E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
alpha-1 antitrypsin deficiency (AATD)-associated liver disease |
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E.1.1.1 | Medical condition in easily understood language |
alpha-1 antitrypsin deficiency (AATD)-associated liver disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
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 |
To evaluate change from baseline over time in total, soluble, and insoluble Z-AAT concentrations in the liver of patients with AAT-associated liver disease. |
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E.2.2 | Secondary objectives of the trial |
• To determine the effect of multiple doses of ARO-AAT on circulating levels of Z-AAT alpha-1 antitrypsin over time versus baseline.
• To evaluate the effect of ARO-AAT on changes in ALT over time.
• To evaluate the effect of ARO-AAT on changes in GGT over time.
• To evaluate the effect of ARO-AAT on changes in FIB4 and APRI over time.
• To evaluate the effect of ARO-AAT on changes in PRO-C3 over time.
• To evaluate the effect of ARO-AAT on changes in hepatic stiffness based on FibroScan® over time versus baseline (when available).
• To evaluate effect of ARO-AAT on histological metrics of liver disease in patients with AAT-associated liver disease over time.
• To evaluate change from baseline in Ishak fibrosis score over time in ARO-AAT treated patients.
• To determine the incidence and severity of adverse events as a measure of the safety and tolerability of ARO-AAT. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
To be eligible for enrollment, participants must meet all the following inclusion criteria:
1. Male or non-nursing female patients 18-75 years of age, inclusive, at the time of Screening with previous diagnosis of PiZZ genotype Alpha-1 Antitrypsin Deficiency. PiZZ diagnosis from source verifiable medical records is permitted. Otherwise, patients must undergo PiZZ confirmatory testing at Screening. PiMZ or PiSZ genotypes are not permitted.
2. Able and willing to provide written informed consent prior to the performance of any study specific procedures.
3. A 12-lead ECG at Screening that, in the opinion of the Investigator, has no abnormalities that compromise participant’s safety in this study.
4. Non-smoker (defined as does not smoke cigarettes daily for at least 12 months) with current non-smoking status confirmed by urine cotinine at screening and throughout the study. Patients may be on nicotine replacement (patch or gum). E-cigarettes (vapor) are not permitted. A positive urine cotinine result due to nicotine replacement is acceptable for enrollment at the discretion of the Investigator.
5. Participants using highly effective contraception during the study and for 12 weeks following the last dose of ARO-AAT. Males must not donate sperm for at least 12 weeks post last dose of study treatment. Females of childbearing potential must have a negative urine pregnancy test at Screening and on Day 1 pre-dose. Females not of childbearing potential must be post-menopausal (defined as cessation of regular menstrual periods for at least 12 months), confirmed by follicle-stimulating hormone (FSH) consistent with post-menopausal state based on lab reference ranges.
• Using twice the normal protection of birth control by using a condom AND one other form of either birth control pills (The Pill), depot or injectable birth control, IUD (Intrauterine Device), birth Control Patch (e.g., Ortho Evra), NuvaRing®, OR Surgical sterilization as a single form of birth control: i.e., tubal ligation, hysterectomy, bilateral oophorectomy, vasectomy or equivalently effective surgical form of birth control.
• True subject abstinence for the duration of the study and 12 weeks after the dose of ARO-AAT is acceptable only when in line with the preferred and usual lifestyle of the subject. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea methods are not considered “true” abstinence and are not acceptable methods of contraception.
6. Participants who are willing and able to comply with all study assessments and adhere to the protocol schedule.
7. Must have suitable venous access for blood sampling.
8. No abnormal finding of clinical relevance at the Screening evaluation that in the opinion of the Investigator could adversely impact subject safety during the study or adversely impact study results.
9.Liver biopsy indicating Metavir F1- F3 (or equivalent on other grading scales, see Appendix 3) liver fibrosis based on local pathologist read. All patients will require a liver biopsy during the screen period except for prior screened patients who now meet the fibrosis criteria as long as there is sufficient material for a baseline assessment as per specifications in the laboratory manual.
All laboratory tests used as inclusion criteria may be repeated once and the repeat value may be used for inclusion purposes. Central labs will be utilized for the study, however local labs may be utilized as necessary due to emergent situations. |
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E.4 | Principal exclusion criteria |
1. INR ≥ 1.5 at Screening. If based on opinion of Investigator and/or prescribing physician patient is appropriate for anticoagulant holiday, patient may stop taking anticoagulant for an appropriate washout period or reversal with vitamin K and if indicated a repeat INR within < 1.5 would be acceptable. If INR is not indicated (direct thrombin inhibitors or Xa inhibitors) then appropriate washout period alone may be acceptable.
2. ALT and AST levels > 250 U/L at Screening (one retest permitted)
3. eGFR < 60 ml/min at Screening (one retest permitted)
4. Post-bronchodilation (if available) FEV1 <65% of predicted at Screening in any subject not receiving AAT augmentation therapy.
5. Post-bronchodilation (if available) FEV1 <45% of predicted at Screening in any subject currently receiving AAT augmentation therapy on a regular basis and planning to continue AAT augmentation therapy for the duration of the study.
6. Patients expected to have severe and unavoidable high-level exposure to inhaled pulmonary toxins during the study.
7. Patients with recent (last 3 months) diagnosis of pneumonia are also excluded.
8. Human immunodeficiency virus infection, as shown by the presence of anti-HIV antibody (sero-positive)
9. Seropositive for HBV (HBsAg positive at Screening) or HCV (detectable HCV RNA at Screening). Cured HCV (positive antibody test without detectable HCV RNA is acceptable).
