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Effects of Anti-TSLP in Patients With Asthma (UPSTREAM)

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ClinicalTrials.gov Identifier: NCT02698501
Recruitment Status : Recruiting
First Posted : March 3, 2016
Last Update Posted : January 4, 2017
Sponsor:
Collaborators:
Lund University
University of Newcastle, Australia
University of Copenhagen
Information provided by (Responsible Party):
Celeste Porsbjerg, University Hospital Bispebjerg and Frederiksberg

Brief Summary:

The purpose of this study is to determine whether anti-TSLP will decrease airway hyperresponsiveness in patients with asthma already on daily treatment with inhaled corticosteroids.

The investigators expect that airway hyperresponsiveness will decrease after treatment with anti-TSLP, and that this happens due to a change in the type of mast cells with in the lungs. Also, the investigators expect a decrease in inflammatory cells and mediators measured in material from the lungs.

Half of the participants will receive anti-TSLP (MEDI9929) on top of their regular asthma treatment, while the other half will receive placebo on top of their regular asthma treatment.


Condition or disease Intervention/treatment Phase
Asthma Drug: MEDI9929 Drug: Placebo Phase 2

Detailed Description:

The mannitol test is increasingly used by clinicians to diagnose asthma. It has clinical advantages in terms of being feasible in a wide range of settings with the need of a minimum of equipment. Airway hyper responsiveness (AHR) to mannitol correlates with eosinophilic airway inflammation and the degree of asthma control, predicts the risk of exacerbation and response to inhaled steroids.

Subjects with asthma and indirect AHR have increased levels of intraepithelial carboxypeptidase A3 (CPA3), a metalloexopeptidase specifically expressed by mast cells, compared to asthmatics without AHR. CPA3 is known to be selectively present in the MCTC phenotype (mast cells containing both tryptase and chymase), and recent studies suggest that increased CPA3 levels also constitutes a marker of a Th2-high/eosinophilic and steroid-responsive asthma. Interestingly, treating mast cell precursors with TSLP increases CPA3 immunostaining, suggesting that TSLP released by e.g. airway epithelium up-regulate a mast cell phenotype that is potentially important in AHR and also promotes eosinophilic airway inflammation. Previous published data by the investigators confirm that increased MCTC in submucosa of subjects with asthma is associated with an increased CPA3 and TSLP expression.

The investigators speculate that the effect of MEDI9929 on AHR to mannitol is likely to be primarily a consequence of functional differences in mast cells. Treating subjects with asthma with MEDI9929 will potentially block downstream effects on mast cell activation as well as eosinophilic inflammation, which may reduce AHR to inhaled mannitol.

The purpose of this study is to investigate whether AHR to mannitol is a suitable marker of response to MEDI9929, but also to better understand the anti-inflammatory effects of MEDI9929 in the lungs, including whether a reduced AHR to mannitol following treatment with MEDI9929 is related to a reduction in chymase/CPA-3 positive mast cells. The investigators hypothesize that MEDI9929 will decrease the response to mannitol (measured as an increase in PD15) after 12 weeks of treatment as compared to placebo. It is further hypothesized that the number of chymase/CPA-3 positive mast cells in airway epithelium and submucosa will be reduced after 12 weeks of treatment with MEDI9929 in subjects with AHR to mannitol.

This trial offers the opportunity to study potential biomarkers and surrogate endpoints, but also to identify the anti-inflammatory effects of MEDI9929 on a mechanistic level.

This study is a randomized, double-blind, placebo-controlled trial. It includes a enrolment period of maximum 2 weeks, 12 weeks of treatment (three IV doses of either 700mg MEDI9929 or placebo) and 8 weeks follow-up after the second bronchoscopy.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Effects of Anti-TSLP on Airway Hyperresponsiveness and Mast Cell Phenotype in Asthma - A Randomized Double-blind, Placebo-controlled Trial of MEDI9929
Study Start Date : August 2016
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Asthma

Arm Intervention/treatment
Experimental: MEDI9929
MEDI9929 is a human monoclonal antibody immunoglobulin IgG2λ directed against TSLP. MEDI9929 binds with human TSLP and prevents its interaction with thymic stromal lymphopoietin receptor (TSLPR).
Drug: MEDI9929
MEDI9929 700mg (3 doses in total, 4-week intervals), administered intravenously

Placebo Comparator: Placebo
Apart from the active substance, the placebo is otherwise identical to IMP.
Drug: Placebo
Placebo (3 doses in total, 4-week intervals), administered intravenously




Primary Outcome Measures :
  1. Decrease in airway hyperresponsiveness to mannitol in response to treatment with MEDI9929 in patients with asthma [ Time Frame: 12 weeks ]
    Change in PD15 to mannitol (provoking dose for 15% reduction in FEV1, expressed as doubling doses) measured at baseline and after the 12-week treatment period between groups.

  2. Supportive primary objective 1: Mannitol test negative in response to treatment with MEDI9929 in patients with asthma [ Time Frame: 12 weeks ]
    Number of mannitol test negative (PD15 > 635mg) subjects after a 12-week treatment period between groups

  3. Supportive primary objective 2: Decrease in airway hyperresponsiveness to mannitol in response to treatment with MEDI9929 in patients with asthma [ Time Frame: 12 weeks ]
    The change in PD15 to mannitol measured at baseline and after the 12-week treatment period, expressed as geometric mean calculated by linear interpolation, compared between treatments.

  4. Supportive primary objective 3: Decrease in airway hyperresponsiveness to mannitol in response to treatment with MEDI9929 in patients with asthma [ Time Frame: 12 weeks ]
    Change in RDR (Response Dose Ratio) to mannitol measured at baseline and after the 12-week treatment period between groups


Secondary Outcome Measures :
  1. Change in number of Chymase/CPA-3 positive mast cells following treatment with MEDI9929 [ Time Frame: 12 weeks ]
    Cell count (MCT, MCTC and MCCPA3) in airway submucosa, airway epithelium and airway smooth muscle measured at baseline and after the 12-week treatment period between groups

  2. Changes in percentage of airway eosinophils and neutrophils in sputum in patients treated with MEDI9929 compared to placebo. [ Time Frame: 12 weeks ]
    Percentage of eosinophils and neutrophils in sputum measured at baseline and after the 12-week treatment period.

  3. Changes in percentage of airway eosinophils and neutrophils in airway submucosa in patients treated with MEDI9929 compared to placebo. [ Time Frame: 12 weeks ]
    Percentage of eosinophils and neutrophils in airway submucosa measured at baseline and after the 12-week treatment period.

  4. Changes in number of airway eosinophils and neutrophils in blood in patients treated with MEDI9929 compared to placebo. [ Time Frame: 12 weeks ]
    Number of eosinophils and neutrophils in blood, measured at baseline and after the 12-week treatment period.


Other Outcome Measures:
  1. Change in diversity in airway microbiota in patients treated with MEDI9929 compared to placebo [ Time Frame: 12 weeks ]
    Diversity of airway microbiota as measured by 16S gene sequencing in BAL measured at baseline and after the 12-week treatment period

  2. Change in airway microbiota in patients treated with MEDI9929 compared to placebo [ Time Frame: 12 weeks ]
    Relative abundances of airway microbiota as measured by 16S gene sequencing in BAL measured at baseline and after the 12-week treatment period

  3. The effect of MEDI9929 on TSLP mRNA expression [ Time Frame: 12 weeks ]
    mRNA expression of TSLP in airway submucosa, airway epithelium and sputum.

  4. The effect of MEDI9929 on IL-33 mRNA expression [ Time Frame: 12 weeks ]
    mRNA expression of IL-33 in airway submucosa, airway epithelium and sputum.

  5. The effect of MEDI9929 on TLRs mRNA expression [ Time Frame: 12 weeks ]
    mRNA expression of TLRs in airway submucosa, airway epithelium and sputum.

  6. The effect of MEDI9929 on IL-4 mRNA expression [ Time Frame: 12 weeks ]
    mRNA expression of IL-4 in airway submucosa, airway epithelium and sputum.

  7. The effect of MEDI9929 on IL-5 mRNA expression [ Time Frame: 12 weeks ]
    mRNA expression of IL-5 in airway submucosa, airway epithelium and sputum.

  8. The effect of MEDI9929 on IL-13 mRNA expression [ Time Frame: 12 weeks ]
    mRNA expression of IL-13 in airway submucosa, airway epithelium and sputum.

