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The Effect of Allergen Immunotherapy on Anti-viral Immunity in Patients With Allergic Asthma (VITAL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04100902
Recruitment Status : Not yet recruiting
First Posted : September 24, 2019
Last Update Posted : September 24, 2019
Sponsor:
Collaborators:
University of Copenhagen
Allergy- and pulmonary Clinic, Vanloese.
ALK-Abelló A/S
Lund University
Information provided by (Responsible Party):
Celeste Porsbjerg, Bispebjerg Hospital

Brief Summary:

Aim: To investigate the possible immune modulatory effects of allergen immunotherapy (AIT) on respiratory immunity in patients with allergic asthma (AA).

Background: Allergic sensitization to aeroallergens is a common co-morbidity in asthma that is associated with more frequent and severe asthma attacks. We have recently shown that patients with allergic asthma also have an increased risk of pneumonia, and hence allergy in asthma may be associated with a relative respiratory immunodeficiency. However, the increased risk was obliterated in patients treated with AIT.

Methods: Patients with asthma sensitized to house-dust mite (HDM) is enrolled in a randomized, double-blind, placebo-controlled study of HDM-AIT. Patients will be scheduled for 9 visits through 8 months including, randomization to 6 months of treatment with either HDM-AIT (Acarizax/Odactra) or placebo. Primary interferons (IFN) type I and III will be investigated in human bronchial epithelial cells as the primary outcome. Secondary outcomes such as: Inflammatory cytokines, immunologic phenotype and immunohistochemistry will be investigated in bronchial biopsies, blood, bronchoalveolar lavage fluid, sputum and HDM-patch biopsies as well as a thorough respiratory and allergic evaluation.

Expected outcomes: We expect that, patients with AA have 1) decreased production of anti-viral type I and III IFN and that AIT increases these measures. 2) Anti-bacterial response is reduced through IL12, ß-defensin and IFN-γ and that AIT increases these measures. 3) Lastly, we expect that T-cell response is dysregulated (Th1↓1/Th2↑) in patients with AA and that these findings are modulated in an immuno-protective direction after AIT.

Perspectives: This project will expand our understanding of the clinical significance of allergy in asthma in a completely novel direction and show how AIT may modulate the immune response to prevent infections.


Condition or disease Intervention/treatment Phase
Allergic Asthma Due to Dermatophagoides Pteronyssinus Allergic Asthma Due to Dermatophagoides Farinae Allergic Rhinitis Due to House Dust Mite Drug: ODACTRA 12 SQ-HDM Sublingual Tablet Drug: Placebo oral tablet Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: The Effect of Allergen Immunotherapy on Anti-viral Immunity in Patients With Allergic Asthma - A Randomized, Double-blind, Placebo-controlled Trial of HDM-AIT
Estimated Study Start Date : December 1, 2019
Estimated Primary Completion Date : March 1, 2021
Estimated Study Completion Date : June 15, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Asthma Vital Signs
Drug Information available for: Odactra

Arm Intervention/treatment
Active Comparator: Odactra 12-sq HDM sublingual tablet Drug: ODACTRA 12 SQ-HDM Sublingual Tablet
Subjects are assigned standard scheme for administration of ODACTRA 12 SQ-HDM Sublingual Tablet.

Placebo Comparator: Placebo sublingual tablet Drug: Placebo oral tablet
Subjects randomized to placebo are assigned standard scheme for administration of ODACTRA 12 SQ-HDM Sublingual Tablet.




Primary Outcome Measures :
  1. ΔIFN-ß gene and/or protein expression [ Time Frame: 6,2 months ]
    To investigate the potential change in viral induced interferon response in HBECs from V2 to V7, after 24 weeks of HDM-SLIT therapy or placebo, after stimulation with a combination of: HDM-allergen +/- viral infection mimics (RV16 or Poly(I:C))

  2. ΔIFN-λ gene and/or protein expression [ Time Frame: 6,2 months ]
    To investigate the potential change in viral induced interferon response in HBECs from V2 to V7, after 24 weeks of HDM-SLIT therapy or placebo, after stimulation with a combination of: HDM-allergen +/- viral infection mimics (RV16 or Poly(I:C))

  3. ΔViral load [ Time Frame: 6,2 months ]
    To investigate the potential change in viral load in HBECS from from V2 to V7, after 24 weeks of HDM-SLIT therapy or placebo, after stimulation with a combination of HDM-allergen +/- viral infection mimics (RV16 or Poly(I:C))


Secondary Outcome Measures :
  1. ΔIFN-ß gene and/or protein expression [ Time Frame: 6,2 months ]
    To investigate the potential change in viral induced interferon response in HBECs from V2 to V7, after 24 weeks of HDM-SLIT therapy, after stimulation with a combination of: HDM-allergen +/- viral infection mimics (RV16 or Poly(I:C) +/- bacterial infection mimics

  2. ΔIFN-λ gene and/or protein expression [ Time Frame: 6,2 months ]
    To investigate the potential change in viral induced interferon response in HBECs from V2 to V7, after 24 weeks of HDM-SLIT therapy, after stimulation with a combination of: HDM-allergen +/- viral infection mimics (RV16 or Poly(I:C) +/- bacterial infection mimics

  3. ΔIL-12 [ Time Frame: 6,2 months ]
    To investigate the potential change in IL-12 response in HBECs from V2 to V7, after 24 weeks of HDM-SLIT therapy, after stimulation with a combination of: HDM-allergen +/- viral infection mimics (RV16 or Poly(I:C) +/- bacterial infection mimics

  4. Δß-defensin [ Time Frame: 6,2 months ]
    To investigate the potential change in ß-defensin response in HBECs from V2 to V7, after 24 weeks of HDM-SLIT therapy, after stimulation with a combination of: HDM-allergen +/- viral infection mimics (RV16 or Poly(I:C) +/- bacterial infection mimics

  5. ΔIFN- γ [ Time Frame: 6,2 months ]
    To investigate the potential change in IFN- γ response in HBECs from V2 to V7, after 24 weeks of HDM-SLIT therapy, after stimulation with a combination of: HDM-allergen +/- viral infection mimics (RV16 or Poly(I:C) +/- bacterial infection mimics

  6. Th1/Th2 balance [ Time Frame: 6,2 months ]
    To investigate the potential change in immunologic phenotype in BAL-fluid from V2 to V7, after 24 weeks of HDM-SLIT therapy. Analyses will be performed using flowcytometri and/or ELISA/Luminex/MSD

  7. ΔNK-cells [ Time Frame: 6,2 months ]
    To investigate the potential change in immunologic phenotype in BAL-fluid from V2 to V7, after 24 weeks of HDM-SLIT therapy. Analyses will be performed using flowcytometri and/or ELISA/Luminex/MSD

  8. ΔCD8+ T-cells. [ Time Frame: 6,2 months ]
    To investigate the potential change in immunologic phenotype in BAL-fluid from V2 to V7, after 24 weeks of HDM-SLIT therapy. Analyses will be performed using flowcytometri and/or ELISA/Luminex/MSD

  9. Inflammatory cytokines such as but not restricted to: IL-4, IL-5, IL-13, IL-33, IL-25, IL-ß and TSLP [ Time Frame: 6,2 months ]
    To investigate the potential change in immunologic phenotype in BAL-fluid from V2 to V7, after 24 weeks of HDM-SLIT therapy. Analyses will be performed using flowcytometri and/or ELISA/Luminex/MSD

  10. IFN-ß/TSLP ratio [ Time Frame: 6,2 months ]
    To investigate the potential change in the cell supernatants for epithelial derived Th1/Th2-cytokines as well as Th1/Th2 (anti)-inflammatory cytokines.

  11. Mast cells, eosinophils, Neutrophils, pDC's [ Time Frame: 6,2 months ]
    To evaluate the potential change in histologic phenotype in bronchial biopsies from V2 to V7, after 24 weeks of HDM-SLIT therapy

  12. Number / percentage of eosinophils and neutrophils in sputum. [ Time Frame: 6,2 months ]
    To investigate potential change in airway inflammation markers in sputum



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Written informed consent
  • Age ≥18 through ≤ 65, inclusive at the time of V1
  • A historic verified diagnosis of asthma as defined by >/=1 positive of following tests:

Reversibility to ß2-agonist Positive mannitol challenge test Positive methacholine test Positive peak-flow variation test Positive eucapnic voluntary hyperventilation test Exercise test Persistent moderate to severe symptoms of of HDM induced rhinitis

  • >/=1 self-reported worsening of asthma symptoms in relations to viral infection within last 12 months
  • 1 present or historical marker of Th2 asthma: FeNO > 25 ppb at V0 Blood eosinophils > 0,3 x 109/L Sputum eosinophils > 3%
  • A postbronchodilator FEV1 value of ≥ 70% at V0
  • ACQ-6 > 1 (partly controlled) at V0
  • A stable asthma controller regimen with ICS (+LABA/LTRA/LAMA) for at least 4 weeks prior to V0 (GINA step 3-4)
  • Sensitisation to HDM defined by ≥1 of following:

Positive skin prick test for either: Dermatophagoides pteronyssinus or Dermatophagoides farina IgEHDM > 0.7 x103 IU/L

- Subjects must demonstrate acceptable inhaler and spirometry techniques during screening (as evaluated and in the opinion of study site staff)

Exclusion Criteria:

  • Any of the following would exclude the subject from participation in the study:

    1. Oral corticosteroids (any dose for more than 3 days) 8 weeks prior to V1 and during run-in.
    2. Acute upper or lower respiratory infections requiring antibiotics or antiviral medications 6 weeks prior to V0 and during run-in.
    3. Severe oral conditions such as but not limited to:

      1. Oral ulcers
      2. Oral lichen planus
      3. Oral mycosis
    4. Current smokers

      a. Quit > 6 months prior to V0.

    5. Any of the following concomitant allergies:

      a. Birch, Cat, Dog, Horse

    6. Ever in treatment with any AIT
    7. Previous medical history or evidence of an uncontrolled intercurrent illness such as but not limited to (e.g. Autoimmune disease, immunodeficiency, immunosuppression, malignant neoplastic conditions with current relevance) that in the opinion of the investigator may compromise the safety of the subject in the study or interfere with evaluation of the investigational product or reduce the subject's ability to participate in the study. Subjects with well-controlled comorbid disease (eg, hypertension, hyperlipidaemia, gastroesophageal reflux disease) on a stable treatment regimen for 15 days prior to Visit 0 are eligible.
    8. Any concomitant respiratory disease that in the opinion of the investigator and/or medical monitor will interfere with the evaluation of the investigational product or interpretation of subject safety or study results (eg, chronic obstructive pulmonary disease, cystic fibrosis, pulmonary fibrosis, bronchiectasis, allergic bronchopulmonary aspergillosis, Churg-Strauss syndrome, alpha-1-antitrypsin deficiency, Wegeners granulomatosis, Sarcoidosis).
    9. Any clinically relevant abnormal findings in haematology or clinical chemistry (laboratory results from Visit 1), physical examination, vital signs during the screening, which in the opinion of the investigator, may put the subject at risk because of his/her participation in the study, or may influence the results of the study, or the subject's ability to participate in the study.
    10. Evidence of active liver disease, including jaundice, alanine transaminase, bilirubin, greater than twice the upper limit of normal (laboratory results from Visit 0).
    11. History of cancer:

      1. Subjects who have had basal cell carcinoma or in situ carcinoma of the cervix are eligible to participate in the study provided that curative therapy was completed at least 12 months prior to Visit 1.
      2. Subjects who have had other malignancies are eligible provided that curative therapy was completed at least 5 years prior to Visit 1.
    12. A helminth parasitic infection diagnosed within 24 weeks of Visit 1 that has not been treated or has not responded to standard of care therapy.
    13. Known history of active tuberculosis (TB). Subjects may be enrolled if they have ALL of the following:

      1. No symptoms of TB: productive, prolonged cough (> 3 weeks); coughing up blood; fever; night sweats; unexplained appetite loss; unintentional weight loss.
      2. No known exposure to a case of active TB after most recent prophylaxis (prophylaxis required only if positive).
      3. No evidence of active TB on chest radiograph within 3 months prior to the first dose of investigational product.
    14. Positive hepatitis B surface antigen, or hepatitis C virus antibody serology at screening, or a positive medical history for hepatitis B or C. Subjects with a history of hepatitis B vaccination without history of hepatitis B are allowed to enrol.
    15. A positive human immunodeficiency virus (HIV) test at screening or subject taking antiretroviral medications, as determined by medical history and/or subject's verbal report.
    16. History of any known primary immunodeficiency disorder excluding asymptomatic selective immunoglobulin A or IgG subclass deficiency.
    17. Use of 5-lipoxygenase inhibitors (eg, zileuton) within 15 days prior to Visit 1.
    18. Use of immunosuppressive medication (eg, methotrexate, troleandomycin, oral gold, cyclosporine, azathioprine, intramuscular long-acting depot corticosteroid, or any experimental anti-inflammatory therapy) within 3 months prior to Visit 1.
    19. Receipt of any of the following within 30 days prior to Visit 1:

      1. Immunoglobulin or blood products, or
      2. Receipt of any investigational nonbiologic agent within 30 days or 5 half-lives prior Visit 0, whichever is longer.
    20. Receipt or treatment with of any marketed or investigational biologic agent within 6 months or 5 half-lives prior to Visit 1, whichever is longer, specifically:

      1. Anti-IgE
      2. Anti-IL4
      3. Anti-IL-5
      4. Anti-IL5 receptor antagonist
      5. Anti-IL-13
    21. Pregnant, breastfeeding or lactating females
    22. History of chronic alcohol or drug abuse within 12 months prior to Visit 1.
    23. Planned surgical procedures requiring general anaesthesia or in-patient status for > 1 day during the conduct of the study.
    24. Unwillingness or inability to follow the procedures outlined in the protocol.
    25. Concurrent enrolment in another clinical study involving an investigational treatment.
    26. Receipt of the Th2 cytokine inhibitor Suplatast Tosilate within 15 days prior to Visit 1.
    27. Receipt of any live or attenuated vaccines within 15 days prior to Visit 1.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04100902


Contacts
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Contact: Christian U. Woehlk, M.D. +45 30914745 cwoe0007@regionh.dk
Contact: Celeste Porsbjerg, Professor celeste.porsbjerg@regionh.dk

Locations
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Denmark
Respiratory Research Unit
Copenhagen, Denmark, 2400
Contact: Christian U. Woehlk, M.D.    +45 30914745    cwoe0007@regionh.dk   
Sub-Investigator: Christian U. Woehlk, M.D.         
Sponsors and Collaborators
Bispebjerg Hospital
University of Copenhagen
Allergy- and pulmonary Clinic, Vanloese.
ALK-Abelló A/S
Lund University
Investigators
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Principal Investigator: Celeste Porsbjerg, Professor Respiratory Research Unit, department of Respiratory Medicine, Bispebjerg University Hospital

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Responsible Party: Celeste Porsbjerg, Professor, Bispebjerg Hospital
ClinicalTrials.gov Identifier: NCT04100902    
Other Study ID Numbers: VITAL
First Posted: September 24, 2019    Key Record Dates
Last Update Posted: September 24, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Celeste Porsbjerg, Bispebjerg Hospital:
allergic asthma, allergen immunotherapy, anti-viral immunity, house dust mite
Additional relevant MeSH terms:
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Asthma
Rhinitis
Rhinitis, Allergic
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Nose Diseases
Respiratory Tract Infections
Otorhinolaryngologic Diseases
Antiviral Agents
Anti-Infective Agents