E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
PiZZAlpha-1 Antitrypsin Deficiency Associated Liver Disease |
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E.1.1.1 | Medical condition in easily understood language |
PiZZ A1ATD-associated liver disease is a progressive Alpha1 Antitrypsin-Deficiency Associated Liver Disease condition resulting in liver fibrosis, cirrhosis, and hepatocellular carcinoma. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
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 |
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. |
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E.2.2 | Secondary objectives of the trial |
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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 < 15 pack years, including use of e-cigarettes. Participants may be on nicotine replacement (patch or gum). A positive urine cotinine result due to nicotine replacement is acceptable for enrollment at the discretion of the Investigator. 8. Male or female Male participants: A male participant with a partner of childbearing potential must agree to use contraception, as detailed in Section 10.4.2, during the treatment period and for at least 12 weeks after the last dose of study intervention and refrain from donating sperm during this period. Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Female participants: A female participant is eligible to participate if she is not pregnant (see Section 10.4.3) and not breastfeeding. WOCBP must be using a highly effective method of contraception, as defined in Section 10.4.2. 9. Capable of giving signed informed consent, which includes compliance with the requirements (including consent to undergo paired liver biopsies) and restrictions listed in the ICF and in this protocol. |
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E.4 | Principal 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 < 100,000/ mm3) b. hepatotoxicity, defined as ALT or AST > 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 < 100 ng/mL, the participant is still eligible if an appropriate hepatic imaging study reveals no lesions 16. Positive screening for antimitochondrial antibodies (only required if primary biliary cirrhosis is suspected) 17. Platelets < 100,000/mm 3 at Screening 18. INR > 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 testing can be used for eligibility. |
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E.5 End points |
E.5.1 | 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 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-2. Throughout the study |
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E.5.2 | 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 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary End Points: 1-3. Throughout the study
Exploratory End Points: 1-3. Throughout the study |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | No |
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 | Yes |
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 | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 |
Australia |
Canada |
New Zealand |
United States |
Austria |
France |
Sweden |
Netherlands |
Spain |
Germany |
Belgium |
Ireland |
Portugal |
United Kingdom |
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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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Last Patient Last Visit (LPLV) |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |