E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Alpha-1 antitrypsin deficiency |
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E.1.1.1 | Medical condition in easily understood language |
Alpha-1 antitrypsin deficiency is a genetic disorder that may result in lung disease or liver disease. |
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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 | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10001806 |
E.1.2 | Term | Alpha-1 anti-trypsin deficiency |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the mechanistic effect of alvelestat (MPH966) administered bid for 12 weeks on blood markers of neutrophil elastase activity |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives: • To evaluate the effect of alvelestat (MPH966) on other blood pharmacodynamic markers of neutrophil activation and elastase activity • To evaluate the effect of alvelestat (MPH966) on blood biomarkers of lung tissue degradation • To evaluate the effect of alvelestat (MPH966) on biomarkers of inflammation in blood • To evaluate the safety and tolerability of alvelestat (MPH966) administered bid for 12 weeks Exploratory • To evaluate the effect of alvelestat (MPH966) on other blood PD markers of neutrophil activation and elastase activity • To evaluate the effect of alvelestat (MPH966) on pulmonary function • To evaluate the effect of alvelestat (MPH966) on respiratory symptoms • To evaluate the effects of alvelestat on acute exacerbations of COPD |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Sputum will either be induced or spontaneously produced by participants. • Sputum will be collected from all participants that spontaneously produce sputum according to the MPH966-2-01 Study Procedures Manual. • Participants who do not spontaneously produce sputum will be invited to participate in the induced sputum subset study. The aim to meet the study objectives is to include approximately 30% to 50% of non-sputum producers in the subset study. Sputum induction will not be undertaken if the baseline FEV1 for the procedure is less than 1 L. Further details of sputum induction will be included in the MPH966-2-01 Study Procedures Manual.
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E.3 | Principal inclusion criteria |
1. Age 18 to 75 years at screening 2.Participants with a diagnosis or confirmation of AATD (PiZZ or, null or other rare phenotype/genotype) with an associated serum AAT levelslevel of <11 µM or <57.2 mg/dL 3.Post-bronchodilator FEV1≥20% predicted at screening 4.Computerised tomography (CT) scan evidence of emphysema 5.Non-smokers (for at least 12 months prior to study entry) 6.Absence of advanced liver fibrosis or cirrhosis: a.Fibrosis-4 (FIB-4) score <1.45 or b.FIB-4 score >1.45 and ≤3.25 with transient elastography measurement <12.5 kPa within 3 months of baseline 7.Male or female Male participants: A male participant must agree to use a highly effective contraception as detailed in Appendix 5 during the treatment period and for at least 4 days after the last dose of study treatment and refrain from donating sperm during this period Female participants: A female participant is eligible to participate if she is not pregnant (see Appendix 5), not breastfeeding, and at least 1 of the following conditions applies: a.Not a woman of childbearing potential as defined in Appendix 5 OR b.A woman of childbearing potential who agrees to follow the contraceptive guidance in Appendix 5 during the treatment period and for at least 4 days after the last dose of study treatment 8.Capable of giving signed informed consent as described in Appendix 3, which includes a commitment to comply with the requirements and restrictions listed in the informed consent form (ICF) and within this protocol
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E.4 | Principal exclusion criteria |
1. Participants with PiMZ, PiFF or PiSZ AATD phenotypes/genotypes 2. Primary clinical diagnosis of bronchiectasis or evidence of significant bronchiectasis on CT scan Acute exacerbation of underlying lung disease requiring oral corticosteroids, antibiotics, and/or change in regular treatments within 4 weeks of baseline 3. Acute exacerbation of underlying lung disease requiring oral corticosteroids, antibiotics, and/or change in regular treatments within 4 weeks of baseline 4. Acute or chronic hepatitis, including hepatitis B and or C virus infection (positive hepatitis B surface antigen, and /or hepatitis C antibody) at screening 5. Known history or present diagnosis of cirrhosis (on imaging or biopsy), oesophageal varices, ascites or hepatic encephalopathy 6. History of other chronic liver diseases such as autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, Wilson’s disease, haemochromatosis 7. History of non-alcoholic fatty liver disease 8. A clinical requirement for drugs associated with NAFL or hepatoxicity during the study period (Screening through Week 12 Visit) and up to 4 weeks prior to screening. 9. History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening, defined as an average of >20 g / day in female subjects and >30 g/ day in male subjects 10. History of alcohol and/or drug abuse within the 15 years prior to screening 11. HIV infection OR known other immunodeficiency OR an absolute neutrophil count ≤1.0 × 109/L at screening 12. Any of the following lab abnormalities suggestive of liver disease: abnormal liver-related biochemistry at screening >1.5 × upper limit of normal OR gamma-glutamyl transferase >2 × upper limit of normal OR total bilirubin > upper limit of normal (unless Gilbert’s disease with normal conjugated bilirubin), platelet count <150 x 109/L, serum albumin ≤ 3.5g/dL or INR ≥1.2 (in the absence of drugs known to elevate INR, for example anticoagulant therapy) or CPK > 1.5 x ULN 13. FIB-4 score >3.25 at screening 14. Any of the following cardiovascular conditions within 6 months prior to the screening visit: a. Myocardial infarction or unstable angina b. Stroke or transient ischaemic attack c. Coronary artery bypass surgery, balloon angioplasty, percutaneous coronary intervention, or carotid revascularisation procedure d. Uncontrolled hypertension within the 3 months prior to screening e. Congestive heart