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    The EU Clinical Trials Register currently displays   42883   clinical trials with a EudraCT protocol, of which   7063   are clinical trials conducted with subjects less than 18 years old.
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    EudraCT Number:2018-003385-14
    Sponsor's Protocol Code Number:AROAAT2001
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2020-09-14
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedAustria - BASG
    A.2EudraCT number2018-003385-14
    A.3Full title of the trial
    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]
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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)
    A.4.1Sponsor's protocol code numberAROAAT2001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorArrowhead Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportArrowhead Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationArrowhead Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointMei Ling Chang-Lok
    B.5.3 Address:
    B.5.3.1Street Address177 East Colorado Boulevard, Suite 700
    B.5.3.2Town/ cityPasadena
    B.5.3.3Post code91105
    B.5.3.4CountryUnited States
    B.5.4Telephone number0016263043400
    B.5.5Fax number0016263043401
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2048
    D.3 Description of the IMP
    D.3.1Product nameARO-AAT Injection
    D.3.2Product code ARO-AAT
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNADS-001
    D.3.9.1CAS number 2175009-08-0
    D.3.9.2Current sponsor codeADS-001
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number230
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    alpha-1 antitrypsin deficiency (AATD)-associated liver disease
    E.1.1.1Medical condition in easily understood language
    alpha-1 antitrypsin deficiency (AATD)-associated liver disease
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level LLT
    E.1.2Classification code 10001806
    E.1.2Term Alpha-1 anti-trypsin deficiency
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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).
    E.2.2Secondary objectives of the trial
    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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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 or current participation in an investigational study involving a therapeutic intervention. Patients who have participated in the ARCAAT-1001 study or observational studies are acceptable. Patients previously enrolled in but no longer enrolled in gene therapy studies are acceptable. Patients receiving AAT augmentation therapy as part of a post-marketing study or other access program for approved therapies are acceptable.
    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. Patients enrolled with NASH should have no plans to undergo bariatric surgery or have initiated or plan to initiate pharmaceutical therapy for NASH (such as Vitamin E or pioglitazone) during the course of the study.
    20. A history of thromboembolic disease (including deep vein thrombosis or pulmonary embolism), myocardial infarction, stroke within three (3) months of screening.
    *Please refer to protcol for exclusion criteria #21-24.

    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(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)
    E.5.2Secondary 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part B:
    Days 1, 29, 113 then every 84 days (Days 197, 281, 365, 449, 533, 617)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E. trial design description
    Phase 2 to Phase 3 adaptive design
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 110
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 120
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    There will be a follow-up telephone call to assess for pregnancy occurrence 90 days post last dose.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-10-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-01-28
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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