alpha-1 antitrypsin deficiency (AATD)-associated liver disease MedDRA version: 23.1 Level: LLT Classification code 10001806 Term: Alpha-1 anti-trypsin deficiency System Organ Class: 100000004850
Conditions
Sponsors
Arrowhead Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
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, h
Exclusion criteria
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 250 U/L at Screening (one retest permitted) 3. eGFR 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, wel
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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;Timepoint(s) of evaluation of this end point: See Schedule of Assessments;Main Objective: 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.;Secondary Objective: • To determine the effect of multiple doses of ARO-AAT on circu | — |
Secondary
| Measure | Time frame |
|---|---|
| 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);Timepoint(s) of evaluation of this end point: See Schedule of Assessments | — |
Countries
Austria, Germany, United Kingdom
Contacts
Public ContactMei Ling Chang-Lok
Arrowhead Pharmaceuticals, Inc.
Outcome results
None listed