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

Overview

This will be a single-centre, double-blinded, placebo- controlled, parallel group, randomised controlled trial comparing MSTT1041A (anti-ST2 antibody) versus placebo in COPD. MSTT1041A 490mg s/c or matched placebo dosed every 4 weeks for a total of 12 doses. Patients 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.

Full Title of Study: “A Randomised Placebo-controlled Trial of Anti-ST2 in COPD (COPD-ST2OP)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: April 30, 2020

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. The treatment period will be followed by a 12-week follow-up period.

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 randomized 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 randomized treatment period. An interim analysis is planned when the last patient completes the 48-week treatment period. Treatment groups will remain blinded until the 48-week follow-up period is completed, and trial database is locked.

This study will be a single-centre randomised controlled trial (RCT), sponsored by the University of Leicester and coordinated by the Leicester National Institute for Health Research (NIHR) Respiratory Biomedical Research Centre (BRC) and Leicester Clinical Trials Unit (LCTU).

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

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. Sputum airway inflammation

5. Upper airway inflammation

6. Systemic inflammation

7. Airway infection and ecology

8. Breath volatile organic compound profiling

9. Airway morphometry and lung densitometry

10. Pharmacogenomics

11. Pharmacokinetics and ADA level

Interventions

  • 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.
  • 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.