10. Uncontrolled hypertension (Systolic BP > 170 and diastolic BP >100 mmHg at Screening). Patients may rescreen once BP is successfully controlled.
11. A history of torsades de pointes, ventricular rhythm disturbances (e.g., ventricular tachycardia or fibrillation), heart block (excluding first-degree block, being PR interval prolongation only), congenital long QT syndrome or new ST segment elevation or depression or new Q wave on ECG. Participants with a history of atrial arrhythmias should be discussed with the Medical Monitor
12. Symptomatic heart failure (per NYHA guidelines), unstable angina, myocardial infarction, severe cardiovascular disease (ejection fraction < 20%, transient ischemic attack (TIA) or cerebrovascular accident (CVA) within 6 months prior to Screening
13. History of malignancy within the last 1 year except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer.
14. History of major surgery within the prior 1 month prior to Screening
15. Regular use of alcohol within one month prior to the Screening visit (i.e., more than 14 units of alcohol per week [1 Unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol])
16. Use of illicit drugs (such as cocaine, phencyclidine [PCP]) within 1 year prior to the Screening visit or positive urine drug screen at Screening (a urine drug screen positive for benzodiazepines, opioids or marijuana is acceptable for enrollment at the discretion of the Investigator if the positive test is due to a substance used for medical reasons).
17. Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study involving a therapeutic intervention.
18. Blood donation (≥500 mL) within 7 days prior to study treatment administration.
19. Any concomitant medical or psychiatric condition or social situation that would make it difficult to comply with protocol requirements or put the participant at additional safety risk. Patients with NASH, NAFLD, metabolic syndrome, well controlled diabetes mellitus (even if on insulin) or hemochromatosis are acceptable if disease is stable and does not pose a significant threat to subject participation.
20. A history of thromboembolic disease (including deep vein thrombosis or pulmonary embolism), myocardial infarction, stroke within six (6) months of screening.
21. Participants who are unable to return for all scheduled study visits.
22. Females of childbearing potential who are breastfeeding.
23. Any other condition, that in the opinion of the Investigator would render the participant unsuitable for enrollment or could interfere with participating in and completing the study.
24. Previous diagnosis of decompensated liver cirrhosis or complications of cirrhosis (e.g. varices, ascites, hepatic encephalopathy) based on source verifiable medical record.
25. Diagnosis of F4 (Metavir) or similar grading scale equivalent indicating definitive cirrhosis on pre-dose liver biopsy completed as part of the AROAAT2002 study based on local pathologist read or based on historical liver biopsy (last 6 months from consent) with a source verifiable pathologist read of definitive liver cirrhosis.
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E.5 End points |
E.5.1 | Primary end point(s) |
Histologic Assessments:
• Changes in AATD related histological metrics (e.g. steatosis, inflammation)
• Measure of size and number of PAS/D + globules (percent change and absolute change)
• Changes in Ishak fibrosis score
Safety Assessments:
• Vital signs: Resting heart rate, semi-supine systolic/diastolic blood pressure, respiratory rate and temperature
• Clinical laboratory measurements (e.g., biochemistry, hematology, cardiac troponin, coagulation, urine cotinine and urinalysis)
• Resting ECG measurements (measured after participant is semi-supine for at least 3 minutes)
• At each visit, participants will be asked about concomitant medications/therapy and will be instructed to volunteer any information regarding AEs and SAEs that they may have experienced. Any known untoward event that occurs beyond the AE reporting period that the Investigator(s) considers an SAE and possibly related to study treatment will be reported to Arrowhead.
• Injection site reactions (ISRs): Injection site reactions will be defined and graded as mild, moderate or severe based on clinical findings
• 90-day, post-last dose follow-up phone call to assess for pregnancy occurrence
• Physical examination (symptom directed as described in Schedule of Assessments)
• Pulmonary Function Testing including spirometry (including FEV1) and DLCO
• Use of augmentation treatment at any time throughout the study and date when last augmentation was administered prior to each ARO-AAT dose
• Time from baseline to initiation of augmentation therapy
• Number and severity of COPD exacerbations based on GOLD criteria will be evaluated as an AE of special interest |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
See Schedule of Assessments |
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E.5.2 | Secondary end point(s) |
• Quantitative and/or % change in alpha-1 antitrypsin levels and Z-AAT levels
• Change in FibroScan® (where available)
• Change in Magnetic Resonance Elastography (optional)
• Percent and absolute change in liver total (soluble plus insoluble) Z-AAT protein levels
• Percent and absolute change in liver Z-AAT soluble protein levels
• Percent and absolute change in liver Z-AAT insoluble protein levels
• Quantified and percent change in liver expression of liver fibrosis associated genes
• Percent and absolute change in SERPINA1 mRNA levels
• Measures of hepatic function including PT, PTT, INR, albumin, ALT, AST, GGT, platelet count, total bilirubin and alkaline phosphatase
• Collagen content measurement (Masson’s Trichrome, Sirius Red, morphometric analysis)
• Serum fibrosis biomarkers (e.g. Pro-C3)
• Calculated values indicative of liver disease (FIB-4, APRI) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
See Schedule of Assessments |
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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 | No |
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 | Yes |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |