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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT02363946




Registration number
NCT02363946
Ethics application status
Date submitted
2/02/2015
Date registered
16/02/2015
Date last updated
3/08/2018

Titles & IDs
Public title
A Study of ARC-AAT in Healthy Volunteer Subjects and Patients With Alpha-1 Antitrypsin Deficiency (AATD)
Scientific title
A Double-Blind, Placebo-Controlled, Dose-Escalating, Phase 1 Study to Determine the Safety, Tolerability, Pharmacokinetics and Effect of Circulating Alpha-1 Antitrypsin Levels of ARC-AAT in Healthy Volunteer Subjects and in Patients With Alpha-1 Antitrypsin Deficiency (AATD)
Secondary ID [1] 0 0
U1111-1171-0247
Secondary ID [2] 0 0
ARCAAT-1001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alpha-1 Antitrypsin Deficiency 0 0
Condition category
Condition code
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Respiratory 0 0 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - ARC-AAT Injection
Other interventions - Placebo
Treatment: Drugs - Diphenhydramine

Experimental: Part A: 0.38 mg/kg - Single dose administration of ARC-AAT intravenous (IV) injection, 0.38 mg/kg in healthy volunteers

Experimental: Part A: 1.0 mg/kg - Single dose administration of ARC-AAT IV injection, 1.0 mg/kg in healthy volunteers

Experimental: Part A: 2.0 mg/kg - Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in healthy volunteers

Experimental: Part A: 3.0 mg/kg - Single dose administration of ARC-AAT IV injection, 3.0 mg/kg in healthy volunteers

Experimental: Part A: 4.0 mg/kg - Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in healthy volunteers

Experimental: Part A: 5.0 mg/kg - Single dose administration of ARC-AAT IV injection, 5.0 mg/kg in healthy volunteers

Experimental: Part A: 6.0 mg/kg - Single dose administration of ARC-AAT IV injection, 6.0 mg/kg in healthy volunteers

Experimental: Part A: 7.0 mg/kg - Single dose administration of ARC-AAT IV injection, 7.0 mg/kg in healthy volunteers

Experimental: Part A: 8.0 mg/kg - Single dose administration of ARC-AAT IV injection, 8.0 mg/kg in healthy volunteers

Placebo Comparator: Part A: Placebo - Single dose administration of 0.9% normal saline IV injection in healthy volunteers

Experimental: Part B: 2.0 mg/kg - Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in participants with AATD

Experimental: Part B: 4.0 mg/kg - Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in participants with AATD

Experimental: Part B: 6.0 mg/kg - Single dose administration of ARC-AAT IV injection, 6.0 mg/kg in participants with AATD

Experimental: Part B: 7.0 mg/kg - Single dose administration of ARC-AAT IV injection, 7.0 mg/kg in participants with AATD

Placebo Comparator: Part B: Placebo - Single dose administration of 0.9% normal saline IV injection in participants with AATD


Treatment: Drugs: ARC-AAT Injection
RNA interference-based, liver-targeted therapeutic

Other interventions: Placebo
0.9 % normal saline

Treatment: Drugs: Diphenhydramine
Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment.

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), or Discontinuations Due to TEAEs - An adverse event (AE) is defined as any untoward medical occurrence which does not necessarily have to have a causal relationship with this treatment. TEAEs are defined as defined as AEs with onset after administration of the study drug, or when a preexisting medical condition increases in severity or frequency after study drug administration. SAEs are defined as is an AE that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of an existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a medically important event or reaction.
Timepoint [1] 0 0
From the first dose of study treatment through Day 29 ± 1 day
Primary outcome [2] 0 0
Number of Participants With Clinically Significant Treatment-Emergent Abnormalities in Laboratory Values - Laboratory values collected include: hematology (haemoglobin, lymphocytes, neutrophils, platelets, white cell count, monocytes); biochemistry (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, bilirubin, creatine kinase, creatinine, gamma-glutamyltransferase, fasting glucose, troponin I); coagulation parameters (fibrinogen, international normalized ratio); and C-reactive protein.
Timepoint [2] 0 0
Day 1 through Day 29 ± 1 day
Primary outcome [3] 0 0
Number of Participants With Clinically Significant Treatment-Emergent Abnormalities in Vital Signs, Electrocardiograms (ECGs), Pulmonary Function, Physical Findings, and Other Observations - Values collected include: vital signs (clinically concerning or symptomatic treatment emergent changes in heart rate, systolic blood pressure, diastolic blood pressure, respiratory rate, or temperature); ECGs (clinically significant changes from baseline were observed for ventricular rate, RR interval, QRS duration, QT interval or QT interval corrected for heart rate using Fridericia's formula [QTcF]; treatment emergent clinically significant changes in ST segments, P wave or T wave morphology; cardiac telemetry monitoring); clinically significant abnormal physical examination findings; treatment emergent sensitivity to bee venom; pulmonary function (clinically significant worsening in spirometry parameters and carbon monoxide diffusing capacity of the lung for carbon monoxide [DLCO]).
Timepoint [3] 0 0
Day 1 through Day 29 ± 1 day
Primary outcome [4] 0 0
Pharmacokinetics of ARC-AAT: Maximum Observed Plasma Concentration (Cmax) for the Analytes AD00370 and ARC-Melittin-Like Peptide (MLP; Part A)
Timepoint [4] 0 0
Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose
Primary outcome [5] 0 0
Pharmacokinetics of ARC-AAT: Time to Maximum Observed Concentration (Tmax) for the Analytes AD00370 and ARC-MLP (Part A)
Timepoint [5] 0 0
Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose
Primary outcome [6] 0 0
Pharmacokinetics of ARC-AAT: Area Under the Plasma Concentration Versus Time Curve From Time 0 to Time 24 Hours (AUC0-24) for the Analytes AD00370 and ARC-MLP (Part A)
Timepoint [6] 0 0
Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose
Primary outcome [7] 0 0
Pharmacokinetics of ARC-AAT: Area Under the Plasma Concentration Versus Time Curve From From Zero to Infinity (AUCinf) for the Analytes AD00370 and ARC-MLP (Part A)
Timepoint [7] 0 0
Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose
Primary outcome [8] 0 0
Pharmacokinetics of ARC-AAT: Terminal Elimination Rate Constant Obtained From the Slope of the Line (Kel) for the Analytes AD00370 and ARC-MLP (Part A)
Timepoint [8] 0 0
Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose
Primary outcome [9] 0 0
Pharmacokinetics of ARC-AAT: Half-Life (t1/2) for the Analytes AD00370 and ARC-MLP (Part A)
Timepoint [9] 0 0
Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose
Primary outcome [10] 0 0
Percentage Reduction From Baseline of AAT Up to Day 29 - Clinical assay for total serum AAT level was used for Part A. A quantitative measurement of AAT was used for Part B. A negative percent reduction indicates a percentage increase. Baseline AAT levels consisted of a geometric mean based on 3 assessments taken prior to study drug administration: at 2 time points during the Screening window at least 5 days apart, and on Day -1.
Timepoint [10] 0 0
Baseline, Days 3, 8, 15, 22 and 29
Secondary outcome [1] 0 0
Number of Participants With AAT Reduction > 30% From Baseline (First Occurrence) - Data presents the study visit day upon which a participant had the first occurrence of AAT reduction of > 30% from Baseline, and the number of participants who had a > 30% reduction at any visit (overall). Baseline AAT levels consisted of a geometric mean based on 3 assessments taken prior to study drug administration: at 2 time points during the Screening window at least 5 days apart, and on Day -1.
Timepoint [1] 0 0
Baseline, Days 3, 8, 15, 22 and 29
Secondary outcome [2] 0 0
Maximum Percentage Reduction in Mean AAT (Nadir of Mean AAT)
Timepoint [2] 0 0
Study Day for Nadir of Mean AAT: Day 8 (for Part B 2 mg/kg arm), Day 15 (for Part A 0.38 mg/kg, 2 mg/kg, 4 mg/ kg, Placebo arms; Part B 4 mg/kg, Placebo arms), Day 22 (Part A 3 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg arms), Day 29 (1 mg/kg, 8 mg/kg arms)
Secondary outcome [3] 0 0
Number of Participants With a Return From Nadir AAT Blood Levels to Above Normal or Within 15% of Baseline in > 100 Days - Baseline AAT levels consisted of a geometric mean based on 3 assessments taken prior to study drug administration: at 2 time points during the Screening window at least 5 days apart, and on Day -1.
Timepoint [3] 0 0
Baseline, up to Day 29, and through 100 days of follow-up
Secondary outcome [4] 0 0
Mean Percentage Change in Circulating Blood Levels of Cytokines 2 Hours Post-Dose
Timepoint [4] 0 0
Pre-dose, 2 hours post-dose
Secondary outcome [5] 0 0
Mean Percentage Change in Circulating Blood Levels of Complement Factors 2 Hours Post-Dose
Timepoint [5] 0 0
Pre-dose, 2 hours post-dose

Eligibility
Key inclusion criteria
(Part A - Healthy Volunteers)

- Male or female healthy volunteers 18-50 years of age

- Written informed consent

- Body mass index between 18.0 and 28.0 kg/m2

- 12-lead electrocardiogram (ECG) at Screening and pre-dose assessment with no
clinically significant abnormalities

- Non-pregnant/non-nursing females

- Non-smoker for at least one year with current non-smoking status confirmed by urine
cotinine

- Normal lung function (or not clinically significant per investigator assessment) based
on spirometry and diffusion capacity of lung for carbon monoxide (DLCO) according to
American Thoracic Society (ATS) - European Respiratory Society (ERS) criteria

- Highly effective, double barrier contraception (both male and female partners) during
the study and for 3 months following the dose of ARC-AAT

- Willing and able to comply with all study assessments and adhere to protocol schedule

- Suitable venous access for blood sampling

- No abnormal finding of clinical relevance at screening

- Normal AAT level

(Part B-Patients) - As for Part A with the following exceptions:

- Male or female patients 18-70 years of age

- Confirmed diagnosis of homozygous alpha 1-protease inhibitor deficiency (PiZZ
genotype) not receiving alpha-1 antitrypsin augmentation therapy for more than 4 weeks

- BMI between 18.0 and 35.0 kg/m2

- Non-smoker for at least three years with current non-smoking status confirmed by urine
cotinine
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
(Part A-Healthy Volunteers)

- Current regular smoker of cigarettes or cigars or was a regular smoker over the past 1
year

- Recent (within last 6 weeks) transfusion of fresh frozen plasma, platelets, or packed
red blood cells, or anticipated need for transfusion during study

- Acute signs of hepatitis/other infection within 4 weeks of screening and/or baseline

- Concurrent anticoagulants

- Use of dietary and/or herbal supplements that can interfere with liver metabolism
within 7 days of screening

- Use of any drugs known to induce or inhibit hepatic drug metabolism within 14 days
prior to study treatment

- Depot injection/implant of any drug other than birth control within 3 months prior to
study treatment

- Diagnosis of diabetes mellitus or history of glucose intolerance

- History of poorly controlled autoimmune disease or any history of autoimmune hepatitis

- Human immunodeficiency virus (HIV) infection

- Seropositive for hepatitis B virus (HBV) or hepatitis C virus (HCV), and/or history of
delta virus hepatitis

- Uncontrolled hypertension (blood pressure > 150/100 mmHg)

- History of cardiac rhythm disturbances

- Family history of congenital long QT syndrome or unexplained sudden cardiac death

- Symptomatic heart failure (per New York Heart Association [NYHA] guidelines)

- Unstable angina, myocardial infarction, severe cardiovascular disease, transient
ischemic attack (TIA) or cerebrovascular accident (CVA) within past 6 months

- History of malignancy within last 5 years except adequately treated basal cell
carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical
cancer.

- History of major surgery within 3 months of screening

- Regular use of alcohol within 1 month prior to screening (i.e., more than fourteen
units of alcohol per week)

- Evidence of acute inflammation, sepsis or hemolysis or clinical evidence of lower
respiratory tract infection

- Diagnosis of significant psychiatric disorder

- Use of illicit drugs (such as cocaine, phencyclidine [PCP] and crack) within 1 year
prior to screening or positive urine drug screen

- History of allergy or hypersensitivity reaction to bee venom

- Use of an investigational agent or device within 30 days prior to dosing or current
participation in an investigational study

- Clinically significant history/presence of any gastrointestinal pathology, unresolved
gastrointestinal symptoms, liver or kidney disease

- Other conditions known to interfere with the absorption, distribution, metabolism, or
excretion of drugs

- Any clinically significant history/presence of poorly controlled neurological,
endocrinal, cardiovascular, pulmonary, hematological, immunologic, psychiatric,
metabolic or other uncontrolled systemic disease

- Blood donation (500 mL) within 7 days prior to study treatment

- History of fever within 2 weeks of screening

- Concomitant medical/psychiatric condition or social situation that would affect
compliance or result in additional safety risk

- Excessive exercise/physical activity within 3 days of screening or enrollment or
planned during the study

- History of thromboembolic disease, stroke within 6 months of baseline, and/or
concurrent anticoagulant medication(s)

(Part B-Patients) - As for Part A with the following exceptions:

- History of major surgery within 2 months of Screening

- Forced expiratory volume at one second (FEV1) at baseline < 60%

- AATD patients with liver elastography score > 11 at Screening

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 0 0
Nucleus Network Ltd - Melbourne
Recruitment postcode(s) [1] 0 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 0 0
Germany
State/province [1] 0 0
Homburg
Country [2] 0 0
Netherlands
State/province [2] 0 0
Leiden
Country [3] 0 0
United Kingdom
State/province [3] 0 0
Birmingham

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Arrowhead Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The purpose of the study is to determine the safety and tolerability of escalating doses of
ARC-AAT and to evaluate the pharmacokinetics of ARC-AAT and the effect of ARC-AAT on
circulating levels of alpha-1 antitrypsin (AAT). The study will consist of two parts, Part A
(conducted in healthy volunteers) and Part B (conducted in AATD patients) at up to 9
escalating dose levels with 6 participants per dose level.
Trial website
https://clinicaltrials.gov/show/NCT02363946
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT02363946