AsthmaPhase 1/2LateAnaNCT03513458
Late Phase Administration Anakinra as a Rescue Treatment for Inhaled Allergen Challenge-Induced Airway Inflammation
A Phase 1/2 study testing Anakinra and Dermatophagoides Farinae in people with Asthma, run by University of North Carolina, Chapel Hill.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 to 45 years
- Conditions the study is for
- Asthma
- What is being tested?
- Anakinra and Dermatophagoides Farinae
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- No sites listed yet
- Study dates
- Sep 2020to Dec 2021
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
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 18 to 45 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Age range 18-45 years, inclusive
- FEV1 of at least 80% of predicted and FEV1/FVC (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.
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- 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
Who cannot join
- 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.
Show all 37Show fewer
- 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
About this study
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: 25 mild allergic asthmatics sensitized to Dermatophagoides farinae (D. farinae) Procedures (methods): 12 eligible subjects of 25 volunteers 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.
Read the detailed description
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. Numerous studies indicate that IL-1 signaling mediates key features of viral- and allergen-induced airway inflammation. 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 LPR 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.
- Conditions
- Asthma
- Being tested
- Anakinra, Anakinra Matching Placebo, Dermatophagoides Farinae
- Keywords
- Late Phase Asthmatic Response, Allergen Challenge
- Medical subject headings
- Asthma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AnakinraBiological
Also called Kinaret
A single 1mg/kg subcutaneous injection (up to 100 mg) of Anakinra will be administered at the onset of the LPR, roughly three hours post allergen challenge, to model Anakinra use in an emergency care setting.
Anakinra Matching PlaceboOther
Also called dummy
A single dose of matching placebo will be administered at the onset of the LPR, roughly three hours post allergen challenge, to model Anakinra use in an emergency care setting.
Dermatophagoides FarinaeDrug
Also called Allergen extract
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).
| Study group | Role | What they receive |
|---|---|---|
| Anakinra then Placebo | Experimental | Subjects randomized to this arm will receive the experimental treatment of Anakinra on their first exposure to Dermatophagoides Farinae (dust mite) allergen challenge, followed by the Anakinra matching placebo on their second exposure. Receives: Biological: Anakinra; Other: Anakinra Matching Placebo; Drug: Dermatophagoides Farinae |
| Placebo then Anakinra | Experimental | 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. Receives: Biological: Anakinra; Other: Anakinra Matching Placebo; Drug: Dermatophagoides Farinae |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline and 3-10 hours following PD20
Secondary outcomes (11)
Area under the curve (AUC) measuring % 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Baseline and 24 hours post allergen challenge
Change in Sputum levels of major respiratory mucin MUC5AC
An induced sputum sample will be processed and analyzed for the amount of protein MUC5AC between the two time points.
Measured: Baseline and 24 hours post allergen challenge
Change in Sputum levels of major respiratory mucin MUC5B
An induced sputum sample will be processed and analyzed for the amount of protein MUC5B between the two time points.
Measured: 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.
Measured: 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.
Measured: 4 hours post allergen challenge
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 May 2018
- Study startSep 2020 (estimated)
- Primary completionDec 2021 (estimated)
- Study completionDec 2021 (estimated)
Why it stopped: \[The risk of inhaled allergen challenge and anakinra treatment outweigh benefits to participants with allergic asthma due to the COVID-19 pandemic.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (23)Papers the sponsor has linked to this study.
- Other trials for AsthmaStudies of the same condition, open and under way.
- More trials run by University of North Carolina, Chapel HillThe 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 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Subjects are randomized to one of two arms, either taking Anakinra or placebo. After a washout period, the subjects will be moved to the opposite arm.
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of North Carolina, Chapel Hill
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Sponsor
- Investigators
- Michelle Hernandez, MD, Principal investigator, University of North Carolina, Chapel Hill
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03513458
- Sponsor's protocol ID
- 17-0779
- Other IDs
- 1R01HL135235-01A1
- Acronym
- LateAna
- Status last verified
- May 2021
- First submitted
- 19 Apr 2018
- Last updated
- 14 May 2021
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: The investigators will not be sharing individual participant data (IPD) with other researchers.
Publications
Moorman JE, Akinbami LJ, Bailey CM, Zahran HS, King ME, Johnson CA, Liu X. National surveillance of asthma: United States, 2001-2010. Vital Health Stat 3. 2012 Nov;(35):1-58.
