Anti-ST2 (MSTT1041A) in COPD (COPD-ST2OP)
Condition: COPD Exacerbation
MeSH terms: Pulmonary Disease, Chronic Obstructive
Intervention: MSTT1041A; Placebo
Intervention description: 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.; 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.
Intervention MeSH terms: Astegolimab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
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
Enrollment: 81.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: COPD; Exacerbations; ST2 MAb; RG6149; MSTT1041A; Anti-ST2; Phase IIa; Placebo controlled

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.
    

Eligibility 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)