E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Obstructive Pulmonary Disease (COPD) |
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E.1.1.1 | Medical condition in easily understood language |
describes progressive lung diseases including emphysema, chronic bronchitis, with increasing breathlessness. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010952 |
E.1.2 | Term | COPD |
E.1.2 | System Organ Class | 100000004855 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010953 |
E.1.2 | Term | COPD exacerbation |
E.1.2 | System Organ Class | 100000004855 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
We hypothesise that anti-ST2 will impact on airway inflammation in COPD and consequently will reduce COPD exacerbation frequency.
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. |
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E.2.2 | Secondary objectives of the trial |
Another key objective is to assess the safety and tolerability of 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
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E.2.3 | Trial contains a sub-study | No |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Statistical analysis plan will include a priory sub-group analysis including but not limited to IL-33 ST2 genotype. |
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E.3 | Principal 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 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 trial procedures and trial visits. 8. Able to understand written and spoken English
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E.4 | Principal exclusion criteria |
1. Significant known respiratory disorders other than COPD that in the view of the investigator will affect the trial 2. Patients whose treatment is considered palliative (life expectancy <12 months) 3. Known hypersensitivity to the active substance of IMP 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. NYHA class III (e.g. less than ordinary activity causes fatigue, palpitation, or dyspnoea) patients will be excluded if they have had exacerbation of their HF in previous 6 months, and class IV (e.g. Symptoms of heart failure at rest)] that will affect the trial. 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 (see protocol section 9.7)) 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 trial 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)
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome is: Frequency 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 An inpatient hospitalization or death due to COPD
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
0-60 weeks (Day 0, week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60, withdrawals and exacerbations) |
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E.5.2 | Secondary end point(s) |
1. AE event rate per year in the 48 weeks of the study from first dose 2. SAE event rate per year in the 48 weeks of the study from first dose 3. Lab variables 4. Physical examination 5. Medical history including current medications 6. Vital signs (pulse, BP, temp, Oxygen saturation (O2 sats)) 7. Demographics (age, gender, BMI, ethnicity, smoking status) 8. Cardiac function: • Echocardiogram (ECHO) • 12 lead Electrocardiogram (ECG) (If, in the opinion of investigator, the ECG is grossly abnormal (e.g. Left bundle branch block (LBBB), prolonged QTc), it will be compared to old ECGs. If there are no old ECGs for comparison, the investigator will make a clinical judgement about the suitability of the patients to take part in trial). 9. Lung function: • Whole body plethysmography (body box) (to be done anytime between screening and week 12, unless patient has had the test within 12 months prior to screening visit) • Pre and post BD Spirometry • Post BD Forced Expiratory Volume in 1 Second (FEV1) 10. Sputum airway inflammation • sputum cytology • mediator profiling (biomarkers) 11. Upper airway inflammation: • nasosorption and • nasal epithelial sampling 12. Systemic inflammation: • blood inflammatory cell differentials • mediators • cell subset analysis including but not restricted to exploration of ILC2 cells • urine biomarkers of inflammation 13. Airway infection and ecology: • targeted qPCR (bacteria and viruses) for common airway pathogens • microbiomics 14. Breath volatile organic compound (VOC) profiling (PTRMS & ADVION) - breathomics 15. Airway morphometry and lung densitometry: • Thoracic CT-derived outcomes (non-contrast CT Scan) • Chest X-Ray (CXR) 16. Pharmacogenomics- response analysis in subgroups determined by SNPs for alleles associated with the IL33/ST2 axis. 17. Pharmacokinetics PK and ADA level 18. Pregnancy testing (urine and/or blood) 19. Questionnaires and Scores: • SGRQ-c and CAT - to evaluate Health status • mMRC Dyspnea Scale - to evaluate respiratory symptoms • Visual analogue score for dyspnoea, cough sputum production (100mm) – to evaluate respiratory symptoms • sputum purulence colour card – to evaluate respiratory symptoms
20. Blood Tests: • Full Blood Count (FBC) • U&Es • Lung Function Tests (LFTs) • C-Reactive Protein (CRP) • RNA (PAXgene) • DNA (PAXgene) • Total IgE & RAST (HDM, pollen, cat, dog) • Serum/plasma for inflammatory biomarkers • Lipid profile • NTproBNP • Hb1c • PK and ADA - (Pk samples should be taken pre-dose at dosing visits)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Screening -2weeks 0 - 60 weeks Study Visit Schedule: Screening, (Day 0, week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 60, withdrawals and exacerbations)
15 total study visits (repeat measures, safety and retention) (Screen, 0-60 weeks) Including 12 Dosing visits Week 0 - Week 44 (V1-V12) 12 Week Wash out Period from Week 48-60 (V13-V14) Unscheduled (Exacerbation) visits and withdrawals.
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | No |
E.8.5.1 | Number of sites anticipated in the EEA | 1 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 29 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 29 |