failure 15. Any clinically significant 12-lead electrocardiogram abnormalities at screening or baseline OR corrected QT interval by Fridericia’s correction method >450 ms OR history of significant cardia dysrhythmia, including long QT syndrome 16. Significant renal disease or infection (as determined by the Investigator) including stage 4 chronic kidney disease or estimated glomerular filtration rate <45 mL/min 17. History of cancer within the 5 years prior to screening, except for well-treated cutaneous basal cell carcinoma, squamous cell carcinoma of the skin and cervical cancer 18. Other clinically relevant haematology parameters that could impact the safety of the participant in the Investigator’s judgement 19. Other documented comorbidities that in the opinion of the Investigator could affect the outcome of the study assessments or ability of the participant to comply with the requirements of the protocol 20. Lung or lung volume reduction surgery or liver transplant has been performed or the participant is listed and active on a transplant waiting list 21. Immunosuppressive therapies including regular systemic corticosteroids (>5 mg daily or equivalent for greater than 14 consecutive days) within 4 weeks prior to screening 22. Immunomodulating monoclonal antibodies within the 6 months prior to screening 23. Previous AAT augmentation therapy within the 6 months prior to screening 24. Requirement for non-steroidal anti-inflammatory drugs (however, paracetamol [acetaminophen] up to 2 g per day and up to 100 mg acetylsalicylic acid daily is allowed) 25. Requirement for medications mainly metabolised by CYP2C9 and with a narrow therapeutic index 26. Requirement for medications substantially reliant on OATP1B1 for metabolism (e.g., statins, valsartan, olmesartan, enalapril, repaglinide) 27. Commenced treatment with PDE4 inhibitor or regular azithromycin within 4 weeks of screening (stable therapy for greater than 4 weeks is acceptable) 28. Participation in any clinical investigation using medical devices or non-biologic treatments within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to the initial dosing 29. Participation in any clinical investigation using biologic treatment within 6 months of screening 30. Previous participation in a gene therapy study for AATD at any time 31. History of hypersensitivity to alvelestat (MPH966) or any of its excipients or the class of neutrophil elastase inhibitors.
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E.5 End points |
E.5.1 | Primary end point(s) |
Within-individual % change from baseline in plasma desmosine/isodesmosine at end of treatment compared to placebo |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Blood sample for desmosine/isodesmosine: Base, W4, W8, W12 (EOT) and W16 (Safety FU visit) |
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E.5.2 | Secondary end point(s) |
• Change from baseline in absolute plasma desmosine/isodesmosine levels at end of treatment compared to placebo • Change from baseline in blood Aα-Val360, neutrophil elastase, EL-NE, EL-CG, and EP-3 at end of treatment compared to placebo • Change from baseline in blood MMP: C6M, Pro-C6, C1M, and PGP at end of treatment compared to placebo • Change from baseline in blood inflammatory biomarkers (interleukin [IL]-6, IL-8, IL-1β, RANTES, high-sensitivity C-reactive protein, fibrinogen) at end of treatment compared to placebo • Numbers and % of participants who experience at least 1 treatment-emergent adverse event • Adverse events of special interest (liver function abnormalities, corrected QT interval/cardiac, infections, and neutropenia) • Relationship of pharmacokinetics (PK) and safety Exploratory • Change from baseline in markers of neutrophil elastase activity, desmosine, and inflammatory biomarkers (IL-6, IL-8, IL-1β, LTB4, RANTES, PGP) at end of treatment in induced sputum compared to placebo • Change from baseline in markers of neutrophil elastase activity, desmosine, and inflammatory biomarkers (IL-6, IL-8, IL-1β, LTB4, RANTES, PGP) at end of treatment in spontaneous sputum compared to placebo • Change from baseline in forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC (total and percent predicted), and maximal mid-expiratory flow at end of treatment • Change from baseline in St. George’s Respiratory Questionnaire (SGRQ-C) at end of treatment • Frequency of adverse events of acute exacerbations of COPD, at 12 weeks • PK/pharmacodynamic (PD) relationship with efficacy biomarkers in blood and sputum |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Blood sample for PD BK and PK: Alvelestat PK; IL-6, IL-8, IL-1β, RANTES, hsCRP, fibrinogen; desmosine/isodesmosine, neutrophil elastase; Aα-Val360; PGP; neutrophil elastase, EL-NE, EL-CG, EP-3, C6M, C1M, PRO-C6: Base, W4, W8, W12 (EOT) + W16 (Safety FU visit) for desmosine/isodesmosine, neutrophil elastase and Aα-Val360
Sputum collection for biomarkers of desmosine, neutrophil elastase and inflammation RANTES, IL-1β, IL-6, IL-8, LTB4, PGP: Base, W4, W8, W12 (EOT). For induced sputum collection: Screening, baseline, W8, W12 (EOT)
Lung function tests (FEV1, FVC, FEV1/FVC, maximal mid-expiratory flow): Base, W4, W8, W12 (EOT) 12-Lead ECG: Baseline, W4, W8, W12 (EOT)
Clinical laboratory tests: Scr, Base, W-1, W2, W4, W8, W12, Safety FU visit
SGRQ-C: Base, W4, W8, W12 (EOT) |
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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 | No |
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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
Denmark |
Poland |
Spain |
Sweden |
United Kingdom |
United States |
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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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The end of the study is defined as the date of all data being entered into the study database and the database being locked and ready for analysis.
Mereo BioPharma 4 Ltd (sponsor) considers that the trial is ended when the clinical database is locked and all data is ready for analysis, which should occur within 1 month after the last patient last visit. |
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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 18 |