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| ID | Type | Description | Link |
|---|---|---|---|
| U1111-1171-0247 | Other Identifier | WHO | |
| 2015-001147-36 | EudraCT Number |
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Company decision to terminate the trial
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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.
Healthy volunteers and AATD patients will be randomized to receive a single intravenous injection of either ARC-AAT or Placebo in double-blind fashion. Up to thirteen cohorts (6 participants per cohort) will be enrolled. Participants in all cohorts will be confined to the clinical facility beginning on Day -1 with discharge on Day 2. Escalation to the next dose level will proceed until a participant experiences a dose-limiting toxicity (DLT) or there is achievement of pre-determined threshold reductions in AAT levels. Dosing in participants with AATD will commence based on pre-determined threshold reductions in AAT levels for healthy volunteers. For each participant, the duration of the study clinic visits is up to 11 weeks, from Screening to the End-of-Study examination. However, including a Day 90 Follow-Up telephone call, the maximum study duration is approximately 20 weeks.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part A: 0.38 mg/kg | Experimental | Single dose administration of ARC-AAT intravenous (IV) injection, 0.38 mg/kg in healthy volunteers |
|
| Part A: 1.0 mg/kg | Experimental | Single dose administration of ARC-AAT IV injection, 1.0 mg/kg in healthy volunteers |
|
| Part A: 2.0 mg/kg | Experimental | Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in healthy volunteers |
|
| Part A: 3.0 mg/kg | Experimental | Single dose administration of ARC-AAT IV injection, 3.0 mg/kg in healthy volunteers |
|
| Part A: 4.0 mg/kg | Experimental | Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in healthy volunteers |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| ARC-AAT Injection | Drug | RNA interference-based, liver-targeted therapeutic |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | From the first dose of study treatment through Day 29 ± 1 day |
| 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. | Day 1 through Day 29 ± 1 day |
| 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]). |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
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Inclusion Criteria:
(Part A - Healthy Volunteers)
(Part B-Patients) - As for Part A with the following exceptions:
Exclusion Criteria:
(Part A-Healthy Volunteers)
(Part B-Patients) - As for Part A with the following exceptions:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site 1 | Melbourne | Victoria | 3004 | Australia | ||
| Research Site 2 |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29572094 | Derived | Turner AM, Stolk J, Bals R, Lickliter JD, Hamilton J, Christianson DR, Given BD, Burdon JG, Loomba R, Stoller JK, Teckman JH. Hepatic-targeted RNA interference provides robust and persistent knockdown of alpha-1 antitrypsin levels in ZZ patients. J Hepatol. 2018 Aug;69(2):378-384. doi: 10.1016/j.jhep.2018.03.012. Epub 2018 Mar 21. |
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This study terminated early and no participants were enrolled in the 6.0 mg/kg and 7.0 mg/kg arms planned in Part B.
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| ID | Title | Description |
|---|---|---|
| FG000 | Part A: 0.38 mg/kg | Single dose administration of ARC-AAT intravenous (IV) injection, 0.38 mg/kg in healthy volunteers |
| FG001 | Part A: 1.0 mg/kg | Single dose administration of ARC-AAT IV injection, 1.0 mg/kg in healthy volunteers |
| FG002 | Part A: 2.0 mg/kg | Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in healthy volunteers |
| FG003 | Part A: 3.0 mg/kg | Single dose administration of ARC-AAT IV injection, 3.0 mg/kg in healthy volunteers |
| FG004 | Part A: 4.0 mg/kg | Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in healthy volunteers |
| FG005 | Part A: 5.0 mg/kg | Single dose administration of ARC-AAT IV injection, 5.0 mg/kg in healthy volunteers |
| FG006 | Part A: 6.0 mg/kg | Single dose administration of ARC-AAT IV injection, 6.0 mg/kg in healthy volunteers |
| FG007 | Part A: 7.0 mg/kg | Single dose administration of ARC-AAT IV injection, 7.0 mg/kg in healthy volunteers |
| FG008 | Part A: 8.0 mg/kg | Single dose administration of ARC-AAT IV injection, 8.0 mg/kg in healthy volunteers |
| FG009 | Part A: Placebo | Single dose administration of 0.9% normal saline IV injection in healthy volunteers |
| FG010 | Part B: 2.0 mg/kg | Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in participants with alpha-1 antitrypsin deficiency (AATD) |
| FG011 | Part B: 4.0 mg/kg | Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in participants with AATD |
| FG012 | Part B: Placebo | Single dose administration of 0.9% normal saline IV injection in participants with AATD |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Part A: 0.38 mg/kg | Single dose administration of ARC-AAT IV injection, 0.38 mg/kg in healthy volunteers |
| BG001 | Part A: 1.0 mg/kg | Single dose administration of ARC-AAT IV injection, 1.0 mg/kg in healthy volunteers |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | All participants receiving at least 1 dose of study medication | Posted | Number | participants | From the first dose of study treatment through Day 29 ± 1 day |
|
Day -1 through Day 29 ± 1 day
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Part A: 0.38 mg/kg | Single dose administration of ARC-AAT IV injection, 0.38 mg/kg in healthy volunteers |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Rhabdomyolosis | Musculoskeletal and connective tissue disorders | MedDRA (17.1) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Conjunctivitis | Infections and infestations | MedDRA (17.1) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Chief Operating Officer | Arrowhead Pharmaceuticals, Inc. | 6263043400 |
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| ID | Term |
|---|---|
| D019896 | alpha 1-Antitrypsin Deficiency |
| ID | Term |
|---|---|
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D004155 | Diphenhydramine |
| ID | Term |
|---|---|
| D005021 | Ethylamines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D001559 | Benzhydryl Compounds |
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| Part A: 5.0 mg/kg |
| Experimental |
Single dose administration of ARC-AAT IV injection, 5.0 mg/kg in healthy volunteers |
|
| Part A: 6.0 mg/kg | Experimental | Single dose administration of ARC-AAT IV injection, 6.0 mg/kg in healthy volunteers |
|
| Part A: 7.0 mg/kg | Experimental | Single dose administration of ARC-AAT IV injection, 7.0 mg/kg in healthy volunteers |
|
| Part A: 8.0 mg/kg | Experimental | Single dose administration of ARC-AAT IV injection, 8.0 mg/kg in healthy volunteers |
|
| Part A: Placebo | Placebo Comparator | Single dose administration of 0.9% normal saline IV injection in healthy volunteers |
|
| Part B: 2.0 mg/kg | Experimental | Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in participants with AATD |
|
| Part B: 4.0 mg/kg | Experimental | Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in participants with AATD |
|
| Part B: 6.0 mg/kg | Experimental | Single dose administration of ARC-AAT IV injection, 6.0 mg/kg in participants with AATD |
|
| Part B: 7.0 mg/kg | Experimental | Single dose administration of ARC-AAT IV injection, 7.0 mg/kg in participants with AATD |
|
| Part B: Placebo | Placebo Comparator | Single dose administration of 0.9% normal saline IV injection in participants with AATD |
|
|
| Placebo | Other | 0.9 % normal saline |
|
| Diphenhydramine | Drug | Diphenhydramine 50 mg p.o. was administered 2 hours (±30 minutes) pre-dose as antihistamine pre-treatment. |
|
| Day 1 through Day 29 ± 1 day |
| Pharmacokinetics of ARC-AAT: Maximum Observed Plasma Concentration (Cmax) for the Analytes AD00370 and ARC-Melittin-Like Peptide (MLP; Part A) | Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose |
| Pharmacokinetics of ARC-AAT: Time to Maximum Observed Concentration (Tmax) for the Analytes AD00370 and ARC-MLP (Part A) | Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose |
| 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) | Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose |
| 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) | Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose |
| 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) | Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose |
| Pharmacokinetics of ARC-AAT: Half-Life (t1/2) for the Analytes AD00370 and ARC-MLP (Part A) | Day 1, 2, and 3 at pre-dose and then at 0.08, 0.5, 1, 3, 6, 24 and 48 hours post-dose |
| 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. | Baseline, Days 3, 8, 15, 22 and 29 |
| Baseline, Days 3, 8, 15, 22 and 29 |
| Maximum Percentage Reduction in Mean AAT (Nadir of Mean AAT) | 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) |
| 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. | Baseline, up to Day 29, and through 100 days of follow-up |
| Mean Percentage Change in Circulating Blood Levels of Cytokines 2 Hours Post-Dose | Pre-dose, 2 hours post-dose |
| Mean Percentage Change in Circulating Blood Levels of Complement Factors 2 Hours Post-Dose | Pre-dose, 2 hours post-dose |
| Homburg |
| Germany |
| Research Site 3 | Leiden | 2333ZA | Netherlands |
| Research Site 4 | Edgbaston | Birmingham | B15 2WB | United Kingdom |
| BG002 | Part A: 2.0 mg/kg | Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in healthy volunteers |
| BG003 | Part A: 3.0 mg/kg | Single dose administration of ARC-AAT IV injection, 3.0 mg/kg in healthy volunteers |
| BG004 | Part A: 4.0 mg/kg | Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in healthy volunteers |
| BG005 | Part A: 5.0 mg/kg | Single dose administration of ARC-AAT IV injection, 5.0 mg/kg in healthy volunteers |
| BG006 | Part A: 6.0 mg/kg | Single dose administration of ARC-AAT IV injection, 6.0 mg/kg in healthy volunteers |
| BG007 | Part A: 7.0 mg/kg | Single dose administration of ARC-AAT IV injection, 7.0 mg/kg in healthy volunteers |
| BG008 | Part A: 8.0 mg/kg | Single dose administration of ARC-AAT IV injection, 8.0 mg/kg in healthy volunteers |
| BG009 | Part A: Placebo | Single dose administration of 0.9% normal saline IV injection in healthy volunteers |
| BG010 | Part B: 2.0 mg/kg | Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in participants with alpha-1 antitrypsin deficiency (AATD) |
| BG011 | Part B: 4.0 mg/kg | Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in participants with AATD |
| BG012 | Part B: Placebo | Single dose administration of 0.9% normal saline IV injection in participants with AATD |
| BG013 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
Single dose administration of ARC-AAT IV injection, 0.38 mg/kg in healthy volunteers |
| OG001 | Part A: 1.0 mg/kg | Single dose administration of ARC-AAT IV injection, 1.0 mg/kg in healthy volunteers |
| OG002 | Part A: 2.0 mg/kg | Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in healthy volunteers |
| OG003 | Part A: 3.0 mg/kg | Single dose administration of ARC-AAT IV injection, 3.0 mg/kg in healthy volunteers |
| OG004 | Part A: 4.0 mg/kg | Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in healthy volunteers |
| OG005 | Part A: 5.0 mg/kg | Single dose administration of ARC-AAT IV injection, 5.0 mg/kg in healthy volunteers |
| OG006 | Part A: 6.0 mg/kg | Single dose administration of ARC-AAT IV injection, 6.0 mg/kg in healthy volunteers |
| OG007 | Part A: 7.0 mg/kg | Single dose administration of ARC-AAT IV injection, 7.0 mg/kg in healthy volunteers |
| OG008 | Part A: 8.0 mg/kg | Single dose administration of ARC-AAT IV injection, 8.0 mg/kg in healthy volunteers |
| OG009 | Part A: Placebo | Single dose administration of 0.9% normal saline IV injection in healthy volunteers |
| OG010 | Part B: 2.0 mg/kg | Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in participants with AATD |
| OG011 | Part B: 4.0 mg/kg | Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in participants with AATD |
| OG012 | Part B: Placebo | Single dose administration of 0.9% normal saline IV injection in participants with AATD |
|
|
