A Placebo-Controlled, Multi-dose, Phase 2 Study to Determine the Safety, Tolerability and Pharmacodynamic Effect of ARO-AAT in Patients with Alpha-1 Antitrypsin Deficiency (AATD) (SEQUOIA)
- Conditions
- alpha-110019654
- Registration Number
- NL-OMON54898
- Lead Sponsor
- Arrowhead Pharmaceuticals Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 5
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. A patient with no fibrosis may participate based in a previous biopsy
conducted
within one year if a source verifiable medical record specifies no evidence of
fibrosis.
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 patient*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. Use 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 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
without an alternative medical cause), 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 abstinence for the duration of the study and 12 weeks after the dose of
AROAAT
is acceptable only when in line with the preferred and usual lifestyle of the
patient. 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.
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/1.73m2 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. Patients 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
Investigat
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Primary Endpoint:<br /><br>• Percent change from baseline at Week 16 in serum Z-AAT</p><br>
- Secondary Outcome Measures
Name Time Method <p>Secundary endpoints:<br /><br><br /><br>• Safety of ARO-AAT versus placebo based on frequency of adverse events (AEs)<br /><br>at Week 16 and over time through End of Study (EOS)<br /><br>• Absolute and percent change from baseline in total liver Z-AAT (insoluble +<br /><br>soluble) protein at post-dose biopsy visit<br /><br>• Absolute and percent change from baseline in liver Z-AAT soluble protein at<br /><br>postdose biopsy visit<br /><br>• Absolute and percent change from baseline in liver Z-AAT insoluble protein at<br /><br>postdose biopsy visit<br /><br>• Absolute and percent change from baseline in liver function tests including<br /><br>ALT, AST, alkaline phosphatase, GGT, total bilirubin, direct bilirubin and INR<br /><br>at Week 16 and over time through EOS<br /><br>• Absolute and percent change in serum Z-AAT over time through EOS<br /><br>• Change over time in pharmacokinetic measurements of ARO-AAT at timepoints<br /><br>specified in the Schedule of Assessments</p><br>