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Anti-ST2 (MSTT1041A) in COPD (COPD-ST2OP) (COPD-ST2OP)

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ClinicalTrials.gov Identifier: NCT03615040
Recruitment Status : Completed
First Posted : August 3, 2018
Last Update Posted : February 25, 2021
Sponsor:
Collaborators:
Biomedical Research Centre- Respiratory (Glenfield Hospital, Leicester UK)
Leicester Clinical Trials Unit
Genentech, Inc.
Information provided by (Responsible Party):
University of Leicester

Brief Summary:

Chronic obstructive pulmonary disease (COPD) is a significant cause of morbidity and mortality worldwide. In contrast to other chronic diseases, COPD is increasing in prevalence and is projected to be the third-leading cause of death and disability worldwide by 2030. The costs to society for treating COPD are high, accounting for approximately 3.4% of the total health care budget of the European Union. Acute exacerbations of COPD (AECOPD) are responsible for a large portion of the economic burden of COPD. More than 500,000 hospitalisations and 100,000 deaths are attributed to AECOPD in the US each year. In addition to a substantial economic burden, AECOPD is also responsible for much of the morbidity and mortality from COPD.

Interleukin-33 (IL-33) is an alarmin released from the epithelium following damage. IL-33 is an IL-1 family alarmin cytokine constitutively expressed at epithelial barrier surfaces where it is rapidly released from cells during tissue injury. IL-33 signals through a receptor complex of IL-1 receptor-like 1 (IL1RL1) (known as ST2) and IL-1 receptor accessory protein (IL1RAcP) to initiate MyD88-dependent inflammatory pathways. The role of the IL33/ST2 axis in COPD is uncertain. IL33 has been implicated in eosinophil recruitment to the airway and maturation in the bone marrow largely via its effects upon innate lymphoid cells. IL33 increased following experimental cold in asthma and thus might play a role in the consequent inflammatory response and possible susceptibility to secondary bacterial infection in obstructive lung disease. Both eosinophilic inflammation and viral infection drive COPD exacerbations and therefore targeting the IL33/ST2 axis might reduce COPD exacerbations.

The main aim of this trial is to evaluate whether anti-ST2 will impact on airway inflammation in COPD and therefore reduce the frequency of exacerbations. For the purposes of this trial, exacerbations are defined as flare-ups of symptoms involving the use of healthcare resulting in treatment with steroids and/or antibiotics and/or hospitalisation or death due to COPD.


Condition or disease Intervention/treatment Phase
COPD Exacerbation Drug: MSTT1041A Drug: Placebo Phase 2

Detailed Description:

This is a single-centre, double-blind, placebo- controlled, parallel group, randomised controlled trial to assess the efficacy and safety of anti-ST2 compared to placebo, in patients with moderate to very severe COPD (GOLD II-IV). Anti-ST2 will be administered via subcutaneous injection once every 4 weeks (Week 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44) during the 48-week treatment period. Participants will be followed up for 60 weeks (i.e. 48 week treatment period and 12 week follow-up), with secondary outcome measures at baseline, 4, 12, 24, 36, 48 and 60 weeks and at exacerbation events presenting prior to treatment initiation.

After signing the informed consent at the initial visit, patients will enter a screening period which should last for up to 2 weeks unless extension of the screening period is necessary under certain circumstances. Patients who qualify to participate in the study will be randomised into a 48-week treatment period in which they will receive either 490 mg anti-ST2 or a matching placebo. Patients will be evaluated for an additional 12 weeks following completion of the randomised treatment period. Treatment groups will remain blinded until the 60-week follow-up period is completed, and trial database is locked.

This trial is sponsored by the University of Leicester, coordinated by the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) - Respiratory and Leicester Clinical Trials Unit (LCTU) and funded by Genentech, Inc.

The primary objective of the study is to evaluate the efficacy of anti-ST2 versus placebo on frequency of moderate-to-severe exacerbations (health care utilisation resulting in treatment with systemic corticosteroids and/or antibiotics or hospitalisation, respectively) as add-on to standard of care.

Secondary objectives: another key objective is to assess the safety and tolerability of subcutaneous (SC) doses of anti-ST2 compared to placebo in adult patients with moderate to very severe COPD.