PubMed 24252609Kaur BP, Lahewala S, Arora S, Agnihotri K, Panaich SS, Secord E, Levine D. Asthma: Hospitalization Trends and Predictors of In-Hospital Mortality and Hospitalization Costs in the USA (2001-2010). Int Arch Allergy Immunol. 2015;168(2):71-8. doi: 10.1159/000441687. Epub 2015 Nov 24.
PubMed 26595589Bahadori K, Doyle-Waters MM, Marra C, Lynd L, Alasaly K, Swiston J, FitzGerald JM. Economic burden of asthma: a systematic review. BMC Pulm Med. 2009 May 19;9:24. doi: 10.1186/1471-2466-9-24.
PubMed 19454036Hasegawa K, Tsugawa Y, Brown DF, Camargo CA Jr. Childhood asthma hospitalizations in the United States, 2000-2009. J Pediatr. 2013 Oct;163(4):1127-33.e3. doi: 10.1016/j.jpeds.2013.05.002. Epub 2013 Jun 12.
PubMed 23769497Jackson DJ, Sykes A, Mallia P, Johnston SL. Asthma exacerbations: origin, effect, and prevention. J Allergy Clin Immunol. 2011 Dec;128(6):1165-74. doi: 10.1016/j.jaci.2011.10.024.
PubMed 22133317Stoppelenburg AJ, Salimi V, Hennus M, Plantinga M, Huis in 't Veld R, Walk J, Meerding J, Coenjaerts F, Bont L, Boes M. Local IL-17A potentiates early neutrophil recruitment to the respiratory tract during severe RSV infection. PLoS One. 2013 Oct 23;8(10):e78461. doi: 10.1371/journal.pone.0078461. eCollection 2013.
PubMed 24194936Zhu J, Message SD, Qiu Y, Mallia P, Kebadze T, Contoli M, Ward CK, Barnathan ES, Mascelli MA, Kon OM, Papi A, Stanciu LA, Jeffery PK, Johnston SL. Airway inflammation and illness severity in response to experimental rhinovirus infection in asthma. Chest. 2014 Jun;145(6):1219-1229. doi: 10.1378/chest.13-1567.
PubMed 24457412Grunberg K, Smits HH, Timmers MC, de Klerk EP, Dolhain RJ, Dick EC, Hiemstra PS, Sterk PJ. Experimental rhinovirus 16 infection. Effects on cell differentials and soluble markers in sputum in asthmatic subjects. Am J Respir Crit Care Med. 1997 Aug;156(2 Pt 1):609-16. doi: 10.1164/ajrccm.156.2.9610079.
PubMed 9279247Nagarkar DR, Bowman ER, Schneider D, Wang Q, Shim J, Zhao Y, Linn MJ, McHenry CL, Gosangi B, Bentley JK, Tsai WC, Sajjan US, Lukacs NW, Hershenson MB. Rhinovirus infection of allergen-sensitized and -challenged mice induces eotaxin release from functionally polarized macrophages. J Immunol. 2010 Aug 15;185(4):2525-35. doi: 10.4049/jimmunol.1000286. Epub 2010 Jul 19.
PubMed 20644177Fanta CH, Rossing TH, McFadden ER Jr. Glucocorticoids in acute asthma. A critical controlled trial. Am J Med. 1983 May;74(5):845-51. doi: 10.1016/0002-9343(83)91076-8.
PubMed 6340496Ellul-Micallef R. The acute effects of corticosteroids in bronchial asthma. Eur J Respir Dis Suppl. 1982;122:118-25.
PubMed 6958475Scarfone RJ, Fuchs SM, Nager AL, Shane SA. Controlled trial of oral prednisone in the emergency department treatment of children with acute asthma. Pediatrics. 1993 Oct;92(4):513-8.
PubMed 8414819Stuck AE, Minder CE, Frey FJ. Risk of infectious complications in patients taking glucocorticosteroids. Rev Infect Dis. 1989 Nov-Dec;11(6):954-63. doi: 10.1093/clinids/11.6.954.
PubMed 2690289Ulich TR, Yin SM, Guo KZ, del Castillo J, Eisenberg SP, Thompson RC. The intratracheal administration of endotoxin and cytokines. III. The interleukin-1 (IL-1) receptor antagonist inhibits endotoxin- and IL-1-induced acute inflammation. Am J Pathol. 1991 Mar;138(3):521-4.
PubMed 1825745Hudock KM, Liu Y, Mei J, Marino RC, Hale JE, Dai N, Worthen GS. Delayed resolution of lung inflammation in Il-1rn-/- mice reflects elevated IL-17A/granulocyte colony-stimulating factor expression. Am J Respir Cell Mol Biol. 2012 Oct;47(4):436-44. doi: 10.1165/rcmb.2012-0104OC. Epub 2012 May 16.
