A Randomised Placebo-controlled Trial of Anti-ST2 in COPD (COPD-ST2OP)
Overview
- Phase
- Phase 2
- Intervention
- MSTT1041A
- Conditions
- COPD Exacerbation
- Sponsor
- University of Leicester
- Enrollment
- 81
- Locations
- 1
- Primary Endpoint
- Number of Moderate to Severe Exacerbation (Defined as Requiring Treatment With Systemic Corticosteroids and/or Antibiotics in the Community or Hospital or Hospitalisation).
- Status
- Completed
- Last Updated
- 3 years ago
Overview
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.
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.
Investigators
Eligibility Criteria
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
Arms & Interventions
Anti-ST2
Anti-ST2 (MSTT1041A) received as subcutaneous injection by infusion pump at 490mg every 4 weeks over a 48 week treatment period.
Intervention: MSTT1041A
Placebo
Placebo (no active component) received as subcutaneous injection by infusion pump at 490mg every 4 weeks over a 48 week treatment period.
Intervention: Placebo
Outcomes
Primary Outcomes
Number 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 Outcomes
- Serious Adverse Event Rate 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(Weeks 0, 4, 12, 24, 36, 48)
- Sputum Purulence Colour Card(Screening, week 12, 28, 36, 48)
- Post BD Forced Expiratory Volume in 1 Second (FEV1)(Screening, Weeks 4, 12, 24, 36, 48)
- Adverse Event Rate in the 48 Weeks of the Trial From First Dose(Weeks 0 , 4, 12, 24, 26, 48)
- Visual Analogue Score (VAS) Total and Individual Dyspnoea, Cough, Sputum Production (100mm) Scores(Weeks 0, 4, 12, 24, 36, 48)
- Body Plethysmography ('Body Box') Total Lung Capacity and Residual Volume(Week 0 and week 48)
- Blood Inflammatory Cell Differentials(Weeks 0, 4, 12, 24, 36, 48)
- Sputum Inflammatory Cell Differentials: Macrophages(Weeks 0, 4, 12, 24, 36, 48)
- Pre and Post Bronchodilator (BD) Spirometry - FEV1/FVC Ratio(Week 0 and Week 48)
- Sputum Inflammatory Cell Differentials: Eosinophils(Weeks 0, 4, 12, 24, 36, 48)
- Pre and Post Bronchodilator (BD) Spirometry- FEV1 and FVC(Week 0 and Week 48)
- Pre and Post Bronchodilator (BD) Spirometry- FEV1 Predicted and FVC Predicted(Week 0 and Week 48)
- Body Plethysmography ('Body Box') - Residual Volume/Total Lung Capacity Ratio(Week 0 and week 48)
- COPD Assessment Test (CAT) (Questionnaire)(Weeks 0, 4, 12, 24, 36, 48)
- Modified Medical Research Council (mMRC) Dyspnea Scale(Screening, weeks 0, 4, 12, 24, 36, 48)
- Sputum Inflammatory Cell Differentials: Epithelium(Weeks 0, 4, 12, 24, 36, 48)