Additionally, to assess the effects of anti-ST2 versus placebo both during stable visits and at the exacerbation events on the following:

  1. Symptoms
  2. Health status
  3. Lung function
  4. Inflammatory cell differentials i. Sputum cell count ii. Blood cell count
  5. Airway morphometry
  6. Pharmacogenomics

Exploratory objectives include:

  1. Systemic inflammation
  2. Upper airway inflammation
  3. Airway infection and ecology
  4. Breath volatile organic compound profiling
  5. Quantitative airway geometry and densitometry
  6. Pharmacogenomics
  7. Pharmacokinetics and ADA level
  8. Pharmacogenomics response analysis in subgroups determined by SNPs for alleles associated with the IL33/ST2 axis.

Subgroup objectives: to evaluate the efficacy of anti-ST2 versus placebo on the outcome rate of protocol-defined COPD exacerbations through 48 weeks treatment period, patient reported outcomes (PROs) [SGRQ-c], and lung function [FEV1] in subgroups defined by baseline blood eosinophil count.

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Study Type : Interventional
Actual Enrollment : 81 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Single-centre, double-blinded, placebo-controlled, parallel group, randomised controlled trial
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: A or B
Primary Purpose: Treatment
Official Title: A Randomised Placebo-controlled Trial of Anti-ST2 in COPD (COPD-ST2OP)
Actual Study Start Date : October 11, 2018
Actual Primary Completion Date : May 29, 2020
Actual Study Completion Date : December 31, 2020

Arm Intervention/treatment
Experimental: Anti-ST2
Anti-ST2 (MSTT1041A) received as subcutaneous injection by infusion pump at 490mg every 4 weeks over a 48 week treatment period.
Drug: MSTT1041A

MSTT1041A (RO7187807; formerly made by Amgen [AMG] and referred to as AMG 282) is a novel biopharmaceutical that blocks signaling of interleukin (IL)-33, an inflammatory cytokine of the IL-1 family and member of the newly discovered "alarmin" class of molecules. IL-33 is released from airway epithelial cells in response to allergens, irritants, and infection. IL-33 release can trigger acute exacerbations in both asthma and COPD. MSTT1041A has the ability to block inflammation,prevent exacerbations, and improve lung function and quality of life.

Anti-ST2 is presented as sterile, clear, and colourless to slightly yellow liquid. Each sterile vial is filled with a 1 mL deliverable volume of 70 mg/mL. It is formulated with 15 mM sodium acetate, 9.0% (w/v) sucrose, 0.01% (w/v) polysorbate 20, pH 5.2.

Other Names:
  • RO7187807
  • ST2 MAb
  • Anti-ST2
  • AMG 282
  • RG6149

Placebo Comparator: Placebo
Placebo (no active component) received as subcutaneous injection by infusion pump at 490mg every 4 weeks over a 48 week treatment period.
Drug: Placebo
Placebo for Anti-ST2 (MSTT1041A) is formulated with 10 mM sodium acetate, 9.0% (w/v) sucrose, 0.004% (w/v) polysorbate 20, pH 5.2, and is supplied in an identical vial configuration.




Primary Outcome Measures :
  1. Frequency of moderate to severe exacerbation (defined as requiring treatment with systemic corticosteroids and/or antibiotics in the community or hospital or hospitalisation). [ Time Frame: 0-48 weeks ]

    Where a COPD exacerbation is defined by symptomatic worsening of COPD requiring:

    • Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or
    • Use of antibiotics and/or
    • inpatient hospitalisation or death due to COPD


Secondary Outcome Measures :
  1. Adverse Event rate in the 48 weeks of the trial from first dose [ Time Frame: Weeks 0 , 4, 12, 24, 26, 48, 60 and unscheduled visit(s) at any time point between 0-60 weeks ]
    To assess safety and tolerability

  2. Serious Adverse Event rate in the 48 weeks of the trial from first dose [ Time Frame: Weeks 0 , 4, 12, 24, 26, 48, 60 and unscheduled visit(s) at any time point between 0-60 weeks ]
    To assess safety and tolerability

  3. St George's Respiratory Questionnaire for COPD Patients (SGRQ-C) [ Time Frame: Weeks 0, 12, 24, 36, 48, 60 ]
    Patient reported outcome (PRO). To evaluate health status; designed to measure health impairment in patients with asthma and COPD. It is in two parts. Part I produces the Symptoms score, and Part 2 the Activity and Impact scores. A Total score is also produced. The Total score is calculated by summing the weights to all the positive responses in each component. The score for each component is calculated separately by dividing the summed weights by the maximum possible weight for that component and expressing the result as a percentage. Maximum possible weights for components: Symptoms (566.2), Activity (982.9), Impacts (1652.8). Total (3201.9, which would represent the worst possible state of the patient.

  4. COPD Assessment Test (CAT) (Questionnaire) [ Time Frame: Weeks 0, 4, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks ]
    Patient reported outcome (PRO). To evaluate health status: evaluation and rehabilitation education guidance on the respiratory and motor functions of patients with chronic obstructive pulmonary disease. The CAT has a scoring range of 0-40, with Since COPD is a progressive disease, a fi xed target score for all patients cannot be set. In Practice, a target for improvement in individual patient CAT scores may be set, based on an holistic assessment of the patient. A change of 2 units suggests a meaningful difference. This test should be used in conjunction with the mMRC and forced expiratory volume in one second (FEV1) to determine COPD health assessment of participants.

  5. modified Medical Research Council (mMRC) Dyspnea Scale [ Time Frame: Screening, weeks 0, 4, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks ]
    Patient reported outcome (PRO). To evaluate respiratory breathlessness symptoms (Grade 0-4, with Grade 0 being breathlessness with strenuous exercise to Grade 4 being breathlessness for daily activities like dressing). The mMRC Dyspnea Scale score must be contextualized with an individual patient's history, physical, and available diagnostic test results. For patients with a higher mMRC grade (e.g. ≥2) and clinical circumstances consistent with respiratory disease, measuring spirometry (e.g., FEV₁ and FVC), determining the patient's Body-mass index, airflow Obstruction, Dyspnea, and Exercise (BODE) Index and/or GOLD stage, and pursuing further targeted diagnostic and/or therapeutic interventions is appropriate. A patient's mMRC Dyspnea Scale score, or another dyspnea measurement, such as the COPD Assessment Test (CAT), is combined with the patient's FEV₁ percent predicted and the frequency of COPD exacerbations to guide treatment interventions

  6. Visual analogue score (VAS) total and individual dyspnoea, cough, sputum production (100mm) scores [ Time Frame: Weeks 0, 4, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks ]
    Patient reported outcome (PRO). To evaluate respiratory symptoms. The participant is asked to place a mark (X) on the scale at the point that best describes their health currently. Minimum score 0mm (better outcome), maximum score 100mm (worse outcome) for each section of the scale (dyspnoea, cough, sputum).

  7. Sputum purulence colour card [ Time Frame: Screening, week 12, 28, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks ]
    Patient reported outcome (PRO) using the Bronko Test sputum colour chart. To evaluate respiratory symptoms and verify a bacterial cause of an exacerbation.

  8. Pre and Post Bronchodilator (BD) Spirometry [ Time Frame: Week 0 and Week 48 ]
    To assess lung function. The participant will take a maximum inhalation, release maximum exhalation and then continue to exhale afterwards. They will then be treated with a bronchodilator. The spirometry test is then repeated to determine how much the bronchodilator medication helped with breathing. FEV1, FEV1 % predicted, FVC, FEV1/FVC % will be measured.

  9. Post BD Forced Expiratory Volume in 1 Second (FEV1) [ Time Frame: Screening, Weeks 4, 12, 24, 36, 48 and 60, unscheduled visit(s) at any time point between 0-60 weeks ]
    To assess lung function. FEV1 is the volume of air that can forcibly be blown out in first 1 second, after full inspiration. Pre and post FEV1, pre and post FEV1 % predicted, pre and post FVC, pre and post FEV1/FVC % and BD reversibility will be measured.

  10. Body plethysmography ('body box') [ Time Frame: Anytime between screening and week 12, unless patient has had the test within 12 months prior to screening visit. ]
    To assess lung function, i.e. the functional residual capacity of the lungs. The participant sits inside an airtight box, inhales or exhales to a particular volume (usually FRC), and then a shutter drops across their breathing tube. The participant makes respiratory efforts against the closed shutter, causing their chest volume to expand and decompressing the air in their lungs. The increase in their chest volume slightly reduces the box volume (the non-person volume of the box) and thus slightly increases the pressure in the box. TLC, RV and RV/TLC% will be measured.

  11. Blood inflammatory cell differentials [ Time Frame: Weeks 0, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks ]
    To assess inflammation at exacerbation events. White blood cells, eosinophils and neutrophils will be measured.

  12. Sputum inflammatory cell differentials [ Time Frame: Weeks 0, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks ]
    To assess inflammation at exacerbation events. Eosinophils, neutrophils, macrophages, lymphocytes and epithelial cells and total will be measured.


Other Outcome Measures:
  1. Non-contrast thoracic CT derived outcomes [Exploratory Outcome] [ Time Frame: Screening and week 48 ]
    Quantitative measures of airway geometry and densitometry. Mean lung density expiratory/inspiratory [MLD E/I] (small airway), % wall area [WA] and LA (larger airways) will be measured.

  2. Sputum mediator profiling (biomarkers) [Exploratory Outcome] [ Time Frame: Weeks 0, 4, 12, 24, 36, 48, 60 and unscheduled visit(s)at any time point between 0-60 weeks ]
    Various biomarkers of inflammation will be measured in sputum.

  3. Blood biomarkers [Exploratory Outcome] [ Time Frame: Screening, weeks 4, 12, 24, 36, 48, 60, withdrawal visit (if applicable) and unscheduled visit(s)at any time point between 0-60 weeks ]
    Various biomarkers of inflammation will be measured in blood.

  4. Cell subset analysis including but not restricted to exploration of ILC2 cells [Exploratory Outcome] [ Time Frame: Screening, weeks 4, 12, 24, 36, 48, 60, withdrawal visit (if applicable) and unscheduled visit(s)at any time point between 0-60 weeks ]
    ILC2 cells will be analysed using plasma for biomarkers.

  5. Urine biomarkers of inflammation [Exploratory Outcome] [ Time Frame: Screening, weeks 0, 4, 12, 24, 36, 48, 60, withdrawal visit (if applicable) and unscheduled visit(s) at any time point between 0-60 weeks ]
    Various biomarkers of inflammation will be measured in urine.

  6. Mediator profiling (biomarkers) [Exploratory Outcome] [ Time Frame: Weeks 0, 4, 12, 24, 36, 48, 60 and unscheduled visit(s)at any time point between 0-60 weeks ]
    Mediators of inflammation in blood, sputum and urine will be assessed.

  7. Nasosorption [Exploratory Outcome] [ Time Frame: Screening, Weeks 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks ]
    To assess upper airway inflammation. This is a non-invasive method to sample nasal mucosal lining fluid using a synthetic absorptive matrix (SAM) of low protein binding. The SAM is advanced up the lumen of the nasal cavity, and then the outside of the nose is gently pressed to oppose the SAM against the nasal mucosa for 30 seconds.

  8. Nasal Epithelial Sampling [Exploratory Outcome] [ Time Frame: Screening, weeks 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks ]
    To assess airway upper inflammation. Nasal epithelial cells will be sampled from the anterior nares using either a polyester swab or a cytology brush with the standard collection method - cytology brush sampling from beneath the inferior turbinate. This test is optional for participants.

  9. Breath volatile organic compound (VOC) profiling [Exploratory Outcome] [ Time Frame: Screening, Weeks 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks ]
    To assess inflammation. PTR-MS, ADVION and ReCIVA will be used to measure gaseous molecules found in the breath that are from inside and outside the lungs. We aim to collect these molecule and analyse them to see if there are any changes in a persons breath that could be linked to the metabolic health, before, during and after taking the drug or placebo.

  10. Microbiomics [Exploratory Outcome] [ Time Frame: Weeks 0, 4, 12, 24, 36, 48, 60 and unscheduled visit(s) at any time point between 0-60 weeks ]
    To assess airway infection and ecology. We will analyse the microbes in patients' lungs using their sputum samples and profile the effect of treatment on these microbes.

  11. Targeted qPCR (bacteria and viruses) for common airway pathogens [Exploratory Outcome] [ Time Frame: Weeks 0, 4, 12, 24, 36, 48, 60 and unscheduled visit(s) at any time point between 0-60 weeks ]
    To assess airway infection and ecology. We will analyse the microbes in patients' lungs and profile the effect of treatment on these microbes.

  12. Pharmacogenomics response analysis in subgroups determined by SNPs for alleles associated with the IL33/ST2 axis. [Exploratory Outcome] [ Time Frame: Baseline and week 48 ]
    To evaluate the rate of protocol-defined COPD exacerbations through 48 weeks treatment period, patient reported outcomes (PROs), and lung functions, by subgroup outcomes.

  13. Baseline blood eosinophil count [Subgroup objective] [ Time Frame: Screening, weeks 4, 12, 24, 36, 48, 60, withdrawal and unscheduled visits (if applicable) ]
    To evaluate the efficacy of anti-ST2 versus placebo on the outcome rate of protocol-defined COPD exacerbations through 48 weeks treatment period, patient reported outcomes (PROs) and lung function in subgroups defined by baseline blood eosinophil count.

  14. St George's Respiratory Questionnaire for COPD patients (SGRQ-c) [Subgroup Objective] [ Time Frame: Weeks 0, 4, 12, 24, 36, 48, 60, withdrawal and unscheduled visits (if applicable) ]
    To evaluate the efficacy of anti-ST2 versus placebo on the outcome rate of protocol-defined COPD exacerbations through 48 weeks treatment period, patient reported outcomes (PROs) and lung function in subgroups defined by baseline blood eosinophil count.

  15. FEV1 [Subgroup Objective] [ Time Frame: Weeks 0 and 48 ]
    To evaluate the efficacy of anti-ST2 versus placebo on the outcome rate of protocol-defined COPD exacerbations through 48 weeks treatment period, patient reported outcomes (PROs) and lung function in subgroups defined by baseline blood eosinophil count.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Symptoms typical of COPD when stable (baseline mMRC dyspnoea score ≥ 2)
  2. GOLD COPD stage 2-4
  3. Smoking pack years ≥ 10 years
  4. Age > 40 years
  5. Receiving standard-of-care drug therapy as per British Thoracic Society (BTS) guidance for COPD
  6. A history of ≥ 2 moderate-to-severe exacerbations in the last 12 months.
  7. Be able to give valid written consent; compliant with study procedures and study visits.
  8. Able to understand written and spoken English

Exclusion Criteria:

  1. Significant known respiratory disorders other than COPD that in the view of the investigator will affect the study
  2. Patients whose treatment is considered palliative (life expectancy <12 months)
  3. Known hypersensitivity to the active substance of the investigational product (IP) or any of the excipients
  4. Known history of anaphylaxis
  5. Patients with a COPD exacerbation and/or pneumonia within the 4 weeks prior to visit 1
  6. Have, in the opinion of investigator, uncontrolled co-morbid conditions, such as diabetes mellitus, hypertension and heart failure [e.g. New York Heart Association (NYHA) class III (e.g. less than ordinary activity causes fatigue, palpitation, or dyspnoea), and class IV (e.g. Symptoms of heart failure at rest)] that will affect the study.
  7. Myocardial infarction, unstable angina or stroke within 12 month prior to screening
  8. Diagnosis of malignancy within 5 years of visit 1 (except for excised localised carcinoma of skin not including malignant melanoma)
  9. Clinically significant ECG changes, which in the opinion of investigator warrants further investigations
  10. Laboratory abnormalities, which in the opinion of investigator warrants further investigations
  11. Have, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse.
  12. Pregnant, breastfeeding, or lactating women. Women of child-bearing potential (i.e. not surgically sterilised or post- menopausal) must have a negative blood serum pregnancy test performed at the screening visit and must agree to use two methods of birth control, (one of which must be a barrier method).
  13. Participation in an interventional clinical study within 3 months of visit 1 or receipt of any investigational medicinal product within 3 months or 5 half- lives.
  14. Upon questioning the patient has blood born infection (e.g. HIV, hepatitis B or C)

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): NCT03615040


Locations
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United Kingdom
Biomedical Research Centre- Respiratory, Glenfield Hospital
Leicester, Leicestershire, United Kingdom, LE3 9QP
Sponsors and Collaborators
University of Leicester
Biomedical Research Centre- Respiratory (Glenfield Hospital, Leicester UK)
Leicester Clinical Trials Unit
Genentech, Inc.
Investigators
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Principal Investigator: Christopher Brightling, Prof University of Leicester
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Responsible Party: University of Leicester
ClinicalTrials.gov Identifier: NCT03615040    
Other Study ID Numbers: 0671
2018-000919-24 ( EudraCT Number )
GB40568 ( Other Grant/Funding Number: Genentech )
U1111-1210-1335 ( Other Identifier: WHO Universal Trial Number )
244758 ( Other Identifier: IRAS Number )
18/EM/0189 ( Other Identifier: East Midlands - Leicester South Research Ethics Committee )
First Posted: August 3, 2018    Key Record Dates
Last Update Posted: February 25, 2021
Last Verified: June 2020
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 University of Leicester:
COPD
Exacerbations
ST2 MAb
RG6149
MSTT1041A
Anti-ST2
Phase IIa
Placebo controlled
Additional relevant MeSH terms:
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Pulmonary Disease, Chronic Obstructive
Lung Diseases, Obstructive
Lung Diseases
Respiratory Tract Diseases