| Primary | 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. | All participants receiving at least 1 dose of study medication | Posted | Number | participants | Day 1 through Day 29 ± 1 day |
|
|
|
| Primary | 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]). | All participants receiving at least 1 dose of study medication | Posted | Number | participants | Day 1 through Day 29 ± 1 day |
|
|
|
| Primary | Pharmacokinetics of ARC-AAT: Maximum Observed Plasma Concentration (Cmax) for the Analytes AD00370 and ARC-Melittin-Like Peptide (MLP; Part A) | Per protocol pharmacokinetic analysis set: all participants with evaluable concentration time profiles for each dose level who had no major protocol violations | Posted | Mean | Standard Deviation | ng/mL | 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 | Pharmacokinetics of ARC-AAT: Time to Maximum Observed Concentration (Tmax) for the Analytes AD00370 and ARC-MLP (Part A) | Per protocol pharmacokinetic analysis set: all participants with evaluable concentration time profiles for each dose level who had no major protocol violations | Posted | Median | Full Range | hour | 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 | 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) | Per protocol pharmacokinetic analysis set: all participants with evaluable concentration time profiles for each dose level who had no major protocol violations | Posted | Mean | Standard Deviation | hr*ng/mL | 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 | 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) | Per protocol pharmacokinetic analysis set: all participants with evaluable concentration time profiles for each dose level who had no major protocol violations | Posted | Mean | Standard Deviation | hr*ng/mL | 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 | 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) | Per protocol pharmacokinetic analysis set: all participants with evaluable concentration time profiles for each dose level who had no major protocol violations | Posted | Mean | Standard Deviation | 1/hour | 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 | Pharmacokinetics of ARC-AAT: Half-Life (t1/2) for the Analytes AD00370 and ARC-MLP (Part A) | Per protocol pharmacokinetic analysis set: all participants with evaluable concentration time profiles for each dose level who had no major protocol violations | Posted | Mean | Standard Deviation | hours | 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 | 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. | All participants who received a full dose of study drug with evaluable data at given time point. | Posted | Mean | Standard Deviation | percentage reduction | Baseline, Days 3, 8, 15, 22 and 29 |
|
|
|
| Secondary | 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. | All participants who received a full dose of study drug with evaluable data at given time point. | Posted | Number | participants | Baseline, Days 3, 8, 15, 22 and 29 |
|
|
|
| Secondary | Maximum Percentage Reduction in Mean AAT (Nadir of Mean AAT) | All participants who received a full dose of study drug. | Posted | Number | percentage reduction | 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 | 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. | All participants | Posted | Number | participants | Baseline, up to Day 29, and through 100 days of follow-up |
|
|
|
| Secondary | Mean Percentage Change in Circulating Blood Levels of Cytokines 2 Hours Post-Dose | Participants with available data for given parameter. | Posted | Mean | Standard Deviation | percentage change | Pre-dose, 2 hours post-dose |
|
|
|
| Secondary | Mean Percentage Change in Circulating Blood Levels of Complement Factors 2 Hours Post-Dose | Participants with available data for given parameter. | Posted | Mean | Standard Deviation | percentage change | Pre-dose, 2 hours post-dose |
|
|
|
| 0 |
| 4 |
| 0 |
| 4 |
| 2 |
| 4 |
| EG001 | Part A: 1.0 mg/kg | Single dose administration of ARC-AAT IV injection, 1.0 mg/kg in healthy volunteers | 0 | 4 | 0 | 4 | 2 | 4 |
| EG002 | Part A: 2.0 mg/kg | Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in healthy volunteers | 0 | 4 | 0 | 4 | 2 | 4 |
| EG003 | Part A: 3.0 mg/kg | Single dose administration of ARC-AAT IV injection, 3.0 mg/kg in healthy volunteers | 0 | 4 | 0 | 4 | 1 | 4 |
| EG004 | Part A: 4.0 mg/kg | Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in healthy volunteers | 0 | 4 | 0 | 4 | 3 | 4 |
| EG005 | Part A: 5.0 mg/kg | Single dose administration of ARC-AAT IV injection, 5.0 mg/kg in healthy volunteers | 0 | 4 | 0 | 4 | 3 | 4 |
| EG006 | Part A: 6.0 mg/kg | Single dose administration of ARC-AAT IV injection, 6.0 mg/kg in healthy volunteers | 0 | 4 | 0 | 4 | 3 | 4 |
| EG007 | Part A: 7.0 mg/kg | Single dose administration of ARC-AAT IV injection, 7.0 mg/kg in healthy volunteers | 0 | 4 | 0 | 4 | 1 | 4 |
| EG008 | Part A: 8.0 mg/kg | Single dose administration of ARC-AAT IV injection, 8.0 mg/kg in healthy volunteers | 0 | 4 | 0 | 4 | 3 | 4 |
| EG009 | Part A: Placebo | Single dose administration of 0.9% normal saline IV injection in healthy volunteers | 0 | 18 | 1 | 18 | 9 | 18 |
| EG010 | Part B: 2.0 mg/kg | Single dose administration of ARC-AAT IV injection, 2.0 mg/kg in participants with AATD | 0 | 4 | 0 | 4 | 3 | 4 |
| EG011 | Part B: 4.0 mg/kg | Single dose administration of ARC-AAT IV injection, 4.0 mg/kg in participants with AATD | 0 | 3 | 0 | 3 | 2 | 3 |
| EG012 | Part B: Placebo | Single dose administration of 0.9% normal saline IV injection in participants with AATD | 0 | 4 | 0 | 4 | 4 | 4 |
| Gastroenteritis viral | Infections and infestations | MedDRA (17.1) | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA (17.1) | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA (17.1) | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA (17.1) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (17.1) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (17.1) | Systematic Assessment |
|
| Lethargy | Nervous system disorders | MedDRA (17.1) | Systematic Assessment |
|
| Migraine | Nervous system disorders | MedDRA (17.1) | Systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA (17.1) | Systematic Assessment |
|
| Tension headache | Nervous system disorders | MedDRA (17.1) | Systematic Assessment |
|
| Paraesthesia | Nervous system disorders | MedDRA (17.1) | Systematic Assessment |
|
| Tremor | Nervous system disorders | MedDRA (17.1) | Systematic Assessment |
|
| Tachycardia | Cardiac disorders | MedDRA (17.1) | Systematic Assessment |
|
| Peripheral coldness | Vascular disorders | MedDRA (17.1) | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (17.1) | Systematic Assessment |
|
| Asthma | Respiratory, thoracic and mediastinal disorders | MedDRA (17.1) | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (17.1) | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA (17.1) | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (17.1) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (17.1) | Systematic Assessment |
|
| Rash erythematous | Skin and subcutaneous tissue disorders | MedDRA (17.1) | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (17.1) | Systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA (17.1) | Systematic Assessment |
|
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA (17.1) | Systematic Assessment |
|
| Musculoskeletal Chest Pain | Musculoskeletal and connective tissue disorders | MedDRA (17.1) | Systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA (17.1) | Systematic Assessment |
|
| Neck pain | Musculoskeletal and connective tissue disorders | MedDRA (17.1) | Systematic Assessment |
|
| Dysuria | Renal and urinary disorders | MedDRA (17.1) | Systematic Assessment |
|
| Dysmenorrhoea | Reproductive system and breast disorders | MedDRA (17.1) | Systematic Assessment |
|
| Chest discomfort | General disorders | MedDRA (17.1) | Systematic Assessment |
|
| Chills | General disorders | MedDRA (17.1) | Systematic Assessment |
|
| Feeling cold | General disorders | MedDRA (17.1) | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA (17.1) | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA (17.1) | Systematic Assessment |
|
| Troponin increased | Investigations | MedDRA (17.1) | Systematic Assessment |
|
| Infusion related reaction | Injury, poisoning and procedural complications | MedDRA (17.1) | Systematic Assessment |
|
| Ligament sprain | Injury, poisoning and procedural complications | MedDRA (17.1) | Systematic Assessment |
|
Not provided
Not provided
| D030342 |
| Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D013352 | Subcutaneous Emphysema |
| D004646 | Emphysema |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D001555 |
| Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| Neutrophils |
|
| Creatine Kinase |
|
| White Cell Count |
|
| Monocytes |
|
| Red Cell Distribution Width |
|
| ECGs |
|
| Physical Examination Findings |
|
| Bee Venom Sensitivity |
|
| Pulmonary Function |
|
| Analyte ARC-MLP |
|
| Dose-Proportionality of Pharmacokinetic Parameter Cmax for Analyte AD00370 | beta estimate | 1.173 | Standard Error of the Mean | 0.027 | 2-Sided | 95 | 1.128 | 1.218 | Estimation of model: Parameter = alpha * Dose^beta. Determined from linear regression model: Log(Parameter) = log(Dose) | Other | R-square (r^2)=0.98 |
| Dose-Proportionality of Pharmacokinetic Parameter Cmax for Analyte ARC-MLP | alpha estimate | 9.824 | Standard Error of the Mean | 0.030 | 2-Sided | Estimation of model: Parameter = alpha * Dose^beta. Determined from linear regression model: Log(Parameter) = log(Dose) | Other |
| Dose-Proportionality of Pharmacokinetic Parameter Cmax for Analyte ARC-MLP | beta estimate | 1.103 | Standard Error of the Mean | 0.029 | 2-Sided | 95 | 1.054 | 1.153 | Estimation of model: Parameter = alpha * Dose^beta. Determined from linear regression model: Log(Parameter) = log(Dose) | Other | R-square (r^2)=0.98 |
| Analyte ARC-MLP |
|
| Analyte ARC-MLP |
|
| Dose-Proportionality of Pharmacokinetic Parameter AUC0-24 for Analyte AD00370 | beta estimate | 1.181 | Standard Error of the Mean | 0.040 | 2-Sided | 95 | 1.112 | 1.249 | Estimation of model: Parameter = alpha * Dose^beta. Determined from linear regression model: Log(Parameter) = log(Dose) | Other | R-square (r^2)=0.96 |
| Dose-Proportionality of Pharmacokinetic Parameter AUC0-24 for Analyte ARC-MLP | alpha estimate | 12.133 | Standard Error of the Mean | 0.040 | 2-Sided | Estimation of model: Parameter = alpha * Dose^beta. Determined from linear regression model: Log(Parameter) = log(Dose) | Other |
| Dose-Proportionality of Pharmacokinetic Parameter AUC0-24 for Analyte ARC-MLP | beta estimate | 1.147 | Standard Error of the Mean | 0.040 | 2-Sided | 95 | 1.080 | 1.215 | Estimation of model: Parameter = alpha * Dose^beta. Determined from linear regression model: Log(Parameter) = log(Dose) | Other | R-square (r^2)=0.96 |
| Analyte ARC-MLP |
|
| Dose-Proportionality of Pharmacokinetic Parameter AUCinf for Analyte AD00370 | beta estimate | 1.179 | Standard Error of the Mean | 0.041 | 2-Sided | 95 | 1.110 | 1.249 | Estimation of model: Parameter = alpha * Dose^beta. Determined from linear regression model: Log(Parameter) = log(Dose) | Other | R-square (r^2)=0.96 |
| Dose-Proportionality of Pharmacokinetic Parameter AUCinf for Analyte ARC-MLP | alpha estimate | 12.347 | Standard Error of the Mean | 0.049 | 2-Sided | Estimation of model: Parameter = alpha * Dose^beta. Determined from linear regression model: Log(Parameter) = log(Dose) | Other |
| Dose-Proportionality of Pharmacokinetic Parameter AUCinf for Analyte ARC-MLP | beta estimate | 1.163 | Standard Error of the Mean | 0.049 | 2-Sided | 95 | 1.081 | 1.245 | Estimation of model: Parameter = alpha * Dose^beta. Determined from linear regression model: Log(Parameter) = log(Dose) | Other | R-square (r^2)=0.95 |
| Analyte ARC-MLP |
|
| Analyte ARC-MLP |
|
|
| Day 8 |
|
|
| Day 15 |
|
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| Day 22 |
|
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| Day 29 |
|
|
| Day 3 |
|
| Day 8 |
|
| Day 15 |
|
| Day 22 |
|
| Day 29 |
|
| Serum interleukin-6 |
|
| Serum interleukin-8 |
|
| Serum interleukin-10 |
|
| Serum interleukin-12p40 |
|
| Serum interleukin-12p70 |
|
| Serum monocyte chemoattractant protein-1 |
|
| Serum macrophage inflammatory protein-1 alpha |
|
| Serum tumor necrosis factor alpha |
|
| Serum interferon alpha 2 |
|
| Serum C3a |
|
| Serum C4a |
|
| Serum C5a |
|
| Serum CH50 |
|