PubMed 22592923
Study at a glance
From the registry record, last updated by the sponsor on 14 May 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Late Phase Administration Anakinra as a Rescue Treatment for Inhaled Allergen Challenge-Induced Airway Inflammation
- ClinicalTrials.gov ID
- NCT03513458
- Acronym / sponsor ID
- LateAna / 17-0779
- Conditions
- Asthma
- Keywords
- Late Phase Asthmatic Response, Allergen Challenge
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: \[The risk of inhaled allergen challenge and anakinra treatment outweigh benefits to participants with allergic asthma due to the COVID-19 pandemic.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- University of North Carolina, Chapel HillUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- Sep 2020 (estimated)
- Primary completion
- Dec 2021 (estimated)
- Study completion
- Dec 2021 (estimated)
- First posted
- 1 May 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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: 25 mild allergic asthmatics sensitized to Dermatophagoides farinae (D. farinae) Procedures (methods): 12 eligible subjects of 25 volunteers 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
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. Numerous studies indicate that IL-1 signaling mediates key features of viral- and allergen-induced airway inflammation. 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 LPR 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
- Model description
- Subjects are randomized to one of two arms, either taking Anakinra or placebo. After a washout period, the subjects will be moved to the opposite arm.
| Arm | Type | Receives |
|---|---|---|
| Anakinra then Placebo | Experimental | Biological: Anakinra, Other: Anakinra Matching Placebo, Drug: Dermatophagoides FarinaeSubjects randomized to this arm will receive the experimental treatment of Anakinra on their first exposure to Dermatophagoides Farinae (dust mite) allergen challenge, followed by the Anakinra matching placebo on their second exposure. |
| Placebo then Anakinra | Experimental | Biological: Anakinra, Other: Anakinra Matching Placebo, Drug: Dermatophagoides FarinaeSubjects 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. |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (10 listed)
- Age range 18-45 years, inclusive
- FEV1 of at least 80% of predicted and FEV1/FVC (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
Key exclusion criteria (37 listed)
- 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.
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 |
|---|---|---|
| AnakinraAlso: KinaretA single 1mg/kg subcutaneous injection (up to 100 mg) of Anakinra will be administered at the onset of the LPR, roughly three hours post allergen challenge, to model Anakinra use in an emergency care setting. | Biological | Anakinra then Placebo, Placebo then Anakinra |
| Anakinra Matching PlaceboAlso: dummyA single dose of matching placebo will be administered at the onset of the LPR, roughly three hours post allergen challenge, to model Anakinra use in an emergency care setting. | Other | Anakinra then Placebo, Placebo then Anakinra |
| Dermatophagoides FarinaeAlso: Allergen extractStandardized house dust mite Dermatophagoides farinae (D. farinae) allergen extract at 30,000 allergen units (AU)/mL for inhalation (provided by Greer Laboratories, Lenoir, NC). | Drug | Anakinra then Placebo, Placebo then Anakinra |
Primary outcome
Maximum % FEV1 drop from Baseline during LPR period
Time frame: Baseline and 3-10 hours following PD20
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.
11 secondary outcomes
Area under the curve (AUC) measuring % drop in FEV1 in the LPR
Time frame: 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)
Time frame: Baseline and 24 hours post allergen challenge
Fractional exhaled Nitric Oxide (FeNO) as an exploratory biomarker
Time frame: Baseline and 24 hours post allergen challenge
Change in % eosinophils in induced sputum
Time frame: Baseline and 24 hours post allergen challenge
Change in % neutrophils in induced sputum
Time frame: Baseline and 24 hours post allergen challenge
Change in eosinophils per mg of induced sputum
Time frame: Baseline and 24 hours post allergen challenge
Change in neutrophils per mg of induced sputum
Time frame: Baseline and 24 hours post allergen challenge
Change in Sputum levels of major respiratory mucin MUC5AC
Time frame: Baseline and 24 hours post allergen challenge
Change in Sputum levels of major respiratory mucin MUC5B
Time frame: Baseline and 24 hours post allergen challenge
Change in Mucociliary clearance (MCC)
Time frame: 4 hours post allergen challenge
Central (C) vs. peripheral (P) deposition ratio (C/P)
Time frame: 4 hours post allergen challenge
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 May 2021.
- Background: PubMed 24252609Moorman JE, Akinbami LJ, Bailey CM, Zahran HS, King ME, Johnson CA, Liu X. National surveillance of asthma: United States, 2001-2010. Vital Health Stat 3. 2012 Nov;(35):1-58.
- Background: PubMed 26595589Kaur BP, Lahewala S, Arora S, Agnihotri K, Panaich SS, Secord E, Levine D. Asthma: Hospitalization Trends and Predictors of In-Hospital Mortality and Hospitalization Costs in the USA (2001-2010). Int Arch Allergy Immunol. 2015;168(2):71-8. doi: 10.1159/000441687. Epub 2015 Nov 24.
- Background: PubMed 19454036Bahadori K, Doyle-Waters MM, Marra C, Lynd L, Alasaly K, Swiston J, FitzGerald JM. Economic burden of asthma: a systematic review. BMC Pulm Med. 2009 May 19;9:24. doi: 10.1186/1471-2466-9-24.
- Background: PubMed 23769497Hasegawa K, Tsugawa Y, Brown DF, Camargo CA Jr. Childhood asthma hospitalizations in the United States, 2000-2009. J Pediatr. 2013 Oct;163(4):1127-33.e3. doi: 10.1016/j.jpeds.2013.05.002. Epub 2013 Jun 12.
- Background: PubMed 22133317Jackson DJ, Sykes A, Mallia P, Johnston SL. Asthma exacerbations: origin, effect, and prevention. J Allergy Clin Immunol. 2011 Dec;128(6):1165-74. doi: 10.1016/j.jaci.2011.10.024.
- Background: PubMed 24194936Stoppelenburg AJ, Salimi V, Hennus M, Plantinga M, Huis in 't Veld R, Walk J, Meerding J, Coenjaerts F, Bont L, Boes M. Local IL-17A potentiates early neutrophil recruitment to the respiratory tract during severe RSV infection. PLoS One. 2013 Oct 23;8(10):e78461. doi: 10.1371/journal.pone.0078461. eCollection 2013.
- Background: PubMed 24457412Zhu J, Message SD, Qiu Y, Mallia P, Kebadze T, Contoli M, Ward CK, Barnathan ES, Mascelli MA, Kon OM, Papi A, Stanciu LA, Jeffery PK, Johnston SL. Airway inflammation and illness severity in response to experimental rhinovirus infection in asthma. Chest. 2014 Jun;145(6):1219-1229. doi: 10.1378/chest.13-1567.
- Background: PubMed 9279247Grunberg K, Smits HH, Timmers MC, de Klerk EP, Dolhain RJ, Dick EC, Hiemstra PS, Sterk PJ. Experimental rhinovirus 16 infection. Effects on cell differentials and soluble markers in sputum in asthmatic subjects. Am J Respir Crit Care Med. 1997 Aug;156(2 Pt 1):609-16. doi: 10.1164/ajrccm.156.2.9610079.
- Background: PubMed 20644177Nagarkar DR, Bowman ER, Schneider D, Wang Q, Shim J, Zhao Y, Linn MJ, McHenry CL, Gosangi B, Bentley JK, Tsai WC, Sajjan US, Lukacs NW, Hershenson MB. Rhinovirus infection of allergen-sensitized and -challenged mice induces eotaxin release from functionally polarized macrophages. J Immunol. 2010 Aug 15;185(4):2525-35. doi: 10.4049/jimmunol.1000286. Epub 2010 Jul 19.
- Background: PubMed 6340496Fanta CH, Rossing TH, McFadden ER Jr. Glucocorticoids in acute asthma. A critical controlled trial. Am J Med. 1983 May;74(5):845-51. doi: 10.1016/0002-9343(83)91076-8.
- Background: PubMed 6958475Ellul-Micallef R. The acute effects of corticosteroids in bronchial asthma. Eur J Respir Dis Suppl. 1982;122:118-25.
- Background: PubMed 8414819Scarfone RJ, Fuchs SM, Nager AL, Shane SA. Controlled trial of oral prednisone in the emergency department treatment of children with acute asthma. Pediatrics. 1993 Oct;92(4):513-8.
- Individual participant dataSharing planned: No. The investigators will not be sharing individual participant data (IPD) with other researchers.
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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.
Michelle Hernandez, MD principal investigator
University of North Carolina, Chapel Hill
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Anakinra and Dermatophagoides Farinae in people with Asthma, run by University of North Carolina, Chapel Hill.
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 10 inclusion and 37 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: withdrawn, as of the sponsor's last update on 14 May 2021. Status can change between updates, so confirm with the study contact before making plans.
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 combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
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?
The study was withdrawn before enrolling participants, so there are no results.
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?
Maximum % FEV1 drop from Baseline during LPR period (time frame: Baseline and 3-10 hours following PD20). 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 NCT03513458, which also lists 23 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 14 May 2021.