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

Effects of Anti-TSLP on Airway Hyperresponsiveness and Mast Cell Phenotype in Asthma - A Randomized Double-blind, Placebo-controlled Trial of MEDI9929

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.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: MEDI9929; Drug: Placebo

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
• Enrollment (Actual): 40
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2400
    • Copenhagen University Hospital Bispebjerg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Decrease in airway hyperresponsiveness to mannitol in response to treatment with MEDI9929 in patients with asthma	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.	12 weeks
Supportive primary objective 1: Mannitol test negative in response to treatment with MEDI9929 in patients with asthma	Number of mannitol test negative (PD15 > 635mg) subjects after a 12-week treatment period between groups	12 weeks
Supportive primary objective 2: Decrease in airway hyperresponsiveness to mannitol in response to treatment with MEDI9929 in patients with asthma	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.	12 weeks
Supportive primary objective 3: Decrease in airway hyperresponsiveness to mannitol in response to treatment with MEDI9929 in patients with asthma	Change in RDR (Response Dose Ratio) to mannitol measured at baseline and after the 12-week treatment period between groups	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in number of Chymase/CPA-3 positive mast cells following treatment with MEDI9929	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	12 weeks
Changes in percentage of airway eosinophils and neutrophils in sputum in patients treated with MEDI9929 compared to placebo.	Percentage of eosinophils and neutrophils in sputum measured at baseline and after the 12-week treatment period.	12 weeks
Changes in percentage of airway eosinophils and neutrophils in airway submucosa in patients treated with MEDI9929 compared to placebo.	Percentage of eosinophils and neutrophils in airway submucosa measured at baseline and after the 12-week treatment period.	12 weeks
Changes in number of airway eosinophils and neutrophils in blood in patients treated with MEDI9929 compared to placebo.	Number of eosinophils and neutrophils in blood, measured at baseline and after the 12-week treatment period.	12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in diversity in airway microbiota in patients treated with MEDI9929 compared to placebo	Diversity of airway microbiota as measured by 16S gene sequencing in BAL measured at baseline and after the 12-week treatment period	12 weeks
Change in airway microbiota in patients treated with MEDI9929 compared to placebo	Relative abundances of airway microbiota as measured by 16S gene sequencing in BAL measured at baseline and after the 12-week treatment period	12 weeks
The effect of MEDI9929 on TSLP mRNA expression	mRNA expression of TSLP in airway submucosa, airway epithelium and sputum.	12 weeks
The effect of MEDI9929 on IL-33 mRNA expression	mRNA expression of IL-33 in airway submucosa, airway epithelium and sputum.	12 weeks
The effect of MEDI9929 on TLRs mRNA expression	mRNA expression of TLRs in airway submucosa, airway epithelium and sputum.	12 weeks
The effect of MEDI9929 on IL-4 mRNA expression	mRNA expression of IL-4 in airway submucosa, airway epithelium and sputum.	12 weeks
The effect of MEDI9929 on IL-5 mRNA expression	mRNA expression of IL-5 in airway submucosa, airway epithelium and sputum.	12 weeks
The effect of MEDI9929 on IL-13 mRNA expression	mRNA expression of IL-13 in airway submucosa, airway epithelium and sputum.	12 weeks
The effect of MEDI9929 on level of Fractional Exhaled Nitric Oxide (FeNO)	Level of FeNO (ppb) before and after 12-weeks treatment between groups	12 weeks
The effect of MEDI9929 on use of rescue medication	Number of puffs / week measured at baseline and after the 12-week treatment period	12 weeks
Frequency of ILC2s in peripheral blood before and after treatment	Number of ILC2 in peripheral blood measured at baseline and after the 12-week treatment period between groups	12 weeks
Adverse Events	number of reported Adverse Events between groups	up to 28 weeks
Change in ACQ	ACQ-score measured at baseline and after the 12-week treatment period between groups	12 weeks
Change in lung function	FEV1 (post beta2) measured at baseline and after the 12-week treatment period	12 weeks

Collaborators and Investigators

• Sponsor: Celeste Porsbjerg
• Collaborators: Lund University; University of Copenhagen; University of Newcastle, Australia
• Investigators: Principal Investigator: Celeste Porsbjerg, MD, PhD, Copehagen University Hospital Bispebjerg, Copenhagen, Denmark

Publications and helpful links

General Publications

• Sverrild A, Hansen S, Hvidtfeldt M, Clausson CM, Cozzolino O, Cerps S, Uller L, Backer V, Erjefalt J, Porsbjerg C. The effect of tezepelumab on airway hyperresponsiveness to mannitol in asthma (UPSTREAM). Eur Respir J. 2021 Dec 31;59(1):2101296. doi: 10.1183/13993003.01296-2021. Print 2022 Jan. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2016
• Primary Completion (Actual): August 7, 2019
• Study Completion (Actual): October 7, 2019

Study Registration Dates

• First Submitted: February 5, 2016
• First Submitted That Met QC Criteria: February 26, 2016
• First Posted (Estimate): March 3, 2016

Study Record Updates

• Last Update Posted (Actual): June 2, 2021
• Last Update Submitted That Met QC Criteria: May 30, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Asthma; Eosinophil; Mast cell; Airway hyperresponsiveness; TSLP
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma
• Other Study ID Numbers: ESR-15-10870

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No