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

NCT03513471 | Withdrawn Phase 1 DMC FDA Drug

• 2 other identifiers: 17-13951R01HL135235-01A1
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief 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 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.

Conditions

Asthma

Keywords

Late Phase Asthmatic Response; Allergen Challenge

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (11)

• Area under the curve (AUC) % drop in FEV1 in the LPR

  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)

  Baseline and 24 hours post allergen challenge

• Fractional exhaled Nitric Oxide (FeNO) as an exploratory biomarker

  Baseline and 24 hours post allergen challenge

• Change in % eosinophils in induced sputum

  Baseline and 24 hours post allergen challenge

• Change in % neutrophils in induced sputum

  Baseline and 24 hours post allergen challenge

Study Arms (2)

Anakinra then Placebo Treatment

EXPERIMENTAL

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; Other: Anakinra Matching Placebo; Drug: Dermatophagoides Farinae

Placebo then Anakinra Treatment

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.

Biological: Anakinra; Other: Anakinra Matching Placebo; Drug: Dermatophagoides Farinae

Interventions

Anakinra BIOLOGICAL

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.

Also known as: Kinaret

Anakinra then Placebo Treatment; Placebo then Anakinra Treatment

Anakinra Matching Placebo OTHER

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.

Also known as: dummy

Anakinra then Placebo Treatment; Placebo then Anakinra Treatment

Dermatophagoides Farinae DRUG

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).

Also known as: Allergen extract

Anakinra then Placebo Treatment; Placebo then Anakinra Treatment

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Related Publications (23)

• 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.

  PMID: 24252609 BACKGROUND

• Kaur 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.

  PMID: 26595589 BACKGROUND

• Bahadori 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.

  PMID: 19454036 BACKGROUND

• Hasegawa 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.

  PMID: 23769497 BACKGROUND

• Jackson 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.

  PMID: 22133317 BACKGROUND

• Stoppelenburg 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.

  PMID: 24194936 BACKGROUND

• Zhu 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.

  PMID: 24457412 BACKGROUND

• Grunberg 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.

  PMID: 9279247 BACKGROUND

• Nagarkar 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.

  PMID: 20644177 BACKGROUND

• Fanta 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.

  PMID: 6340496 BACKGROUND

• Ellul-Micallef R. The acute effects of corticosteroids in bronchial asthma. Eur J Respir Dis Suppl. 1982;122:118-25.

  PMID: 6958475 BACKGROUND

• Scarfone 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.

  PMID: 8414819 BACKGROUND

• Stuck 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.

  PMID: 2690289 BACKGROUND

• Ulich 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.

  PMID: 1825745 BACKGROUND

• Hudock 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.

  PMID: 22592923 BACKGROUND

• Tsukagoshi H, Sakamoto T, Xu W, Barnes PJ, Chung KF. Effect of interleukin-1 beta on airway hyperresponsiveness and inflammation in sensitized and nonsensitized Brown-Norway rats. J Allergy Clin Immunol. 1994 Feb;93(2):464-9. doi: 10.1016/0091-6749(94)90355-7.

  PMID: 8120273 BACKGROUND

• Barchasz E, Naline E, Molimard M, Moreau J, Georges O, Emonds-Alt X, Advenier C. Interleukin-1beta-induced hyperresponsiveness to [Sar9,Met(O2)11]substance P in isolated human bronchi. Eur J Pharmacol. 1999 Aug 20;379(1):87-95. doi: 10.1016/s0014-2999(99)00484-7.

  PMID: 10499376 BACKGROUND

• Wang CC, Fu CL, Yang YH, Lo YC, Wang LC, Chuang YH, Chang DM, Chiang BL. Adenovirus expressing interleukin-1 receptor antagonist alleviates allergic airway inflammation in a murine model of asthma. Gene Ther. 2006 Oct;13(19):1414-21. doi: 10.1038/sj.gt.3302798. Epub 2006 May 25.

  PMID: 16724092 BACKGROUND

• Okada S, Inoue H, Yamauchi K, Iijima H, Ohkawara Y, Takishima T, Shirato K. Potential role of interleukin-1 in allergen-induced late asthmatic reactions in guinea pigs: suppressive effect of interleukin-1 receptor antagonist on late asthmatic reaction. J Allergy Clin Immunol. 1995 Jun;95(6):1236-45. doi: 10.1016/s0091-6749(95)70081-1.

  PMID: 7797792 BACKGROUND

• Chen Y, Garvin LM, Nickola TJ, Watson AM, Colberg-Poley AM, Rose MC. IL-1beta induction of MUC5AC gene expression is mediated by CREB and NF-kappaB and repressed by dexamethasone. Am J Physiol Lung Cell Mol Physiol. 2014 Apr 15;306(8):L797-807. doi: 10.1152/ajplung.00347.2013. Epub 2014 Jan 31.

  PMID: 24487386 BACKGROUND

• Evans CM, Raclawska DS, Ttofali F, Liptzin DR, Fletcher AA, Harper DN, McGing MA, McElwee MM, Williams OW, Sanchez E, Roy MG, Kindrachuk KN, Wynn TA, Eltzschig HK, Blackburn MR, Tuvim MJ, Janssen WJ, Schwartz DA, Dickey BF. The polymeric mucin Muc5ac is required for allergic airway hyperreactivity. Nat Commun. 2015 Feb 17;6:6281. doi: 10.1038/ncomms7281.

  PMID: 25687754 BACKGROUND

• Garlanda C, Dinarello CA, Mantovani A. The interleukin-1 family: back to the future. Immunity. 2013 Dec 12;39(6):1003-18. doi: 10.1016/j.immuni.2013.11.010.

  PMID: 24332029 BACKGROUND

• Hernandez ML, Mills K, Almond M, Todoric K, Aleman MM, Zhang H, Zhou H, Peden DB. IL-1 receptor antagonist reduces endotoxin-induced airway inflammation in healthy volunteers. J Allergy Clin Immunol. 2015 Feb;135(2):379-85. doi: 10.1016/j.jaci.2014.07.039. Epub 2014 Sep 5.

  PMID: 25195169 BACKGROUND

MeSH Terms

Conditions

Asthma

Interventions

Interleukin 1 Receptor Antagonist Protein; Receptors, Interleukin-6; Antigens, Dermatophagoides; Allergens

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Receptors, Interleukin; Receptors, Cytokine; Receptors, Immunologic; Receptors, Cell Surface; Membrane Proteins; Antigens

Study Officials

• Michelle Hernandez, MD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: The randomization will be done by the department biostatistician and communicated with Investigational Drug Services so the experiment will remain blinded.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: April 19, 2018
• First Posted: May 1, 2018
• Study Start: August 9, 2019
• Primary Completion: December 1, 2021
• Study Completion: December 1, 2021
• Last Updated: May 7, 2021

Record last verified: 2021-05