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: 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-SE
- Lead Sponsor
- Mereo BioPharma 4 Ltd
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 182
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 levels <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 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 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 commitment to comply with the requirements and restrictions listed in the informed consent form (ICF) and within 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 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 last 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 current 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 (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
13.FIB-4 score >3.25 at screening
14.Any of the following cardiovascular conditions within 6 months prior to the screening visits:
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 jusdgement
e.Congestive heart failure (New York Heart Association III/IV)
15.Any clinically significant 12-lead ECG abnormalities at screening or baseline OR 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 <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 LVRS or liver transplant has been performed or the p
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