A Phase 2 placebo-controlled study to evaluate the mechanistic effect, safety, and tolerability of alvelestat (MPH966) in participants with alpha-1 (PiZZ or null genotype/phenotype) antitrypsin deficiency
- Conditions
- Alpha-1 (PiZZ or null genotype/phenotype) antitrypsin deficiencyMedDRA version: 20.1Level: PTClassification code 10001806Term: Alpha-1 anti-trypsin deficiencySystem Organ Class: 10010331 - Congenital, familial and genetic disordersTherapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]
- Registration Number
- EUCTR2018-001309-95-ES
- 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
2. Patients with a diagnosis or confirmation of AATD (PiZZ or null phenotype/genotype) with serum AAT levels <11 µM or <57.2 mg/dL
3. FEV1 =25% predicted
4. Computerised tomography (CT) scan evidence of emphysema
5. Non-smokers (for at least 12 months prior to study entry)
6. Absence of moderate/severe 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 randomisation
c. Stable liver transaminases (ALT/AST) and Total bilirubin (TB) as determined by comparison of two separate assessments obtained at least 4 weeks apart
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 compliance with the requirements and restrictions listed in the informed consent form (ICF) and in 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 other AATD phenotypes/genotypes
2. Primary clinical diagnosis of bronchiectasis or evidence of significant bronchiectasis on CT scan (per Investigator judgement and with CT scan taken in the last 3 years)
3. Acute exacerbation of underlying lung disease requiring oral steroids, antibiotics, and/or change in regular treatments within 4 weeks of baseline
4. Acute or chronic hepatitis, including hepatitis B, hepatitis C (positive serologies, including hepatitis B antigen and also hepatitis B and C antibody) at screening
5. History or current diagnosis of cirrhosis (on imaging or biopsy), oesophageal varices, ascites or hepatic encephalopathy
6. History of other chronic liver diseases such as autoimmune liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson’s disease, Haemochromatosis or iron overload
7. History of non-alcoholic fatty liver disease (NAFLD) or use of drugs associated with NAFLD for more than 2 weeks in the year prior to screening [drugs include amiodarone, methotrexate, systemic glucocorticoids (should not exceed >5mgs prednisolone or equivalent daily dose), tetracyclines, tamoxifen, oestrogens at doses greater than those used for hormone replacement, anabolic steroids, valproic acid, and other known hepatotoxins (including but not restricted to statins, anti-epileptics, antibiotics such as amoxicillin, amoxicillin/clavulanate, and NSAIDs)]
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 >2.5units/day in female subjects and >3.75units/day in male subjects
9. History of alcohol and/or drug abuse within the last 15 years
10. HIV infection or other immunodeficiency or with an absolute neutrophil count =1.0 × 109/L at screening
11. Abnormal liver-related biochemistry (ALT, AST, gamma-glutamyl transferase) >1.5 × ULN or total bilirubin > ULN (unless Gilbert’s disease with normal conjugated bilirubin), platelet count <150 x 109/L, serum albumin = 3.5 g/dL, INR =1.2 or CPK = ULN
12. FIB-4 score >3.25
13. Hyperlipidaemia requiring statins, where treatment would be initiated during the study treatment period (participants on established treatment >28 days will not be excluded)
14. Any of the following cardiovascular conditions within 6 months prior to the screening visits:
14.1. Myocardial infarction or unstable angina
14.2. Coronary artery bypass surgery, balloon angioplasty, percutaneous coronary intervention, or carotid revascularisation procedure
14.3. Uncontrolled hypertension within the 3 months of screening
14.4. Congestive heart failure (New York Heart Association III/IV)
14.5. Stroke or transient ischaemic attack
15. Any clinically significant 12-lead ECG abnormalities at screening or baseline, including corrected QT interval by Fridericia’s correction method (QTcF) >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 <60 mL/min
17. History of cancer within the last 5 years, except for well-treated basal cell carcinoma and squamous cell carcinoma
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 stud
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method