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: 16 January 2017
• Main ID: EUCTR2016-000917-59-IE
• Date of registration: 13/04/2016
• 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: An Open-Label, Multi-dose, Phase 2 Study to Determine the Safety, Tolerability and Effect on Circulating and Intrahepatic Alpha-1 Antitrypsin Levels of ARC-AAT as evidenced by changes in liver biopsy in Patients with Alpha-1 Antitrypsin Deficiency (AATD)
• Date of first enrolment: 29/06/2016
• Target sample size: 12
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-000917-59
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: yes Single blind: no Double blind: no Parallel group: Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Canada, Ireland, Sweden

Contacts

• Name: Susan Boynton, Regulatory Affairs
• Affiliation: Arrowhead Pharmaceuticals, Inc

• Name: Susan Boynton, Regulatory Affairs
• Affiliation: Arrowhead Pharmaceuticals, Inc

Key inclusion & exclusion criteria

Inclusion criteria:
To be eligible for enrollment, participants must meet all of 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. Availability of documented PiZ phenotype is sufficient to allow enrollment but a confirmatory genotype must be performed.
2. Able and willing to provide written informed consent prior to the performance of any study specific procedures.
3. Participants with a BMI between 18.0 and 35.0 kg/m2, inclusive. Participants with BMI between 15-18 kg/m2 or between 35-40 kg/m2 may be enrolled at the PI’s discretion in consultation with Sponsor depending on co-morbidities.
4. A 12-lead ECG at Screening that, in the opinion of the investigator, has no abnormalities that compromise participant’s safety in this study.
5. Non-smoker (not a daily cigarette smoker) for at least 12 months with current non-smoking status confirmed by urine cotinine at screening. 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 PI.
6. Participants using highly effective, double barrier contraception (both male and female partners) during the study and for 3 months following the last dose of ARC-AAT Injection. Males must not donate sperm for at least 3 months post last dose of study treatment. Male partners of female patients and female partners of male patients must also use contraception, if they are of childbearing potential. 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 postmenopausal (defined as cessation of regular menstrual periods for at least 12 months), confirmed by follicle-stimulating hormone (FSH) level > 40 mIU/mL or as otherwise consistent with postmenopausal state based on lab reference ranges.
• Using twice the normal protection of birth control by using a condom AND one other form from the following:
• Birth control pills (The Pill)
• Depot or injectable birth control
• IUD (Intrauterine Device)
• Birth Control Patch (e.g., Othro Evra)
• NuvaRing®
• Surgical sterilization. i.e., tubal ligation, hysterectomy, bilateral oophorectomy, vasectomy or equivalently effective surgical form of birth control. Rhythm methods will not be considered as highly effective methods of birth control.
7. Participants who are willing and able to comply with all study assessments and adhere to the protocol schedule
8. Must have suitable venous access for blood sampling
9. 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.
10. ALT, AST levels less than 5X times the upper limit of normal at Screening
11. Creatinine levels < 1.5X upper limit of normal and estimated (calculated) GFR > or equal to 60 at Screening

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 11
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 1

Exclusion criteria:
A potential participant will be excluded from the study if any of the following criteria apply:
1. INR > 1.3. If based on opinion of PI 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 < 1.3 would be acceptable. 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 < 70,000
3. A known diagnosis of hepatic fibrosis from a cause other than AATD (such as non-alcoholic steatohepatitis, alcoholism or infection)
4. A history of poorly controlled autoimmune disease, or any history of autoimmune hepatitis
5. Human immunodeficiency virus infection, as shown by the presence of anti-HIV antibody (seropositive)
6. Seropositive for HBV or HCV
7. Uncontrolled hypertension (Systolic BP > 170 and diastolic BP >100 mmHg at Screening)
8. A history of torsades de pointes, ventricular rhythm disturbances (e.g., ventricular tachycardia or fibrillation), pathologic sinus bradycardia (<50 bpm and symptomatic), 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
9. A family history of congenital long QT syndrome or unexplained sudden cardiac death
10. 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 study entry
11. History of malignancy within the last 2 years 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
12. History of major surgery within 1 month of Screening
13. Regular use of alcohol within one month prior to the Screening visit (i.e., more than fourteen units of alcohol per week [1 Unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol])
14. Use of illicit drugs (such as cocaine, phencyclidine [PCP] and crack) 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 PI)
15. History of known allergy to bee venom, any history of anaphylaxis or any history of severe systemic hypersensitivity reaction
16. Use of an investigational agent or device within 30 days prior to dosing or current participation in an investigational study involving a therapeutic intervention. Subjects who have participated in the ARCAAT-1001 study or observational studies are acceptable.
17. Any clinically significant history or presence of poorly controlled or decompensated neurological, endocrinal, cardiovascular, pulmonary, hematological, immunologic, psychiatric, metabolic or other uncontrolled systemic disease.
18. Blood donation (=500 mL) within 7 days prior to study trea

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 related liver disease
MedDRA version: 19.1 Level: PT Classification code 10001806 Term: Alpha-1 anti-trypsin deficiency System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Product Name: ARC-AAT Injection
Product Code: ARC-AAT
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: API-AAT
Current Sponsor code: API-AAT
Other descriptive name: API-AAT, AD00370, ARC-AAT, API drug Substance
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 52-

Primary Outcome(s)

Main Objective: To determine the safety and tolerability of multiple doses of ARC-AAT Injection

Timepoint(s) of evaluation of this end point: See Schedule of Assessments

Primary end point(s): Safety and tolerability of repeated doses of ARC-AAT Injection.

Secondary Objective: To determine the effect of multiple doses of ARC-AAT Injection on circulating levels of alpha-1 antitrypsin

Secondary Outcome(s)

Secondary end point(s): Serum alpha-1 antitrypsin levels

Timepoint(s) of evaluation of this end point: Pre-dose; Dosing Days 1, 29, 57, 85, 113, 141, 169; Days 197, 227, 257, 287 (EOS)

Secondary ID(s)

ARCAAT2001

Source(s) of Monetary Support

Arrowhead Pharmaceuticals, Inc