  9. The effect of MEDI9929 on level of Fractional Exhaled Nitric Oxide (FeNO) [ Time Frame: 12 weeks ]
    Level of FeNO (ppb) before and after 12-weeks treatment between groups

  10. The effect of MEDI9929 on use of rescue medication [ Time Frame: 12 weeks ]
    Number of puffs / week measured at baseline and after the 12-week treatment period

  11. Frequency of ILC2s in peripheral blood before and after treatment [ Time Frame: 12 weeks ]
    Number of ILC2 in peripheral blood measured at baseline and after the 12-week treatment period between groups

  12. Adverse Events [ Time Frame: up to 28 weeks ]
    number of reported Adverse Events between groups

  13. Change in ACQ [ Time Frame: 12 weeks ]
    ACQ-score measured at baseline and after the 12-week treatment period between groups

  14. Change in lung function [ Time Frame: 12 weeks ]
    FEV1 (post beta2) measured at baseline and after the 12-week treatment period



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent
  2. Age 18 through 75, inclusive at the time of Visit 1
  3. Body mass index between 18-40 kg/m2 (both inclusive) and weight ≥ 40 kg at Visit 1.
  4. A diagnosis of asthma as defined by GINA (ginasthma.org).
  5. ICS (in any dose) on a daily basis for at least three months prior to Visit 1
  6. A stable asthma controller regimen with ICS (±LABA) for at least 4 weeks prior to Visit 1
  7. A FEV1 value of ≥ 70% at Visit 1
  8. ACQ-6 > 1 (partly controlled) at Visit 1
  9. PD15 to mannitol <= 315 mg at visit 1
  10. Subjects must demonstrate acceptable inhaler and spirometry techniques during screening (as evaluated and in the opinion of study site staff)
  11. Subjects must demonstrate ≥ 70% compliance with usual asthma controller ICS±LABA during the screening (V1 to V3).

Exclusion Criteria:

  1. Current smokers or subjects with a smoking history of ≥ 10 pack years. Former smokers with < 10 pack years must have stopped for at least 6 months to be eligible.
  2. Previous medical history or evidence of an uncontrolled intercurrent illness.
  3. 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.
  4. Clinically relevant abnormal findings in hematology or clinical chemistry.
  5. Evidence of active liver disease.
  6. History of cancer.
  7. Acute upper or lower respiratory infections.
  8. Helminth parasitic infection.
  9. Known history of active tuberculosis (TB).
  10. Positive hepatitis B surface antigen, or hepatitis C virus antibody serology.
  11. A positive human immunodeficiency virus (HIV) test.
  12. History of sensitivity to any component of the investigational product.
  13. History of anaphylaxis to any biologic therapy.
  14. History of documented immune complex disease (Type III hypersensitivity reactions) to mAb administration.
  15. History of any known primary immunodeficiency disorder.
  16. Oral corticosteroids.
  17. Use of 5-lipoxygenase inhibitors.
  18. Use of immunosuppressive medication.
  19. Pregnant, breastfeeding or lactating females.
  20. History of chronic alcohol or drug abuse.
  21. Receipt of the Th2 cytokine inhibitor suplatast
  22. Receipt of any live or attenuated vaccines.

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): NCT02698501


Contacts
Contact: Asger Sverrild, MD, PhD +45 26 25 99 61 asgersverrild@gmail.com
Contact: Celeste Porsbjerg, MD, PhD +45 35 31 35 69 porsbjerg@dadlnet.dk

Locations
Denmark
Copenhagen University Hospital Bispebjerg Recruiting
Copenhagen, Denmark, 2400
Contact: Asger Sverrild, MD, PhD    +45 26259961    asgersverrild@gmail.com   
Sponsors and Collaborators
Celeste Porsbjerg
Lund University
University of Newcastle, Australia
University of Copenhagen
Investigators
Principal Investigator: Celeste Porsbjerg, MD, PhD Copehagen University Hospital Bispebjerg, Copenhagen, Denmark

Responsible Party: Celeste Porsbjerg, Chief Physician, PhD, University Hospital Bispebjerg and Frederiksberg
ClinicalTrials.gov Identifier: NCT02698501     History of Changes
Other Study ID Numbers: ESR-15-10870
First Posted: March 3, 2016    Key Record Dates
Last Update Posted: January 4, 2017
Last Verified: January 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Celeste Porsbjerg, University Hospital Bispebjerg and Frederiksberg:
Asthma
Airway hyperresponsiveness
TSLP
Mast cell
Eosinophil

Additional relevant MeSH terms:
Asthma
Respiratory Hypersensitivity
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases