viral infection are among the most common triggers for asthma exacerbations. Exacerbations of allergic asthma are characterized by an early phase response (EPR), mediated by release of preformed mediators like histamine from mast cells, and a late phase response (LPR) 3-7 hours later mediated by chemokines and cytokines, including IL-1β, that attract leukocytes such as neutrophils and eosinophils to the airways, increase mucus production, trigger airway smooth muscle contraction, and result in airway constriction and airway hyper-reactivity (AHR). The LPR is thought to be predominantly responsible for the symptoms associated with acute exacerbations of allergic asthma. While corticosteroids are considered a mainstay of treatment for asthma exacerbation regardless of the trigger, there are limitations to their effectiveness in the acute setting including the initial lag period of 4-6 hours or more before therapeutic effect and the concern for broad immune suppression. Corticosteroids are often ineffective in treating the neutrophilic component of airway inflammation seen with viral infection and allergen-induced airway inflammation. Finally, mucus plugging is a known hallmark of severe and fatal asthma, yet there is a notable lack of effective mucolytic treatments for asthma. Time to therapeutic benefit is key in preventing patient morbidity and mortality. Currently there is an urgent need for anti-inflammatory treatments that work quickly and effectively in acute asthma exacerbations. The investigators propose that IL-1 blockade can achieve these ends and perhaps complement corticosteroid actions. Anakinra is an FDA-approved recombinant form of human IL-1 receptor antagonist (IL-1RA), a natural anti-inflammatory cytokine that competes with agonist binding to the IL-1 receptor, suppressing IL-1β and IL-1a signaling. IL-1 signaling mediates key features of viral- and allergen-induced airway inflammation. Previous studies in animal and in vitro models demonstrate that IL-1 signaling can directly impact three aspects of an airway inflammatory response: granulocyte (neutrophil/eosinophil) recruitment; non-specific and allergen-specific airway reactivity; and mucin production. Numerous IL-1 blocking agents are FDA-approved for conditions where the IL-1β pathway predominates disease pathophysiology, such as in systemic juvenile idiopathic arthritis and the cryopyrin-associated periodic syndromes. Anakinra is an ideal candidate to test as a rescue treatment for acute asthma exacerbation due to its fast onset of action (reaching peak concentrations in 3-7 hours), and a short 4-6 hour half-life. A single 1mg/kg dose (up to 100mg) of anakinra or placebo will be administered at the onset of the EPR to model anakinra use in an emergency care setting. This dose was chosen because it is the current FDA-approved dose for rheumatoid arthritis (RA). Notably, the investigators have previously demonstrated that a 1 mg/kg dose resulted in significant reduction in airway granulocyte recruitment following lipopolysaccharide (LPS) challenge in a study of healthy volunteers. The investigators' objective is to determine if a single 1 mg/kg dose of Anakinra can mitigate key features of asthma exacerbations, namely AHR, airway constriction, airway inflammation, and mucous secretion/clearance.

Official Title
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Early Phase Administration of Anakinra as a Rescue Treatment for Inhaled Allergen Challenge-Induced Airway Inflammation

Conditions
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Asthma

Intervention / Treatment
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* Biological: Anakinra
* Other: Anakinra Matching Placebo
* Drug: Dermatophagoides Farinae


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age range 18-45 years, inclusive FEV1 of at least 80% of predicted and FEV1/FVC (Forced expiratory volume in one second/forced vital capacity) ratio of at least 0.7 (without use of bronchodilator medications for 12 hours or long acting beta agonists for 24 hours), consistent with lung function of persons with no more than mild episodic or mild persistent asthma. Physician diagnosis of asthma Positive methacholine inhalation challenge as performed in the separate screening protocol within the prior 12 months (defined as provocative concentration of methacholine of 10 mg/mL or less producing a 20% fall in FEV1 (PC20 methacholine) Allergic sensitization to house dust mite (D. farinae) as confirmed by positive immediate skin prick test response Clinical reactivity to D. farinae assessed through inhaled allergen challenge with a decline in FEV1 of ≥20% from baseline in the early asthmatic response and ≥15% in the late asthmatic response. Negative pregnancy test for females who are not s/p hysterectomy with oophorectomy or who have not been amenorrheic for 12 months or