Effects of Anti-TSLP in Patients With Asthma
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 2

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.
    

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.
    

Intervention name(s): MEDI9929; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): MEDI9929 700mg (3 doses in total, 4-week intervals), administered intravenously; Placebo (3 doses in total, 4-week intervals), administered intravenously
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Asthma; Airway hyperresponsiveness; TSLP; Mast cell; Eosinophil