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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/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
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
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
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
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)
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
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
Sex
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
Stopped early
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/02/2015
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/11/2016
Sample size
Target
Accrual to date
Final
65
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
Trial website
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

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.

Results are available at https://clinicaltrials.gov/study/NCT02363946