Arms, Groups and Cohorts

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

Clinical Trial Outcome Measures

Primary Measures

  • 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 Measures

  • St George’s Respiratory Questionnaire for COPD Patients (SGRQ-C)
    • Time Frame: Weeks 0, 12, 24, 36, 48, 60
    • 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 Impacts scores. A Total score is also produced. 2. 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.
  • 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
    • 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.
  • 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
    • 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
  • 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
    • 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).
  • Sputum purulence colour card
    • Time Frame: Screening, week 12, 28, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • To evaluate respiratory symptoms and verify a bacterial cause of an exacerbation
  • Pre and post bronchodilator (BD) spirometry
    • Time Frame: Week 0 and Week 60, withdrawal and exacerbation visits
    • To assess lung function
  • Post BD FEV1 Spirometry
    • 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
  • Body plethysmography ‘Body Box’
    • Time Frame: Between weeks 0-12
    • To assess lung function
  • Transfer factor
    • Time Frame: Between weeks 0-12
    • To assess lung function
  • Sputum biomarkers- mediator profiling
    • Time Frame: Weeks 0, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • % eosinophils which is an established biomarker for eosinophilic airways disease
  • Differential Cell Count
    • Time Frame: Weeks 0, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • Differential Cell Count to assess inflammation at exacerbation events.
  • Differential Cell Count
    • Time Frame: Weeks 0, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • Differential Cell Count to assess infection profile at exacerbation events.
  • Nasosorption
    • Time Frame: Screening, Weeks 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • To assess airway inflammation
  • Nasal Epithelial Sampling (optional)
    • Time Frame: Screening, Weeks 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • To assess airway inflammation
  • Breath volatile organic compound (VOC) profiling (PTRMS & ADVION)
    • Time Frame: Screening, Weeks 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • Breathomics
  • Sputum quantitative real-time polymerase chain reaction (qPCR) bacteria and viruses
    • Time Frame: Weeks 0, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • To assess airway ecology
  • Microbiome
    • Time Frame: Weeks 0, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • To assess airway ecology. the pulmonary microbial community consisting of a complex variety of microorganisms found in the lower respiratory tract particularly on the mucous layer and the epithelial surfaces. These microorganisms include bacteria, fungi, viruses and bacteriophages. We will be measuring the abundance or lack of them at defined visits to assess the effect of the trial drug on the microbiota (pleural of microbiome). We will do this using qPCR.
  • Total immunoglobulin E (IgE) & Radioallergosorbent (RAST)
    • Time Frame: Screening
    • (HDM, pollen, cat, dog) To assess systemic inflammation
  • Urine sample
    • Time Frame: Screening, weeks 0, 4, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • Biomarkers of inflammation, to assess systemic inflammation. N-Formyl-methionyl-leucyl-phenylalanine (fMLP) in ng/mL, Club Cell protein 16 (CC16) In ng/mL, CRP in ng/mL, Alpha 1 Anti-Trypsin (A1AT) in ng/mL, Matrix Metalloproteinase 8 (MMP8) in ng/mL
  • Serum/Plasma Inflammatory Biomarkers
    • Time Frame: Screening, weeks 0, 4, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • To assess systemic inflammation. Plasma/ serum biomarkers are exploratory and we do not have a specific list of biomarkers yet.
  • Non-contrast CT scan
    • Time Frame: Weeks 0 and 60
    • Airway morphometry and lung densitometry
  • Sputum for Biomarkers
    • Time Frame: Weeks 0 , 4, 12, 24, 26, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • Severity, inflammatory and infection profile at exacerbation events
  • Differential Cell count
    • Time Frame: Weeks 0 , 4, 12, 24, 26, 48, 60 and unscheduled visit(s) at any time point between 0-60 weeks
    • Severity, inflammatory and infection profile at exacerbation events. Differential cell count in sputum will be eosinophils, neutrophils, macrophages and lymphocytes in absolute numbers and %.
  • Targeted qPCR (bacteria and viruses) for common airway pathogens
    • Time Frame: Weeks 0 , 4, 12, 24, 26, 48, 60 and unscheduled visit(s) at any time point between 0-60 weeks
    • To assess airway infection and ecology. The unit will be gene copies/ sample.
  • Microbiome
    • Time Frame: Weeks 0 , 4, 12, 24, 26, 48, 60 and unscheduled visit(s) at any time point between 0-60 weeks
    • To assess airway infection and ecology
  • Full blood count (FBC)
    • Time Frame: Screening, week 0, 4, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • Blood Biochemistry
  • Urea and electrolytes (U&Es)
    • Time Frame: Screening, week 0, 4, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • To provide essential information on renal function, principally in excretion and homoeostasis.
  • C-reactive protein (CRP)
    • Time Frame: Screening, week 0, 4, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • Blood Biochemistry
  • Liver function tests (LFTs)
    • Time Frame: Week 0, 4, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • Blood Biochemistry
  • Glycated hemoglobin (HbA1c)
    • Time Frame: Screening, week 12, 24, 36, 48, 60
    • Blood Biochemistry
  • N-terminal prohormone of brain natriuretic peptide (NTproBNP)
    • Time Frame: Screening, week 0, 4, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • Blood Biochemistry
  • RNA (PAXgene)
    • Time Frame: Week 0, 4, 12, 24, 36, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • Genetic analysis to investigate whether there are links between response to treatment for COPD and peoples’ genetic make-up
  • DNA (PAXgene)
    • Time Frame: Screening
