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To evaluate the safety and tolerability and pharmacokinetics (PK) of a single intravenous (IV) dose of ETI-204 in adult volunteers.
A double-blind, randomized, placebo-controlled study of a single IV dose of 16 mg/kg ETI-204 in adult volunteers (210 subjects ETI-204; 70 subjects placebo).
The total duration of the study for each subject will be approximately 100 days divided as follows:
Screening: Days -28 to -2; In-unit Phase: Day -1, Day 1, and Day 2; Out-of-unit Visits: Day 8 (±2 days); Day 15 (±3 days); Day 29 (±3 days); Day 43 (±3 days); Final Visit: Day 71 (±4 days).
Following completion of a screening visit subjects who qualify for entry into the study will be randomized to receive either ETI-204 or matching placebo on Day 1 in a 3:1 ratio. Subjects will be discharged from the clinic on Day 2 following completion of study assessments and will return for five additional visits on Days 8, 15, 29, 43 and 71.
The first 12 subjects will be dosed in groups of no more than 4 subjects/day. A blinded safety review of the available clinical and laboratory AE data up to and including Day 2 will be completed for the first 12 subjects before any additional subjects are dosed. This review will be conducted by the Investigator in conjunction with the Clinical Trial Steering Committee. If the outcome of this review is satisfactory, dosing of additional subjects will be permitted to continue and subjects may be dosed in group sizes larger than 4.
After Amendment 1, premedication with 50 mg oral diphenhydramine approximately 30 minutes prior to the start of study drug infusion was required.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| ETI-204 | Experimental | A single intravenous dose of 16 mg/kg ETI-204 infused over 90 minutes on Day 1 |
|
| Placebo for ETI-204 | Placebo Comparator | A single intravenous dose of ETI-204-placebo infused over 90 minutes on Day 1 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| ETI-204 | Biological | Monoclonal Antibody |
| |
| Placebo |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants Who Experienced Adverse Events | Safety was assessed for all subjects in the safety population by collecting and monitoring vital signs, clinical laboratory tests, ECGs, physical examinations, skin assessments, infusion site assessments, and adverse events. | Up to 71 days or 101 days (30 days after the final study visit) for subjects with ongoing adverse events at the final study visit, for each group. |
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Observed Plasma Concentration of ETI-204 (Cmax) | Blood samples were obtained and serum concentrations were determined using a validated enzyme-linked immunosorbent assay method with an assay range of 100 ng/mL to 5000 ng/mL. | On Day 1, prior to the start of infusion, at the end of infusion, and 3 and 8 hours after the start of infusion and on Days 2, 8, 15, 29, 43, and 71. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Alex King, MD | Covance | Principal Investigator |
| Lori Sieboldt, MD | Covance Clinical Research - Evansville, IN | Principal Investigator |
| Debra Mandarino, MD | Covance Research, Madison, WI | Principal Investigator |
| H. Frank Farmer, PhD, MD | Covance Research - Daytona Beach, Fl | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Covance Clinical Research Inc. | Dallas | Texas | 75247 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 27568215 | Derived | Nagy CF, Leach TS, Hoffman JH, Czech A, Carpenter SE, Guttendorf R. Pharmacokinetics and Tolerability of Obiltoxaximab: A Report of 5 Healthy Volunteer Studies. Clin Ther. 2016 Sep;38(9):2083-2097.e7. doi: 10.1016/j.clinthera.2016.07.170. Epub 2016 Aug 24. |
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| ID | Title | Description |
|---|---|---|
| FG000 | ETI-204 | Intravenously (IV), single dose ETI-204: Monoclonal Antibody |
| FG001 | Placebo | Intravenously (IV), single dose Placebo: Placebo comparator |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | ETI-204 | Intravenously (IV), single dose ETI-204: Monoclonal Antibody |
| BG001 | Placebo | Intravenously (IV), single dose Placebo: Placebo comparator |
| 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 Who Experienced Adverse Events | Safety was assessed for all subjects in the safety population by collecting and monitoring vital signs, clinical laboratory tests, ECGs, physical examinations, skin assessments, infusion site assessments, and adverse events. | All randomized participants who received study drug. | Posted | Count of Participants | Participants | Up to 71 days or 101 days (30 days after the final study visit) for subjects with ongoing adverse events at the final study visit, for each group. |
|
Up to 71 days or 101 days (30 days after the final study visit) for subjects with ongoing adverse events at the final study visit, for each group.
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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 | ETI-204 | Intravenously (IV), single dose ETI-204: Monoclonal Antibody | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Ovarian Cyst | Reproductive system and breast disorders | MedDRA 16.0 | Systematic Assessment | A 42-year old, White female was hospitalized on study Day 101 and underwent surgery for removal of both ovaries and appendix. The investigator reported an unrelated serious AE of ovarian cyst of moderate severity that resolved after one day. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA 16.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Senior Director of Regulatory | Elusys Therapeutics, Inc. | 973-808-0222 | cdillon@elusys.com |
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| ID | Term |
|---|---|
| C571912 | Inhalation anthrax |
| D000881 | Anthrax |
| ID | Term |
|---|---|
| D016863 | Bacillaceae Infections |
| D016908 | Gram-Positive Bacterial Infections |
| D001424 | Bacterial Infections |
| D001423 | Bacterial Infections and Mycoses |
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| ID | Term |
|---|---|
| C000611266 | obiltoxaximab |
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| Other |
Placebo for ETI-204 |
|
| Time to Maximum Observed Plasma Concentration of ETI-204 (Tmax) | Blood samples were obtained and serum concentrations were determined using a validated enzyme-linked immunosorbent assay method with an assay range of 100 ng/mL to 5000 ng/mL. | On Day 1, prior to the start of infusion, at the end of infusion, and 3 and 8 hours after the start of infusion and on Days 2, 8, 15, 29, 43, and 71. |
| Area Under the Concentration-Time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) | Blood samples were obtained and serum concentrations were determined using a validated enzyme-linked immunosorbent assay method with an assay range of 100 ng/mL to 5000 ng/mL. | On Day 1, prior to the start of infusion, at the end of infusion, and 3 and 8 hours after the start of infusion and on Days 2, 8, 15, 29, 43, and 71. |
| Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) | Blood samples were obtained and serum concentrations were determined using a validated enzyme-linked immunosorbent assay method with an assay range of 100 ng/mL to 5000 ng/mL. | On Day 1, prior to the start of infusion, at the end of infusion, and 3 and 8 hours after the start of infusion and on Days 2, 8, 15, 29, 43, and 71. |
| Terminal Half-life (t1/2) | Blood samples were obtained and serum concentrations were determined using a validated enzyme-linked immunosorbent assay method with an assay range of 100 ng/mL to 5000 ng/mL. | On Day 1, prior to the start of infusion, at the end of infusion, and 3 and 8 hours after the start of infusion and on Days 2, 8, 15, 29, 43, and 71. |
| Systemic Clearance (CL) | Blood samples were obtained and serum concentrations were determined using a validated enzyme-linked immunosorbent assay method with an assay range of 100 ng/mL to 5000 ng/mL. | On Day 1, prior to the start of infusion, at the end of infusion, and 3 and 8 hours after the start of infusion and on Days 2, 8, 15, 29, 43, and 71. |
| Volume of Distribution (Vd) | Blood samples were obtained and serum concentrations were determined using a validated enzyme-linked immunosorbent assay method with an assay range of 100 ng/mL to 5000 ng/mL. | On Day 1, prior to the start of infusion, at the end of infusion, and 3 and 8 hours after the start of infusion and on Days 2, 8, 15, 29, 43, and 71. |
| Volume of Distribution at Steady State (Vss) | Blood samples were obtained and serum concentrations were determined using a validated enzyme-linked immunosorbent assay method with an assay range of 100 ng/mL to 5000 ng/mL. | On Day 1, prior to the start of infusion, at the end of infusion, and 3 and 8 hours after the start of infusion and on Days 2, 8, 15, 29, 43, and 71. |
