PiZZAlpha-1 Antitrypsin Deficiency Associated Liver Disease MedDRA version: 23.1 Level: LLT Classification code 10001806 Term: Alpha-1 anti-trypsin deficiency System Organ Class: 100000004850
Conditions
Sponsors
Dicerna Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Age 18 to 75 years, inclusive, at the time of signing the ICF. 2. Documented diagnosis of PiZZ-type AATD, confirmed by genotyping. Historical genotyping data may be used, if available. 3. AATLD, with a liver fibrosis score categorized as F1, F2, F3, or F4 in the METAVIR scoring system, documented by liver biopsy during Screening. 4. Post-bronchodilator FEV1 > 45% of predicted at Screening. 5. Participants receiving augmentation therapy on a regular basis and intending to continue augmentation therapy during the study are eligible to participate. 6. eGFR at Screening = 60 mL/min normalized to 1.73 m2 BSA. 7. Non-smokers (defined as having not smoked cigarettes daily for at least the preceding 12 months) with current non-smoking status confirmed by urine cotinine at Screening AND any previous smoking history prior to 12 months must be =65 years) yes F.1.3.1 Number of subjects for this age range 5
Exclusion criteria
Exclusion criteria: 1. Any condition which, in the investigator's opinion might jeopardize participant's safety or compliance with the protocol. 2. History of chronic liver disease other than non-alcoholic fatty liver disease from any cause other than PiZZ-type AATD. Diagnostic testing exclusions are defined in the Diagnostic Assessments section below. 3. Child-Pugh Score B or C 4. History of one single severe exacerbation of underlying lung disease in the year prior to randomization. A severe exacerbation is defined as an exacerbation that requires hospitalization or a visit to the emergency room. 5. History of rapid decline in pulmonary function, as assessed by the Investigator. 6. Known or suspected abuse of drugs in the opinion of the Investigator 7. Known or suspected excessive consumption of alcohol ( = 21 units of alcohol per week in men and = 14 units of alcohol per week in women; where a "unit" of alcohol is equivalent to a 12-ounce beer, 4-ounce glass of wine, or 1 ounce shot of hard liquor as defined by the World Health Organization) 8. Any of the following: myocardial infarction, stroke, classification of heart failure New York Heart Association (NYHA) Class IV, hospitalization for unstable angina pectoris or transient ischaemic attack within the past 90 days prior to the day of screening (V2A) and between screening and randomization 9. History of malignancy, unless the malignancy (other than hepatocellular or lung cancer) has been in complete remission off chemotherapy and without additional medical or surgical interventions within the preceding 5 years, or unless the malignancy has been an adequately treated skin cancer (other than melanoma) or, superficial bladder tumor, or in situ cervical cancer in the preceding 1 year. 10. Use of an RNAi drug at any time. 11. History of one or more of the following reactions to an oligonucleotide-based therapy: a. severe thrombocytopenia (platelet count 3 × ULN and total bilirubin > 2 × ULN or INR > 1.5 c. severe flu-like symptoms leading to discontinuation of therapy d. localized skin reaction from the injection (graded severe) leading to discontinuation of therapy e. coagulopathy/clinically significant prolongation of clotting time 12. Participation in any clinical study in which they received an IMP within 4 months (or 5 times the half-life, whichever is longer) before Screening 13. AST and ALT > 5 × ULN at Screening. For individuals with any serum aminotransferase elevation > 2 × ULN, autoimmune hepatitis should be ruled out through the appropriate screening tests, which may include total IgG or gamma-globulin levels and/or serologic markers (i.e., antinuclear antibodies, anti-smooth-muscle antibodies at a titer of at least 1:40, anti-liver/kidney microsomal-1 antibodies, anti-liver cytosol antibody [anti-LC 1], or antisoluble liver/liver pancreas [anti-SLA/LP] antibodies). 14. ALP 2 × ULN at Screening 15. Serum AFP value > 100 ng/mL at Screening. If AFP at screening is > ULN but 1.6 × ULN at Screening 19. Positive screening for HBsAg, HCV antibodies, or HIV1 and 2 antibodies. If a participant has been tested in the past 3 months, medical record documentation of this t
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 1. To evaluate the safety and tolerability of multiple doses of belcesiran in patients with AATLD. 2. To characterize the PD of belcesiran in patients with AATLD.;Secondary Objective: Secondary Objectives: 1. To characterize the PK of belcesiran in the plasma of patients with AATLD. 2. To assess the effect of belcesiran on liver histology in patients with AATLD Exploratory Endpoints: 1. To assess the effect of belcesiran on liver stiffness in patients with AATLD 2. To assess the effect of belcesiran on liver fibrosis and/or inflammation in patients with AATLD;Primary end point(s): Cohorts 1 and 2: 1. The incidence and nature of TEAEs, and the change from Baseline in PFTs, 12 -lead ECGs, physical examination findings, vital signs, and clinical laboratory tests 2. Changes from baseline to weeks 24 (Cohort 1)/48 (Cohort 2) in serum AAT protein concentrations Cohort 3: 1. Change from baseline to week 24 in serum Z-AAT protein levels 2. Change from baseline to week 24 in liver Z-AAT protein levels;Timepoint(s) of evaluation of this end point: 1-2. Throughout the study | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary End Points: 1. PK profile of belcesiran 2. Change from Baseline up until week 96 in liver fibrosis 3. Change from Baseline up until week 96 in diastase-resistant PAS-positive AAT globules Exploratory End Points: 1. Change from Baseline up until week 96 in FibroScan® score 2. Change from Baseline up until week 96 in ELF score 3. Change from Baseline up until week 96 in CK-18 ;Timepoint(s) of evaluation of this end point: Secondary End Points: 1-3. Throughout the study Exploratory End Points: 1-3. Throughout the study | — |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Ireland, Netherlands, New Zealand, Portugal, Spain, Sweden, United Kingdom, United States
Contacts
Public ContactClinical Trials
Dicerna Pharmaceuticals, Inc.
Outcome results
None listed