    • Genetic analysis to investigate whether there are links between response to treatment for COPD and peoples’ genetic make-up
  • Lipid Profile
    • Time Frame: Screening, week 60
    • Blood Biochemistry
  • Single Nucleotide Polymorphisms (SNPs)
    • Time Frame: Week 0
    • Pharmacogenetics
  • Pharmacokinetic (PK) analysis
    • Time Frame: Week 0, 24, 48 and unscheduled visit(s) at any time point between 0-60 weeks
    • Pharmacokinetics, PK samples should be taken pre-dose at dosing visits. We will be measuring the Cmax (peak concentration after drug administration in mg/L)
  • Pharmacokinetic (PK) analysis
    • Time Frame: Week 0, 24, 48 and unscheduled visit(s) at any time point between 0-60 weeks
    • We will be measuring the tmax (time to reach Cmax in mins or hours)
  • Pharmacokinetic (PK) analysis
    • Time Frame: Week 0, 24, 48 and unscheduled visit(s) at any time point between 0-60 weeks
    • We will be measuring the Cmin (the lowest concentration a drug reaches before the next dose, in mg/L).
  • Antidrug antibody (ADA) Level
    • Time Frame: Week 0, 60 and unscheduled visit(s) at any time point between 0-60 weeks
    • Pharmacokinetics; The analysis of the impact of antibody status on drug pharmacokinetics (PK)
  • Safety and tolerability of SC doses of anti-ST2 compared to placebo in adult patients with moderate to very severe COPD
    • Time Frame: Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60
    • Adverse event (AE) event rate per year in the 48 weeks of the trial from first dose. AEs will be recorded throughout the study whether serious or not. Members of the research team will ask the participants about AEs at each study time point.
  • Safety and tolerability of SC doses of anti-ST2 compared to placebo in adult patients with moderate to very severe COPD
    • Time Frame: Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60
    • Serious adverse event (SAE) event rate per year in the 48 weeks of the trial from first dose.
  • Safety and tolerability of SC doses of anti-ST2 compared to placebo in adult patients with moderate to very severe COPD
    • Time Frame: Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60
    • Monitoring and analysing of all potential cases of anaphylaxis. Separate reporting forms have been provided by Genentech to capture these which will also be captured on the trial database.
  • Safety and tolerability of SC doses of anti-ST2 compared to placebo in adult patients with moderate to very severe COPD
    • Time Frame: Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60
    • Monitoring and analysing of all potential cases major adverse cardiac events (MACE). Separate reporting forms have been provided by Genentech to capture these which will also be captured on the trial database.
  • Safety and tolerability of SC doses of anti-ST2 compared to placebo in adult patients with moderate to very severe COPD
    • Time Frame: Screening, Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60
    • Cardiac safety will be evaluated through monitoring of vital signs: blood pressure
  • Safety and tolerability
    • Time Frame: Screening, Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60
    • Cardiac safety will be evaluated through monitoring of vital signs: temperature
  • Safety and tolerability
    • Time Frame: Screening, Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60
    • Cardiac safety will be evaluated through monitoring of vital signs: heart rate
  • Safety and tolerability
    • Time Frame: Screening, Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60
    • Cardiac safety will be evaluated through monitoring of vital signs: Oxygen saturation (SPO2)
  • Safety and tolerability
    • Time Frame: Screening, Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60
    • Respiratory safety will be evaluated through monitoring of vital signs: respiratory rate
  • Safety and tolerability of SC doses of anti-ST2 compared to placebo in adult patients with moderate to very severe COPD
    • Time Frame: Screening, unscheduled visit
    • Cardiac safety will be evaluated through ECG assessments
  • Safety and tolerability
    • Time Frame: Screening, unscheduled visit
    • Cardiac safety will be evaluated through ECG assessments
  • Safety and tolerability of SC doses of anti-ST2 compared to placebo in adult patients with moderate to very severe COPD
    • Time Frame: Screening, Weeks 0, 4, 12, 24, 36, 48, 60, withdrawal, unscheduled visit
    • Clinical laboratory assessments
  • Pulse
    • Time Frame: Screening, Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • Vital Signs
  • Blood Pressure
    • Time Frame: Screening, Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • Vital Signs. Both Systolic and diastolic BP will be assessed.
  • Temperature (degrees centigrade)
    • Time Frame: Screening, Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • Vital Signs
  • Oxygen saturation
    • Time Frame: Screening, Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60, unscheduled visit(s) at any time point between 0-60 weeks
    • Vital Signs
  • Airway morphometry and lung densitometry
    • Time Frame: Any unscheduled visit(s) due to an exacerbation event at any time point between 0-60 weeks
    • Chest x-ray and non-contrast CT Scan
  • Clinical care at exacerbation
    • Time Frame: Any unscheduled visit(s) due to an exacerbation event at any time point between 0-60 weeks
    • Chest x-ray will be done as part of clinical care at exacerbation visits only to find out the cause of patients’ symptoms.
  • 12 lead Electrocardiogram (ECG)
    • Time Frame: Screening, week 60 and unscheduled visit(s) at any time point between 0-60 weeks
    • Cardiac function
  • Echocardiogram (ECHO)
    • Time Frame: Week 0 and unscheduled visit(s) at any time point between 0-60 weeks
    • Cardiac function

Participating in This Clinical Trial

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)

Gender Eligibility: All

Minimum Age: 40 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Leicester
  • Collaborator
    • Biomedical Research Centre- Respiratory (Glenfield Hospital, Leicester UK)
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Christopher Brightling, Prof, Principal Investigator, University of Leicester

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