| Number of Participants With Anti-ETI-204 Antibodies | Serum anti-ETI-204 antibody titers were determined for all subjects in the safety population. Blood samples were collected and serum samples were assayed at an initial dilution of 1:10. Samples that were positive at the 1:10 dilution were serially diluted 1:2 and assayed until a negative result was attained. The titer of the most dilute sample yielding a positive result was recorded as the titer for that time point. Immunogenicity was measured by the number of participants in each study arm with anti-ETI-204 antibody values post-treatment ≥ 4-times higher than baseline at Day 8, 43 or 71, or if the titer was negative at baseline, the post-treatment sample(s) required a titer of at least 1:20 for it to be considered positive. | On Day 1 prior to the start of infusion and on Days 8, 43, and 71. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Placebo | Participants were administered a single intravenous (IV) infusion of ETI-204 Placebo in 0.9% sterile sodium chloride in a total volume of 250 mL over 90 minutes. , Following a protocol amendment, 48(68.6%) participants were premedicated with 50 mg oral diphenhydramine approximately 30 minutes prior to the start of the infusion. |
|
|
| Secondary | Maximum Observed Plasma Concentration of ETI-204 (Cmax) | Blood samples were obtained and serum concentrations were determined using a validated enzyme-linked immunosorbent assay method with an assay range of 100 ng/mL to 5000 ng/mL. | Of the 210 participants who received ETI-204, 202 were included in the PK population. One was excluded due to missing dosing record and 7 received partial doses of ETI-204 (6 discontinued study drug due to an AE and one received a partial dose because of mechanical issues with the infusion pump). | Posted | Mean | Standard Deviation | µg/mL | On Day 1, prior to the start of infusion, at the end of infusion, and 3 and 8 hours after the start of infusion and on Days 2, 8, 15, 29, 43, and 71. |
|
|
|
| Secondary | Time to Maximum Observed Plasma Concentration of ETI-204 (Tmax) | Blood samples were obtained and serum concentrations were determined using a validated enzyme-linked immunosorbent assay method with an assay range of 100 ng/mL to 5000 ng/mL. | Of the 210 participants who received ETI-204, 202 were included in the PK population. One was excluded due to missing dosing record and 7 received partial doses of ETI-204 (6 discontinued study drug due to an AE and one received a partial dose because of mechanical issues with the infusion pump). | Posted | Median | Full Range | days | On Day 1, prior to the start of infusion, at the end of infusion, and 3 and 8 hours after the start of infusion and on Days 2, 8, 15, 29, 43, and 71. |
|
|
|
| Secondary | Area Under the Concentration-Time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) | Blood samples were obtained and serum concentrations were determined using a validated enzyme-linked immunosorbent assay method with an assay range of 100 ng/mL to 5000 ng/mL. | Of the 210 participants who received ETI-204, 202 were included in the PK population. Reasons for exclusion were: missing dosing record (1), discontinued study drug due to an AE (6) and mechanical issues with the infusion pump (1). 3 additional participants were excluded from the AUC0-last calculation because of missing PK collection time points. | Posted | Mean | Standard Deviation | µg.day/mL | On Day 1, prior to the start of infusion, at the end of infusion, and 3 and 8 hours after the start of infusion and on Days 2, 8, 15, 29, 43, and 71. |
|
|
|
| Secondary | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) | Blood samples were obtained and serum concentrations were determined using a validated enzyme-linked immunosorbent assay method with an assay range of 100 ng/mL to 5000 ng/mL. | In addition, for several participants, certain PK parameter values were set to missing for the purposes of calculating descriptive statistics in the primary analysis, in accordance with the SAP. The extrapolated portion of AUC(0-inf) exceeded 20% of AUC(0-inf) in 8 participants, therefore, AUC(0-inf) was not reported for these individuals. | Posted | Mean | Standard Deviation | µg.day/mL | On Day 1, prior to the start of infusion, at the end of infusion, and 3 and 8 hours after the start of infusion and on Days 2, 8, 15, 29, 43, and 71. |
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|
|
| Secondary | Terminal Half-life (t1/2) | Blood samples were obtained and serum concentrations were determined using a validated enzyme-linked immunosorbent assay method with an assay range of 100 ng/mL to 5000 ng/mL. | In addition, for several participants, certain PK parameter values were set to missing for the purposes of calculating descriptive statistics in the primary analysis, in accordance with the SAP. ETI-204 t1/2 values were not reported for 6 participants as they were greater than 50% of the 71-day sample collection interval. | Posted | Mean | Standard Deviation | days | On Day 1, prior to the start of infusion, at the end of infusion, and 3 and 8 hours after the start of infusion and on Days 2, 8, 15, 29, 43, and 71. |
|
|
|
| Secondary | Systemic Clearance (CL) | Blood samples were obtained and serum concentrations were determined using a validated enzyme-linked immunosorbent assay method with an assay range of 100 ng/mL to 5000 ng/mL. | In addition, for several participants, certain PK parameter values were set to missing for the purposes of calculating descriptive statistics in the primary analysis, in accordance with the SAP. The extrapolated portion of AUC(0-inf) exceeded 20% of AUC(0-inf) in 8 participants, therefore, CL was not reported for these individuals. | Posted | Mean | Standard Deviation | Liters/day | On Day 1, prior to the start of infusion, at the end of infusion, and 3 and 8 hours after the start of infusion and on Days 2, 8, 15, 29, 43, and 71. |
|
|
|
| Secondary | Volume of Distribution (Vd) | Blood samples were obtained and serum concentrations were determined using a validated enzyme-linked immunosorbent assay method with an assay range of 100 ng/mL to 5000 ng/mL. | In addition, for several participants, certain PK parameter values were set to missing for the purposes of calculating descriptive statistics in the primary analysis, in accordance with the SAP. The extrapolated portion of AUC(0-inf) exceeded 20% of AUC(0-inf) in 8 participants, therefore, Vd was not reported for these individuals. | Posted | Mean | Standard Deviation | Liters | On Day 1, prior to the start of infusion, at the end of infusion, and 3 and 8 hours after the start of infusion and on Days 2, 8, 15, 29, 43, and 71. |
|
|
|
| Secondary | Volume of Distribution at Steady State (Vss) | Blood samples were obtained and serum concentrations were determined using a validated enzyme-linked immunosorbent assay method with an assay range of 100 ng/mL to 5000 ng/mL. | In addition, for several participants, certain PK parameter values were set to missing for the purposes of calculating descriptive statistics in the primary analysis, in accordance with the SAP. The extrapolated portion of AUC(0-inf) exceeded 20% of AUC(0-inf) in 8 participants, therefore, Vss was not reported for these individuals. | Posted | Mean | Standard Deviation | Liters | On Day 1, prior to the start of infusion, at the end of infusion, and 3 and 8 hours after the start of infusion and on Days 2, 8, 15, 29, 43, and 71. |
|
|
|
| Secondary | Number of Participants With Anti-ETI-204 Antibodies | Serum anti-ETI-204 antibody titers were determined for all subjects in the safety population. Blood samples were collected and serum samples were assayed at an initial dilution of 1:10. Samples that were positive at the 1:10 dilution were serially diluted 1:2 and assayed until a negative result was attained. The titer of the most dilute sample yielding a positive result was recorded as the titer for that time point. Immunogenicity was measured by the number of participants in each study arm with anti-ETI-204 antibody values post-treatment ≥ 4-times higher than baseline at Day 8, 43 or 71, or if the titer was negative at baseline, the post-treatment sample(s) required a titer of at least 1:20 for it to be considered positive. | All participants who received study drug and were included in the safety population. | Posted | Count of Participants | Participants | On Day 1 prior to the start of infusion and on Days 8, 43, and 71. |
|
|
|
| 210 |
| 0 |
| 210 |
| 52 |
| 210 |
| EG001 | Placebo | Intravenously (IV), single dose Placebo: Placebo comparator | 0 | 70 | 1 | 70 | 18 | 70 |
|
| Nausea | Gastrointestinal disorders | MedDRA 16.0 | Systematic Assessment |
|
| Infusion site erythema | General disorders | MedDRA 16.0 | Systematic Assessment |
|
| Pain | General disorders | MedDRA 16.0 | Systematic Assessment |
|
| Vessel puncture site bruise | General disorders | MedDRA 16.0 | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 16.0 | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA 16.0 | Systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 16.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 16.0 | Systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 16.0 | Systematic Assessment |
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| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | MedDRA 16.0 | Systematic Assessment |
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| D007239 | Infections |