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 | 23.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001806 |
E.1.2 | Term | Alpha-1 anti-trypsin deficiency |
E.1.2 | System Organ Class | 100000004850 |
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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 and pharmacodynamic 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 |
• To evaluate the effect of alvelestat (MPH966) on neutrophil elastase activity • To characterize the pharmacokinetic (PK) profile of alvelestat • To evaluate the safety and tolerability of alvelestat (MPH966) administered bid for 12 weeks and effect of within subject doseescalation on safety and tolerability of within-subject dose escalation in the 240 mg bid dose |
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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. Patients with a diagnosis or confirmation of AATD (PiZZ, or null or other rare phenotype/genotype) with an associated serum AAT level of <11 µM or <57.2 mg/dL 3. Post-bronchodilator ≥20% predicted at screening 4. Computerised tomography (CT) scan evidence of emphysema 5. Non-smokers (for at least 12 months prior to baseline) 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 (per Investigator judgement and with CT scan performed during the 3 years prior to dosing) 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 (NAFLD). 8. 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 (For reference, 14g of alcohol are contained in the following: 12fl oz (355ml) regular beer containing ~5% alcohol; 8-9fl oz (235 to 265ml) malt liquor containing ~7% alcohol; 5fl oz (150ml) of table wine containing ~12% alcohol or 1.5fl oz (45ml) of distilled spirits (e.g. gin, rum, vodka, whiskey) containing ~40% alcohol) 9. History of alcohol and/or drug abuse within the 15 years prior to screening 10. HIV infection OR known other immunodeficiency OR an absolute neutrophil count =1.0 × 109/L at screening 11. Any of the following lab abnormalities suggestive of liver disease: abnormal liver-related biochemistry at screening (alanine aminotransferase, aspartate aminotransferase) >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 12. FIB-4 score >3.25 at screening 13. 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 in the Investigators judgement e. Congestive heart failure (New York Heart Association III/IV) 14. 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 15. Significant renal disease or infection (as determined by the Investigator) including stage 4 chronic kidney disease or estimated glomerular filtration rate <45 mL/min 16. 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 17. Other clinically relevant haematology parameters that could impact the safety of the participant in the Investigator's judgement 18. 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 19. Lung or lung volume reduction surgery (LVRS) or liver transplant has been performed or the participant is listed and active on a transplant waiting list Prior/Concomitant Therapy 20. Immunosuppressive therapies including regular systemic corticosteroids (>5 mg daily or equivalent for greater than 14 consecutive days) within the month prior to baseline 21. Immunomodulating monoclonal antibodies within the 6 months prior to baseline 22. Previous AAT augmentation therapy within the 6 months prior to baseline 23. A clinical requirement to initiate new treatment with drugs associated with NAFLD or hepatoxicity (See Appendix 8) during the study period (Baseline through Week 12 Visit) or within the 4 weeks prior to baseline. Stable therapy initiated more than 4 weeks prior to Baseline is acceptable. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Within individual change from baseline up to end of treatment (weeks 4, 8 and week 12) and in comparison to placebo in: • Blood Neutrophil Elastase activity • Plasma desmosine/isodesmosine levels • Blood Aα-Val360 levels |
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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) |
•Within individual change from baseline up to end of treatment (weeks 4, 8 and week 12) and in comparison to placebo in: • Frequency of neutrophil elastase levels below the limit of detection from baseline to end of treatment (weeks 4, 8 and 12) • Pharmacokinetic concentration and derived parameters up to week 12 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 • Adverse event profile in 240 mg bid dose group in within-subject dose escalation and no within-subject dose-escalation subgroups |
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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, PROC6, PRO-C3, C3M, C4Ma3: 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, 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, 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 | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
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 | 11 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 15 |