A Phase 2 placebo-controlled study to evaluate the mechanistic effect, safety, and tolerability of alvelestat (MPH966) in participants with alpha-1 antitrypsin deficiency
- Conditions
- Alpha-1 antitrypsin deficiencyMedDRA version: 23.1Level: LLTClassification code 10001806Term: Alpha-1 anti-trypsin deficiencySystem Organ Class: 100000004850Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]
- Registration Number
- EUCTR2018-001309-95-BE
- Lead Sponsor
- Mereo BioPharma 4 Ltd
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 182
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 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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 127
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 55
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
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Timepoint(s) of evaluation of this end point: Blood sample for desmosine/isodesmosine: Base, W4, W8, W12 (EOT) and W16 (Safety FU visit) ;Main Objective: To evaluate the mechanistic and pharmacodynamic effect of alvelestat (MPH966) administered bid for 12 weeks on blood markers of neutrophil elastase activity;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:<br>• Blood Neutrophil Elastase activity<br>• Plasma desmosine/isodesmosine levels<br>• Blood Aa-Val360 levels;Secondary Objective: • To evaluate the effect of alvelestat (MPH966) on neutrophil elastase activity<br>• To characterize the pharmacokinetic (PK) profile of alvelestat<br>• To evaluate the safety and tolerability of alvelestat (MPH966) administered bid for 12 weeks and effect of within subject dose-escalation on safety and tolerability of within-subject dose escalation in the 240 mg bid dose<br><br>
- Secondary Outcome Measures
Name Time Method