more. Oxygen saturation of >94% and blood pressure within the following limits: (Systolic between 150-90 mmHg, Diastolic between 90-60 mmHg). Ability to provide an induced sputum sample. Negative intracutaneous tuberculin skin test (PPD) defined as less than 5mm induration for the purpose of this protocol (positive PPD contraindication to anakinra injection). A negative tuberculosis (TB) test within the past year (either PPD or quantiferon TB Gold) is also acceptable Exclusion Criteria: Clinical contraindications: Any chronic medical condition considered by the PI as a contraindication to participation in the study including significant cardiovascular disease, diabetes, chronic renal disease, chronic thyroid disease, history of chronic infections or immunodeficiency. Pregnancy or nursing a baby History of latex allergy/sensitivity Allergy/sensitivity to anakinra or its formulation Physician directed emergency treatment for an asthma exacerbation within the preceding 12 months. Exacerbation of asthma more than 2x/week which could be characteristics of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma. Daily requirements for albuterol due to asthma symptoms (cough, wheeze, chest tightness) which would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma (not to include prophylactic use of albuterol prior to exercise). Viral upper respiratory tract infection within 4 weeks of challenge. Any acute infection requiring antibiotics within 4 weeks of exposure or fever of unknown origin within 4 weeks of challenge. Severe asthma Mental illness of history of drug or alcohol abuse that, in the opinion of the investigator, would interfere with the participant's ability to comply with study requirements. Cigarette smoking >1 pack per month Nighttime symptoms of cough or wheeze greater than 1x/week at baseline (not during a clearly recognized viral induced asthma exacerbation) which would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma. Allergy/sensitivity to study drugs or their formulations Known hypersensitivity to methacholine or to other parasympathomimetic agents History of intubation for asthma Unwillingness to limit coffee, tea, cola drinks, chocolate, or other foods containing caffeine after midnight on the days that methacholine challenge testing and inhaled allergen challenge is to be performed Unwillingness to use reliable contraception if sexually active (IUD, birth control pills/patch, condoms). Radiation history will be collected. Any subject whose exposure history within the past twelve months would cause them to exceed their annual limits will be excluded Usage of the following medications: Use of systemic steroid therapy within the preceding 12 months for an asthma exacerbation. All use of systemic steroids in the last year will be reviewed by a study physician. Subjects who are prescribed daily inhaled corticosteroids, cromolyn, or leukotriene inhibitors (Montelukast or Zafirlukast) will be required to discontinue these medications at least 4 weeks prior to their screening visit. Use of daily theophylline within the past month. Daily requirement for albuterol due to asthma symptoms (cough, wheeze, chest tightness) which would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma. (Not to include prophylactic use of albuterol prior to exercise). Use of any immunosuppressant therapy within the preceding 12 months will be reviewed by the study physician. Use of any immunomodulatory therapy within the preceding 12 months. Use of beta blocking medications Antihistamines in the 5 days prior to allergen challenge Routine use of NSAIDs, including aspirin. Physical/laboratory indications: Abnormalities on lung auscultation Temperature >37.8 C Oxygen saturation of <94% Systolic BP>150 mmHg or <90 mmHg or diastolic BP>90 mmHg or <60 mmHg Absolute neutrophil count <1.4 x 109/L Inability or unwillingness of a participant to give written informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Study subjects will be randomized to one of two arms, either receiving Anakinra or placebo, then having a washout period and receiving the opposite treatment.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anakinra then Placebo Treatment<br>Subjects randomized to this arm will receive the experimental treatment of Anakinra on their first exposure to the Dermatophagoides Farinae (dust mite) allergen challenge, followed by the Anakinra matching placebo on their second exposure. | Biological: Anakinra<br>* A single 1mg/kg subcutaneous injection (up to 100mg) of anakinra will be administered at the onset of the EPR, directly after the allergen challenge, to model anakinra use in an emergency care setting.<br>* Other names: Kinaret;Other: Anakinra Matching Placebo<br>* A single dose of matching placebo will be administered at the onset of the EPR, directly after the allergen challenge, to model anakinra use in an emergency care setting.<br>* Other names: dummy;Drug: Dermatophagoides Farinae<br>* Standardized house dust mite Dermatophagoides farinae (D. farinae) allergen extract at 30,000 allergen units (AU)/mL for inhalation (provided by Greer Laboratories, Lenoir, NC).<br>* Other names: Allergen extract;|
| Experimental: Placebo then Anakinra Treatment<br>Subjects randomized to this arm will receive the inactive placebo on their first exposure to the Dust Mite Allergen challenge, followed by the experimental treatment of Anakinra on their second exposure. | Biological: Anakinra<br>* A single 1mg/kg subcutaneous injection (up to 100mg) of anakinra will be administered at the onset of the EPR, directly after the allergen challenge, to model anakinra use in an emergency care setting.<br>* Other names: Kinaret;Other: Anakinra Matching Placebo<br>* A single dose of matching placebo will be administered at the onset of the EPR, directly after the allergen challenge, to model anakinra use in an emergency care setting.<br>* Other names: dummy;Drug: Dermatophagoides Farinae<br>* Standardized house dust mite Dermatophagoides farinae (D. farinae) allergen extract at 30,000 allergen units (AU)/mL for inhalation (provided by Greer Laboratories, Lenoir, NC).<br>* Other names: Allergen extract;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum % FEV1 drop from Baseline during LPR period | The principal endpoint will be maximal % drop in Forced Expiratory Volume in 1 second (FEV1) from baseline during the LPR period (3-10 hours). The FEV1 following saline and prior to the first dose of antigen during the inhaled allergen challenge will be considered the baseline value. Declines in FEV1 will be measured as a % drop from the baseline. A provocative dose causing a 20% fall FEV1 (PD20) is determined during the allergen challenge. | Baseline and 3-10 hours following PD20 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC) % drop in FEV1 in the LPR | The FEV1 following saline and prior to the first dose of antigen during the inhaled allergen challenge will be considered the baseline value from which the % drop in FEV1 will be determined. | Baseline and 3-10 hours following PD20 | 
| Change in Methacholine reactivity, as measured by the concentration of methacholine resulting in a 20% drop in FEV1 (PC20) | Participants will undergo a methacholine challenge to assess airway hyper-responsiveness at baseline. Change in methacholine reactivity, as measured by the PC20, from baseline to 24 hours after the allergen challenge will be determined. | Baseline and 24 hours post allergen challenge | 
| Fractional exhaled Nitric Oxide (FeNO) as an exploratory biomarker | FeNO is being investigated as a non-invasive airway inflammation marker. FeNO is measured in ppb with a chemoluminescence analyzer before the saline and prior to the first dose of antigen during the inhaled allergen challenge and at 24 hours post the allergen challenge. | Baseline and 24 hours post allergen challenge | 
| Change in % eosinophils in induced sputum | An induced sputum sample will be processed and counted to provide the % change in eosinophils between the two time points. | Baseline and 24 hours post allergen challenge | 
| Change in % neutrophils in induced sputum | An induced sputum sample will be processed and counted to provide the % change in neutrophils between the two time points. | Baseline and 24 hours post allergen challenge | 
| Change in eosinophils per mg of induced sputum | An induced sputum sample will be processed and counted to provide the eosinophils per mg change between the two time points. | Baseline and 24 hours post allergen challenge | 
| Change in neutrophils per mg of induced sputum | An induced sputum sample will be processed and counted to provide the neutrophils per mg change between the two time points. | Baseline and 24 hours post allergen challenge | 
| Change in sputum levels of major respiratory mucin MUC5AC (mucin 5AC, oligomeric mucus/gel-forming) | An induced sputum sample will be processed and analyzed for the amount of protein MUC5AC between the two time points. | Baseline and 24 hours post allergen challenge | 
| Change in sputum levels of major respiratory mucin MUC5B (mucin 5B, oligomeric mucus/gel-forming) | An induced sputum sample will be processed and analyzed for the amount of protein MUC5B between the two time points. | Baseline and 24 hours post allergen challenge | 
| Change in Mucociliary clearance (MCC) | The change in MCC will be measured as % tracheobronchial retention of radiolabeled particles in the airways. | 4 hours post allergen challenge | 
| Central (C) vs. peripheral (P) deposition ratio (C/P) | C/P is a reflection of deposition in the central airways during MCC. | 4 hours post allergen challenge | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Late Phase Asthmatic Response, Allergen Challenge