A clinical trial to assess the safety and effects of a novel medicine intended for the treatment of patients with liver disease due to Alpha-1 Antitrypsin Deficiency (AATD)

• Register: EUCTR
• Last refreshed on: 12 December 2023
• Main ID: EUCTR2018-003385-14-AT
• Date of registration: 14/09/2020
• Prospective Registration: Yes
• Primary sponsor: Arrowhead Pharmaceuticals, Inc.
• Public title: A clinical trial to assess the safety and effects of a novel medicine intended for the treatment of patients with liver disease due to Alpha-1 Antitrypsin Deficiency (AATD)
• Scientific title: A Placebo-Controlled, Multi-dose, Phase 2/3 Study to Determine the Safety, Tolerability and Effect on Liver Histologic Parameters in Response to ARO-AAT in Patients with Alpha-1 Antitrypsin Deficiency (AATD) [SEQUOIA]
• Date of first enrolment: 28/01/2021
• Target sample size: 120
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-003385-14
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: yes Other trial design description: Phase 2 to Phase 3 adaptive design If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Canada, Germany, Ireland, Italy, Netherlands, Portugal, Spain, Sweden, Switzerland, United Kingdom, United States

Contacts

• Name: Mei Ling Chang-Lok
• Affiliation: Arrowhead Pharmaceuticals, Inc.

• Name: Mei Ling Chang-Lok
• Affiliation: Arrowhead Pharmaceuticals, Inc.

Key inclusion & exclusion criteria

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. Liver biopsy indicating a liver fibrosis score less than F4 based on local pathologist read.
a. Metavir F1- F3 (or equivalent on other grading scales) may participate in Part A and Part B. A previous biopsy conducted as part of an AROAAT study within 1 year is acceptable if there is sufficient baseline material for Part B analysis.
b. A patient with no fibrosis (F0) may participate in Part A only. A previous biopsy conducted within 1 year is acceptable if source verifiable medical record specifies F0.
4. A 12-lead ECG at Screening that, in the opinion of the Investigator, has no new acute abnormalities (e.g., new onset atrial fibrillation) that compromise participant’s safety in this study. Stable disease (e.g., stable atrial fibrillation) is acceptable.
5. 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 any previous smoking history prior to 12 months must be < 15 pack years. Patients may be on nicotine replacement (patch or gum). e-cigarettes (vapor) is not permitted. A positive urine cotinine result due to nicotine replacement is acceptable for enrollment at the discretion of the Investigator.
6. Participants using highly effective contraception during the study and for 3 months following the last dose of ARO-AAT. Males must not donate sperm for at least 3 months
Arrowhead Pharmaceuticals, Inc.
Protocol No.: AROAAT2001
Version 3.0, 28 April 2020 Confidential Page 49 of 106
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, is acceptable.
• 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 amenorrhea methods are not considered “true” abstinence and are not acceptable methods of contraception.
* All laboratory tests used as inclusion criteria may be repeated once and the repeat value may be used for inclusion purposes.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
Exclusion criteria:
1. INR = 1.2 at Screening (one retest permitted). 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 and if indicated a repeat INR within < 1.2 would be acceptable. Vitamin K may be used for reversal. If INR is not indicated (direct thrombin inhibitors or Xa inhibitors) then appropriate washout period alone may be acceptable. (Note: Anti-platelet agents, aspirin, clopidogrel or NSAIDS are acceptable but must be held 7 days before and 7 days after liver biopsy)
2. Platelet count < 150 x 109/L at Screening (one retest permitted)
3. ALT and AST levels > 250 U/L at Screening (one retest permitted)
4. eGFR < 60ml/min at Screening (one retest permitted)
5. FEV1 <65% of predicted (preferentially post-bronchodilatory reading) at Screening (one retest permitted)
6. Recent (last 3 months) pneumonia or lower respiratory infection (which must be verifiable from the medical record). Patient reported infection is not sufficient to meet this criterion.
7. Unavoidable exposure to inhaled environmental toxins that in the clinical judgement of the investigator could impair pulmonary function significantly over the course of the study.
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), untreated heart block (excluding first-degree block, being PR interval prolongation only), congenital long QT syndrome or new acute ST segment elevation or depression or new acute Q wave on ECG. Stable atrial dysrhythmias (e.g., stable atrial fibrillation) are acceptable.
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. Participants with other curatively treated malignancies who have no evidence of metastatic disease and >1-year disease-free interval may be entered following approval by the Medical Monitor
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 THC is acceptable for enrollment at the discretion of the Investigator). Subject may still be eligible at discretion of Medical Monitor and Investigator if positive urine drug screen is due to a prescription medication.
17. Use of an investigational agent or device within 30 days prior to dosing

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

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

Intervention(s)

Product Name: ARO-AAT Injection
Product Code: ARO-AAT
Pharmaceutical Form: Solution for injection
INN or Proposed INN: ADS-001
CAS Number: 2175009-08-0
Current Sponsor code: ADS-001
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 230-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

Secondary Objective: Part B:
• To evaluate change in total liver Z-AAT (insoluble + soluble) protein at end of study versus baseline
• To evaluate change in liver Z-AAT soluble protein at end of study versus baseline
• To evaluate change in liver Z-AAT insoluble protein at end of study versus baseline
• To determine the effect of multiple doses of ARO-AAT on circulating levels of total and Z-AAT alpha-1 antitrypsin at multiple post-dose time points versus baseline (patients on and not on AAT augmentation therapy will be evaluated separately)
• To evaluate change from baseline on a histologic grading scale (including, but not limited to histological features such as inflammation, PASD globules, cell death, steatosis, etc.) of AATD associated liver disease on end of study biopsy in ARO-AAT treated patients relative to placebo
*Please refer to protocol for full list of secondary objectives.

Primary end point(s): The primary efficacy endpoint of Part B of the study is the proportion of ARO-AAT treated patients relative to placebo who achieve a 2-point improvement in a histologic grading scale of alpha-1 antitrypsin associated liver disease AND no worsening of liver fibrosis based on Ishak fibrosis score on end of study biopsy.

Main Objective: Part A
• To select a single dose level for use in Part B of the study based on a combined evaluation of safety and pharmacodynamic dose response in each Part A cohort using change over time from baseline to Day 113 in serum Z-AAT levels

Part B:
• To evaluate efficacy (as assessed by the proportion of ARO-AAT treated patients relative to placebo achieving a 2-point improvement in a histologic grading scale of alpha-1 antitrypsin deficiency associated liver disease AND no worsening of liver fibrosis based on Ishak score on end of study biopsy).

Timepoint(s) of evaluation of this end point: Part A:
Days 1, 29, 113, and every 84 days thereafter until a single dose level is selected

Part B:
Days 1, 29, 113 then every 84 days (Days 197, 281, 365, 449, 533, 617)

Secondary Outcome(s)

Secondary end point(s): Part B secondary endpoints include 1) Change from baseline on a histologic grading scale of AATD-associated liver disease on end of study biopsy in ARO-AAT treated patients relative to placebo, 2) Proportion of ARO-AAT treated patients with Ishak fibrosis stage-1 or greater fibrosis relative to placebo achieving at least a 1-stage improvement in fibrosis on end of study biopsy based on Ishak fibrosis score, 3) Change from baseline in Ishak fibrosis score at end of study biopsy in ARO-AAT treated patients relative to placebo.

Timepoint(s) of evaluation of this end point: Part B:
Days 1, 29, 113 then every 84 days (Days 197, 281, 365, 449, 533, 617)

Secondary ID(s)

2018-003385-14-IE

AROAAT2001

Source(s) of Monetary Support

Arrowhead Pharmaceuticals, Inc.

Ethics review

Status: Approved
Approval date: 28/01/2021
Contact: