AsthmaPhase 2UPSTREAMNCT02698501
Effects of Anti-TSLP in Patients With Asthma
A Phase 2 study testing MEDI9929 in people with Asthma, run by Celeste Porsbjerg at 1 site in Denmark.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Asthma
- What is being tested?
- MEDI9929
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 1 siteDenmark
- Study dates
- Aug 2016to 7 Oct 2019
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Written informed consent
- Age 18 through 75, inclusive at the time of Visit 1
- Body mass index between 18-40 kg/m2 (both inclusive) and weight ≥ 40 kg at Visit 1.
- A diagnosis of asthma as defined by GINA (ginasthma.org).
- ICS (in any dose) on a daily basis for at least three months prior to Visit 1
- A stable asthma controller regimen with ICS (±LABA) for at least 4 weeks prior to Visit 1
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- A FEV1 value of ≥ 70% at Visit 1
- ACQ-6 > 1 (partly controlled) at Visit 1
- PD15 to mannitol <= 315 mg at visit 1
- Subjects must demonstrate acceptable inhaler and spirometry techniques during screening (as evaluated and in the opinion of study site staff)
- Subjects must demonstrate ≥ 70% compliance with usual asthma controller ICS±LABA during the screening (V1 to V3).
Who cannot join
- 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.
- Previous medical history or evidence of an uncontrolled intercurrent illness.
- 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.
- Clinically relevant abnormal findings in hematology or clinical chemistry.
- Evidence of active liver disease.
- History of cancer.
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- Acute upper or lower respiratory infections.
- Helminth parasitic infection.
- Known history of active tuberculosis (TB).
- Positive hepatitis B surface antigen, or hepatitis C virus antibody serology.
- A positive human immunodeficiency virus (HIV) test.
- History of sensitivity to any component of the investigational product.
- History of anaphylaxis to any biologic therapy.
- History of documented immune complex disease (Type III hypersensitivity reactions) to mAb administration.
- History of any known primary immunodeficiency disorder.
- Oral corticosteroids.
- Use of 5-lipoxygenase inhibitors.
- Use of immunosuppressive medication.
- Pregnant, breastfeeding or lactating females.
- History of chronic alcohol or drug abuse.
- Receipt of the Th2 cytokine inhibitor suplatast
- Receipt of any live or attenuated vaccines.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the 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.
- Conditions
- Asthma
- Being tested
- MEDI9929, Placebo
- Keywords
- Asthma, Airway hyperresponsiveness, TSLP, Mast cell, Eosinophil
- Medical subject headings
- Asthma, Respiratory Hypersensitivity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MEDI9929Drug
MEDI9929 700mg (3 doses in total, 4-week intervals), administered intravenously
PlaceboDrug
Placebo (3 doses in total, 4-week intervals), administered intravenously
| Study group | Role | What they receive |
|---|---|---|
| MEDI9929 | Experimental | 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). Receives: Drug: MEDI9929 |
| Placebo | Placebo comparator | Apart from the active substance, the placebo is otherwise identical to IMP. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
Measured: 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.
Measured: 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
Measured: 12 weeks
Secondary outcomes (4)
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
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Mar 2016 (estimated)
- Study startAug 2016
- Primary completion7 Aug 2019
- Study completion7 Oct 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for AsthmaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- Celeste Porsbjerg
- Sponsor type
- University, hospital or other
- Collaborators
- Lund University, University of Newcastle, Australia, University of Copenhagen
- Responsible party
- Sponsor-investigator, Celeste Porsbjerg, University Hospital Bispebjerg and Frederiksberg
- Investigators
- Celeste Porsbjerg, MD, PhD, Principal investigator, Copehagen University Hospital Bispebjerg, Copenhagen, Denmark
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02698501
- Sponsor's protocol ID
- ESR-15-10870
- Acronym
- UPSTREAM
- Status last verified
- May 2021
- First submitted
- 5 Feb 2016
- Last updated
- 2 Jun 2021
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
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.
PubMed 34049943
Study at a glance
From the registry record, last updated by the sponsor on 2 Jun 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of Anti-TSLP on Airway Hyperresponsiveness and Mast Cell Phenotype in Asthma - A Randomized Double-blind, Placebo-controlled Trial of MEDI9929
- ClinicalTrials.gov ID
- NCT02698501
- Acronym / sponsor ID
- UPSTREAM / ESR-15-10870
- Conditions
- Asthma
- Keywords
- Asthma, Airway hyperresponsiveness, TSLP, Mast cell, Eosinophil
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 40 participants (actual)
- Lead sponsor
- Celeste PorsbjergUniversity, hospital or other
- Collaborators
- Lund University, University of Newcastle, Australia, University of Copenhagen
- Study start
- Aug 2016 (actual)
- Primary completion
- 7 Aug 2019 (actual)
- Study completion
- 7 Oct 2019 (actual)
- First posted
- 3 Mar 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| MEDI9929 | Experimental | Drug: MEDI9929MEDI9929 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). |
| Placebo | Placebo comparator | Drug: PlaceboApart from the active substance, the placebo is otherwise identical to IMP. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Written informed consent
- Age 18 through 75, inclusive at the time of Visit 1
- Body mass index between 18-40 kg/m2 (both inclusive) and weight ≥ 40 kg at Visit 1.
- A diagnosis of asthma as defined by GINA (ginasthma.org).
- ICS (in any dose) on a daily basis for at least three months prior to Visit 1
Key exclusion criteria (22 listed)
- 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.
- Previous medical history or evidence of an uncontrolled intercurrent illness.
- 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.
- Clinically relevant abnormal findings in hematology or clinical chemistry.
- Evidence of active liver disease.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MEDI9929MEDI9929 700mg (3 doses in total, 4-week intervals), administered intravenously | Drug | MEDI9929 |
| PlaceboPlacebo (3 doses in total, 4-week intervals), administered intravenously | Drug | Placebo |
Primary outcome
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.
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
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.
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
4 secondary outcomes
Change in number of Chymase/CPA-3 positive mast cells following treatment with MEDI9929
Time frame: 12 weeks
Changes in percentage of airway eosinophils and neutrophils in sputum in patients treated with MEDI9929 compared to placebo.
Time frame: 12 weeks
Changes in percentage of airway eosinophils and neutrophils in airway submucosa in patients treated with MEDI9929 compared to placebo.
Time frame: 12 weeks
Changes in number of airway eosinophils and neutrophils in blood in patients treated with MEDI9929 compared to placebo.
Time frame: 12 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jun 2021.
- Derived from this study: PubMed 34049943Sverrild 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Celeste Porsbjerg, MD, PhD principal investigator
Copehagen University Hospital Bispebjerg, Copenhagen, Denmark
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing MEDI9929 in people with Asthma, run by Celeste Porsbjerg at 1 site in Denmark.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Jun 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Decrease in airway hyperresponsiveness to mannitol in response to treatment with MEDI9929 in patients with asthma (time frame: 12 weeks). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02698501, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jun 2021.