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 fibrosis, steatosis, and inflammation in patients with AATLD.
Exploratory Endpoints: 1. To assess the effect of belcesiran on total, soluble, or insoluble Z-AAT protein on paired liver biopsies from patients with AATLD. 2. To assess the effect of belcesiran on liver stiffness in patients with AATLD. 3. To assess the effect of belcesiran on liver fibrosis and/ or inflammation in patients with AATLD. 4. To develop a comprehensive liver disease activity score in patients with AATLD. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Aged 18 to 70 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 fibrosis score categorized as F2, F3, or F4 in the METAVIR scoring scale, documented by liver biopsy. 4. Consent to undergo paired liver biopsies, one at Screening and one at either 24 (± 2) weeks or 48 (± 2) weeks after of the first dose of the study intervention 5. Pre- and Post-bronchodilator FEV1 > 60% of predicted at Screening 6. Postbronchodilator DLCO ≥ 50% of predicted at Screening 7. Serum AAT protein concentration > 10 mg/dL at the first assessment during Screening 8. eGFR at Screening ≥ 60 mL/min normalized to 1.73 m^2 BSA 9. Smoking cessation for at least 3 months prior to Screening 10. Body mass index (BMI) within the range of 18 to 35 kg/m^2 (inclusive) 11. Male or female: - Male: A male participant with a partner of childbearing potential must agree to use contraception, as detailed in Section 10.4.2 of the Protocol, 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: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and not a WOCBP, as defined in Section 10.4.1. of the Protocol 12. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. |
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E.4 | Principal exclusion criteria |
1. Presence of any condition or comorbidities that would interfere with study compliance or data interpretation or potentially affect patient safety including, but not restricted to: a. severe intercurrent illness b. physician concerns about intake of drugs of abuse, alcohol use disorder, excessive alcohol intake, or history of excessive alcohol intake in the 2 years prior to enrollment (defined as ≥ 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) c. clinically relevant history or presence of uncontrolled cardiovascular, respiratory, gastrointestinal, hematological, lymphatic, neurological, musculoskeletal, genitourinary, immunological diseases, and dermatological (including rash, severe eczema, or dermatitis) or connective tissue diseases or disorders. Diagnostic testing exclusions are defined in the Diagnostic Assessments section below 2. History of chronic liver disease from any cause other than PiZZ-type AATD, including hepatitis B, hepatitis C, primary biliary cirrhosis, primary sclerosing cholangitis, cholestatic liver disease, and autoimmune liver diseases. Diagnostic testing exclusions are defined in the Diagnostic Assessments section below. 3. Child-Pugh Score B or C 4. History of acute exacerbations of underlying lung disease in the 3 months prior to Screening, defined as increased dyspnea, sputum volume, and sputum purulence. Individuals meeting this criterion may be re-screened after 2 months 5. History of intolerance to SC injection(s) or significant abdominal scarring that could potentially hinder study intervention administration or evaluation of local tolerability 6. AAT augmentation therapy in the 6 months prior to Screening 7. Routine use of acetaminophen/paracetamol Note. Occasional use of 1000mg/day is acceptable 8. Use of systemically acting steroids in the month prior to Screening and throughout the study period. Occasional use is acceptable if needed for patient safety, e.g., in the case of an exacerbation of underlying pre-existing conditions. 9. Routine use of NSAIDs, or use within 3 days of dosing 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/ mm^3) 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 before Screening 13. AST and ALT > 5 × ULN at Screening Note: 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 (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 anti-soluble liver/liver pancreas [anti-SLA/LP] antibodies). 14. ALP 2 × ULN at Screening 15. Serum alpha fetoprotein (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. HbA1c > 8% at Screening 18. Fasting triglycerides > 400 mg/dL or total cholesterol > 400 mg/dL at Screening 19. Platelets < 50,000/mm^3 at Screening 20. White blood cells < 2000/mm^3 at Screening 21. Neutrophils < 1000/mm^3 at Screening 22. INR > 1.6 × ULN at Screening 23. Hypertension: - Systolic BP > 150 mmHg and diastolic BP > 90 mmHg after 5 minutes rest in sitting position at Screening. Repeat measures are allowed. 24. Positive screening for HBsAg, HCV antibodies, or HIV-1 and -2 antibodies. If a participant has been tested in the past 3 months, medical record documentation of this testing can be used for screening. Note: NOTE: In participants with previous treatment for hepatitis C with direct-acting HCV medication and seropositivity for HCV, or in participants with prior infection and spontaneous resolution, HCV RNA must be undetectable (at least two negative HCV RNA tests at least 12 weeks apart), and the HCV infection must have been resolved or cured > 3 years prior to enrollment. 25. Positive urine drug screen (to include at a minimum: amphetamines, barbiturates, cocaine, opiates, and benzodiazepines), at the discretion of the Investigator 26-27. Please refer to Protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. The incidence and nature of AEs, and the change from Baseline in PFTs, 12-lead ECGs, physical examination findings, vital signs, and clinical laboratory tests 2. Changes in serum AAT protein concentrations over time |
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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. Plasma PK parameters of belcesiran 2. Changes from Baseline in liver histology as determined by METAVIR and Ishak scores, steatosis scores and Sirius Red staining
Exploratory End Points: 1. Changes from Baseline in number and area of diastase resistant PAS-positive AAT globules, and in measurements of soluble, insoluble, and total Z-AAT 2. Changes from Baseline in MRE and FibroScan® scores 3. Changes from Baseline in blood-based biomarkers of liver disease 4. Changes from Baseline in multiple surrogate markers of liver disease |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary End Points: 1-2. Throughout the study
Exploratory End Points: 1-4. 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 | No |
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 | 2 |
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 | 14 |
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 |
Austria |
Belgium |
Brazil |
Canada |
Germany |
Ireland |
Netherlands |
New Zealand |
Portugal |
Spain |
Sweden |
United Kingdom |
United States |
France |
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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 | 3 |
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 | 3 |
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 |