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    Summary
    EudraCT Number:2019-000068-86
    Sponsor's Protocol Code Number:AROAAT2002
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2019-04-03
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2019-000068-86
    A.3Full title of the trial
    A Pilot Open Label, Multi-dose, Phase 2 Study to Assess the Safety and Efficacy of ARO-AAT in Patients with Alpha-1 Antitrypsin Deficiency Associated Liver Disease (AATD)
    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 numberAROAAT2002
    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 codeCA 91105
    B.5.3.4CountryUnited States
    B.5.4Telephone number0016263043400
    B.5.5Fax number0016263043401
    B.5.6E-mailmchanglok@arrowheadpharma.com
    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.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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
    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
    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.
    E.2.2Secondary 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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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.
    E.5 End points
    E.5.1Primary 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
    E.5.1.1Timepoint(s) of evaluation of this end point
    See Schedule of Assessments
    E.5.2Secondary 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)
    E.5.2.1Timepoint(s) of evaluation of this end point
    See Schedule of Assessments
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other 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.8.4.1Number of sites anticipated in Member State concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA5
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    LVLS
    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 months3
    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 months3
    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: 12
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    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 state4
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 16
    F.4.2.2In the whole clinical trial 16
    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 12 weeks (± 5 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 Decision2019-05-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-01
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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