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

Study Overview
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Brief Summary
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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.

Detailed Description
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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: Symptoms Health status Lung function Inflammatory cell differentials i. Sputum cell count ii. Blood cell count Airway morphometry Pharmacogenomics Exploratory objectives include: Systemic inflammation Upper airway inflammation Airway infection and ecology Breath volatile organic compound profiling Quantitative airway geometry and densitometry Pharmacogenomics Pharmacokinetics and ADA level 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.

Official Title
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A Randomised Placebo-controlled Trial of Anti-ST2 in COPD (COPD-ST2OP)

Conditions
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COPD Exacerbation

Intervention / Treatment
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* Drug: MSTT1041A
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Symptoms typical of COPD when stable (baseline mMRC dyspnoea score ≥ 2) GOLD COPD stage 2-4 Smoking pack years ≥ 10 years Age > 40 years Receiving standard-of-care drug therapy as per British Thoracic Society (BTS) guidance for COPD A history of ≥ 2 moderate-to-severe exacerbations in the last 12 months. Be able to give valid written consent; compliant with study procedures and study visits. Able to understand written and spoken English Exclusion Criteria: Significant known respiratory disorders other than COPD that in the view of the investigator will affect the study Patients whose treatment is considered palliative (life expectancy <12 months) Known hypersensitivity to the active substance of the investigational product (IP) or any of the excipients Known history of anaphylaxis Patients with a COPD exacerbation and/or pneumonia within the 4 weeks prior to visit 1 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. Myocardial infarction, unstable angina or stroke within 12 month prior to screening Diagnosis of malignancy within 5 years of visit 1 (except for excised localised carcinoma of skin not including malignant melanoma) Clinically significant ECG changes, which in the opinion of investigator warrants further investigations Laboratory abnormalities, which in the opinion of investigator warrants further investigations Have, in the opinion of the investigator, evidence of alcohol, drug or solvent abuse. 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). 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. Upon questioning the patient has blood born infection (e.g. HIV, hepatitis B or C)

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Single-centre, double-blinded, placebo-controlled, parallel group, randomised controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anti-ST2<br>Anti-ST2 (MSTT1041A) received as subcutaneous injection by infusion pump at 490mg every 4 weeks over a 48 week treatment period. | Drug: MSTT1041A<br>* 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.<br>* Other names: RG6149;|
| Placebo Comparator: Placebo<br>Placebo (no active component) received as subcutaneous injection by infusion pump at 490mg every 4 weeks over a 48 week treatment period. | Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Moderate to Severe Exacerbation (Defined as Requiring Treatment With Systemic Corticosteroids and/or Antibiotics in the Community or Hospital or Hospitalisation). | 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 | 0-48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Event Rate in the 48 Weeks of the Trial From First Dose | Number of Participants with Adverse Events in the 48 Weeks of the Trial From First Dose | Weeks 0 , 4, 12, 24, 26, 48 | 
| Serious Adverse Event Rate in the 48 Weeks of the Trial From First Dose | Number of Participants with Serious Adverse Events in the 48 Weeks of the Trial From First Dose | Weeks 0 , 4, 12, 24, 26, 48 | 
| St George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Total Score | 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. This score is then put onto the scale 0 to 100 by dividing by the Total possible sum (3201.9)- and times by 100. A score of 0 would represent the best health and a score of 100 would represent the worst possible state of the patient. | Weeks 0, 4, 12, 24, 36, 48 | 
| COPD Assessment Test (CAT) (Questionnaire) | 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. CAT score is made by summing the score to eight questions on COPD. For each, the person with COPD picks the number between 0-5 that reflects their response. A zero indicates no effect on quality of life, whereas a 5 suggests a very significant effect.The CAT has a scoring range of 0-40, with 40 indicating the most severe COPD and 0 being the least severe COPD. 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. | Weeks 0, 4, 12, 24, 36, 48 | 
| Modified Medical Research Council (mMRC) Dyspnea Scale | 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). | Screening, weeks 0, 4, 12, 24, 36, 48 | 
| Visual Analogue Score (VAS) Total and Individual Dyspnoea, Cough, Sputum Production (100mm) Scores | 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). The Total VAS score is the sum of the 3 scales, thus the minimum score is 0 (best outcome) and the maximum 300 (worst outcome). | Weeks 0, 4, 12, 24, 36, 48 | 
| Sputum Purulence Colour Card | The sputum purulence colour card using the Bronko test has values of 0, 1, 2, 3, 4, 5 and 6. Lower scores indicate better health. | Screening, week 12, 28, 36, 48 | 
| Pre and Post Bronchodilator (BD) Spirometry - FEV1/FVC Ratio | 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/FVC ratio will be calculated. | Week 0 and Week 48 | 
| Post BD Forced Expiratory Volume in 1 Second (FEV1) | To assess lung function. FEV1 is the volume of air that can forcibly be blown out in first 1 second, after full inspiration. Post BD Forced Expiratory Volume in 1 Second (FEV1) | Screening, Weeks 4, 12, 24, 36, 48 | 
| Body Plethysmography ('Body Box') Total Lung Capacity and Residual Volume | 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. Total Lung Capacity and Residual Volume measured. | Week 0 and week 48 | 
| Blood Inflammatory Cell Differentials | To assess inflammation at exacerbation events. White blood cells, eosinophils and neutrophils will be measured. | Weeks 0, 4, 12, 24, 36, 48 | 
| Sputum Inflammatory Cell Differentials: Eosinophils | To assess inflammation at exacerbation events. Eosinophils cells will be measured. | Weeks 0, 4, 12, 24, 36, 48 | 
| Pre and Post Bronchodilator (BD) Spirometry- FEV1 and FVC | 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 and FVC will be measured. | Week 0 and Week 48 | 
| Pre and Post Bronchodilator (BD) Spirometry- FEV1 Predicted and FVC Predicted | 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 % predicted and FVC % predicted will be measured. | Week 0 and Week 48 | 
| Body Plethysmography ('Body Box') - Residual Volume/Total Lung Capacity Ratio | 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. Residual Volume/Total Lung Capacity ratio will be calculated. RV/TLC ratio: this is the residual volume (RV) to total lung capacity (TLC). It is calculated as a percentage as follows: RV/TLC ×100. | Week 0 and week 48 | 
| Sputum Inflammatory Cell Differentials: Macrophages | To assess inflammation at exacerbation events. Sputum inflammatory cell differentials: Macrophages | Weeks 0, 4, 12, 24, 36, 48 | 
| Sputum Inflammatory Cell Differentials: Epithelium | To assess inflammation at exacerbation events. Epithelium cells will be measured. | Weeks 0, 4, 12, 24, 36, 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COPD, Exacerbations, ST2 MAb, RG6149, MSTT1041A, Anti-ST2, Phase IIa, Placebo controlled