Inhalational Anthrax
Conditions
Keywords
anthrax, monoclonal antibody, ETI-204, safety, PK
Brief summary
To evaluate the safety, tolerability, pharmacokinetics and immunogenicity of repeat administration (two doses) of intravenous (IV) ETI-204.
Detailed description
A double-blind, randomized, placebo-controlled, study in 70 healthy adult subjects. The total duration of the study for each subject will be approximately 220 days divided as follows: * Screening: Days -28 to -2 * Three In-Unit Stays: Days -1 to 2; Days 13 to 15; and Days 119 to 121 * Out-of-Unit Visit Days: Day 8 (±2 days); Day 28 (±3 days); Day 43 (±3 days); Day 71 (±3 days); Day 85 (±3 days); Day 128 (±3 days); Day 134 (±3 days); Day 149 (±3 days); and Day 163 (±3 days) * Final Visit: Day 191 (±3 days) Subjects will be randomized in a 1:1 ratio to one of the following two treatment sequences: * Sequence A: ETI-204 on Days 1 and 14 and placebo on Day 120 * Sequence B: ETI-204 on Days 1 and 120 and placebo on Day 14 Subjects who qualify for entry into the study following completion of the Screening visit will arrive at the clinical research unit (CRU) on Day -1. The next day, Day 1, qualified subjects will be randomized and will receive a single IV dose of ETI-204. Subjects will be pretreated with 50 mg oral diphenhydramine approximately 30 minutes prior to the start of the study drug infusion. Subjects will be discharged from the CRU on Day 2, and will return to the CRU for an additional visit on Day 8. Subjects will return to the CRU on Day 13 for their second in-unit stay. The next day, Day 14, subjects will be pretreated with 50 mg oral diphenhydramine and will receive study drug according to their randomized treatment assignment. Subjects will be discharged on Day 15 and will return to the CRU for four additional visits on Days 28 (±3 days), 43 (±3 days), 71 (±3 days), and 85 (±3 days). Subjects will return to the CRU again on Day 119 for their third in-unit stay. On Day 120, subjects will be pretreated with 50 mg oral diphenhydramine and will receive study drug (either ETI 204 or placebo) according to their randomized treatment assignment. Subjects will be discharged on Day 121 and will return to the CRU for five additional visits on Days 128,134, 149, 163, and 191. The first 20 subjects randomized and treated in the study will be dosed in groups of no more than 4 subjects/day. For the first 8 subjects, dosing of individual subjects on Day 14 and Day 120 will be separated by 30-60 minutes for safety monitoring. If no severe infusion reactions occur in any of the first 8 subjects at the time of the second dose, staggered dosing is not required for the remaining subjects receiving their second dose. Similarly, if no severe infusion reactions occur in any of the first 8 subjects at the time of the third dose, staggered dosing is not required for the remaining subjects receiving their third dose. Enrollment of additional subjects will be paused until the first 20 subjects have received their second dose of study drug and a blinded review of the available clinical and laboratory AE data up to and including Day 15 is completed for the first 20 subjects. This review will be conducted by the Investigator in conjunction with the Clinical Trial Steering Committee and will focus on the possible development of new or more severe AEs with the Day 14 dose. If the outcome of this review is satisfactory, dosing of additional subjects will be permitted to continue in groups larger than 4 subjects. In the event that significant AEs are observed and unblinding should become necessary, it will be performed by an independent statistician who is not involved with the conduct of the study. A second blinded safety review will be completed at least two weeks before any subject receives the third dose of study drug, (i.e. before any subject is dosed on Day 120). The Investigator in conjunction with the Clinical Trial Steering Committee will review all AEs seen to date in the study. This review will focus on AE data seen in association with the second infusion (Day14). If the outcome of this review is satisfactory, subjects may receive their third dose of study drug. A third blinded safety review will be conducted after the initial cohort of 20 subjects has completed Day 121. No additional subjects should receive a third dose of study medication until the Investigator along with the Clinical Trial Steering Committee has completed a blinded safety review of the Day 120 and 121 clinical and laboratory AE data. This review will focus on the development of new or more severe AEs seen with repeat dosing. If the outcome of this review is satisfactory, the remaining subjects may receive their third dose of study drug. In the event that significant AEs are observed and unblinding becomes necessary it will be performed by an independent statistician who is not involved with the conduct of the study.
Interventions
BIOLOGICALETI-204
Monoclonal Antibody
OTHERPlacebo
Placebo for ETI-204
Sponsors
Elusys Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Study drug will be prepared by an unblinded pharmacist not involved with the conduct of the study. The pharmacist will assign the correct study drug (16 mg/kg ETI-204 or placebo) to each subject according to the randomization scheme.
Intervention model description
Seventy subjects will be randomized in a 1:1 ratio to one of the following two treatment sequences: * Sequence A: ETI-204 on Days 1 and 14 and placebo on Day 120 * Sequence B: ETI-204 on Days 1 and 120 and placebo on Day 14
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Females or males ≥ 18 years of age 2. All females, regardless of childbearing potential, must have a negative serum beta human chorionic gonadotropin (β-hCG) pregnancy test at Screening and Day -1 3. Females of childbearing potential (i.e., not postmenopausal or surgically sterile) must agree to practice abstinence or to use a medically accepted method of contraception from the time of Screening through 30 days after the final study visit. Acceptable methods of contraception include diaphragm with spermicide; sponge with spermicide; condom with spermicide; or intrauterine device with condom or spermicide. The following contraceptive methods are acceptable only when used with a condom and spermicide: birth control pills, birth control patches, vaginal ring, hormone under the skin, or hormone injections 4. Postmenopausal females, defined as females who have had amenorrhea for at least 12 months either naturally or following cessation of all exogenous hormonal treatments, and have a follicle-stimulating hormone (FSH) level of \> 40 mIU/mL at Screening 5. Females who have undergone surgical sterilization, including hysterectomy, bilateral oophorectomy, bilateral salpingectomy, tubal ligation, or tubal essure 6. Males must agree to practice abstinence or use a condom with spermicide and refrain from sperm donation during the study and for 30 days after the final study visit 7. Provide written informed consent 8. Willing to comply with study restrictions
Exclusion criteria
1. Pregnant or lactating woman 2. Clinically significant comorbidity that would interfere with completion of the study procedures or objectives or compromise the subject's safety 3. Seated systolic blood pressure (BP) ≥ 150 mmHg or ≤ 90 mmHg or diastolic BP ≥ 95 mmHg 4. Use of H1 receptor antagonists (i.e. antihistamines) within 5 days prior to Day 1 5. Evidence of drug or alcohol abuse as determined by the Investigator within 6 months of Day 1 6. Positive test result for drugs of abuse (with the exception of medically prescribed drugs) at Screening or on Day -1 7. Positive test for alcohol at Screening; exclusion is at the Investigator's discretion; subjects who test positive for alcohol at Day -1 are excluded from the study 8. Treatment with an investigational agent within 30 days or five half-lives of the investigational agent at Day 1 (whichever is longer) 9. Congenital or acquired immunodeficiency syndrome 10. Prior solid organ or bone marrow transplant 11. Positive test for Hepatitis B (surface antigen), Hepatitis C, or human immunodeficiency virus (HIV) at Screening 12. History of prior treatment for anthrax exposure or prior anthrax infection 13. Prior immunization with any approved or investigational anthrax vaccine or prior treatment with an approved or investigational anthrax treatment (i.e., ETI-204, raxibacumab, or anthrax immune globulin) 14. Military personnel deployed in 1990 or after, unless the subject can provide documentation demonstrating they have not previously received any approved or investigational anthrax vaccine 15. Use of systemic steroids, immunosuppressive agents, anticoagulants, or anti-arrhythmics within 1 year prior to Day 1. A single short course (i.e., less than 14 days) of systemic steroid therapy is allowed provided it concluded more than 6 months prior to Day 1 16. Donation or loss of \> 500 mL of blood within 30 days or plasma within 7 days of Day 1 17. Prior stroke, epilepsy, relapsing or degenerative central nervous system disease, or relapsing or degenerative ocular disease 18. Myocardial infarction or acute coronary syndrome in the past 5 years, active angina pectoris, or heart failure (New York Heart Association scale \> 1) 19. History of chronic liver disease 20. Calculated creatinine clearance (CrCl) of \< 30 mL/min using the Cockcroft-Gault equation (see Section 5.1) 21. Any clinically significant abnormality, in the Investigator's opinion, on electrocardiogram (ECG) or clinical laboratory tests (hematology, clinical chemistry, or urinalysis) at Screening; Out of range results may be repeated to confirm. 22. History of allergic or hypersensitivity reactions to other therapeutic antibodies or immunoglobulins 23. History of any malignant neoplasm within the last 5 years, with the exception of adequately treated, localized or in situ non-melanoma carcinoma of the skin (e.g., basal cell carcinoma) or the cervix 24. Subjects who, in the opinion of the Investigator, are not suitable candidates for enrollment or who may not comply with the requirements of the study \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Adverse Events | Up to 191 days or 221 days (30 days after the final study visit) for subjects with ongoing adverse events at the final study visit, for each arm. | Safety was assessed for all subjects in the safety population by collecting and monitoring vital signs, laboratory tests, ECGs, physical examinations, skin assessments, infusion site assessments and adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration of ETI-204 (Cmax) After a Dose of 16 mg/kg on Day 120 (Sequence B) | On Day 120 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Time to Maximum Observed Plasma Concentration of ETI-204 (Tmax) After a Dose of 16 mg/kg on Day 1(Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | On Days 1 and 14 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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.The PK parameter, Tmax, was derived from ETI-204 serum concentrations by sequence group and treatment period for the PK analysis population. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Time to Maximum Observed Plasma Concentration of ETI-204 (Tmax) After a Dose of 16 mg/kg on Day 120 (Sequence B) | On Day 120 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Area Under the Concentration-Time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | On Days 1 and 14 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Area Under the Concentration-Time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B) | On Day 120 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Area Under the Concentration-Time Curve From Time Zero to 191 Days (AUC0-191days) After a Dose of 16 mg/kg ETI-204 on Days 1 and 14 (Sequence A) | On Days 1 and 14 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Area Under the Concentration-Time Curve From Time Zero to 120 Days (AUC0-120days) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) | On Day 1 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | On Days 1 and 14 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B) | On Day 120 prepose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Maximum Observed Plasma Concentration of ETI-204 (Cmax) After a Dose of 16 mg/kg on Day 1(Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | On Days 1 and 14 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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.The PK parameter, Cmax, was derived from ETI-204 serum concentrations by sequence group and treatment period for the PK analysis population. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Terminal Half-life (t1/2) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B) | On Day 120 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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.The PK parameter, Cmax, was derived from ETI-204 serum concentrations by sequence group and treatment period for the PK analysis population. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Systemic Clearance (CL) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | On Days 1 and 14 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Systemic Clearance (CL) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B) | On Day 120 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Volume of Distribution (Vd) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | On Days 1 and 14 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Volume of Distribution (Vd) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B) | On Day 120 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Volume of Distribution at Steady State (Vdss) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) | On Day 1 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Volume of Distribution at Steady State (Vdss) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B) | On Day 120 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
| Number of Participants With Anti-ETI-204 Antibodies | On Days 1,14, and 120 predose and on Days 8, 43, 85, 128, 163, and 191 | 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. |
| Terminal Half-life (t1/2) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | On Days 1 and 14 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191. | 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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sequence A 16 mg/kg ETI-204 IV on Days 1 and 14 and Placebo on Day 120
ETI-204: Monoclonal Antibody
Placebo: Placebo for ETI-204 | 35 |
| Sequence B 16 mg/kg ETI-204 IV on Days 1 and 120 and Placebo on Day 14
ETI-204: Monoclonal Antibody
Placebo: Placebo for ETI-204 | 35 |
| Total | 70 |
Baseline characteristics
| Characteristic | Sequence A | Sequence B | Total |
|---|---|---|---|
| Age, Continuous | 43.0 years STANDARD_DEVIATION 14.71 | 43.3 years STANDARD_DEVIATION 16.76 | 43.1 years STANDARD_DEVIATION 15.65 |
| BMI | 28.23 kg/m2 STANDARD_DEVIATION 5.608 | 27.06 kg/m2 STANDARD_DEVIATION 5.275 | 27.65 kg/m2 STANDARD_DEVIATION 5.437 |
| Body Weight | 83.19 kg STANDARD_DEVIATION 16.452 | 80.55 kg STANDARD_DEVIATION 16.886 | 81.87 kg STANDARD_DEVIATION 16.602 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 33 Participants | 66 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 171.82 cm STANDARD_DEVIATION 10.623 | 172.46 cm STANDARD_DEVIATION 8.52 | 172.14 cm STANDARD_DEVIATION 9.564 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 12 Participants | 22 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 25 Participants | 20 Participants | 45 Participants |
| Sex: Female, Male Female | 13 Participants | 13 Participants | 26 Participants |
| Sex: Female, Male Male | 22 Participants | 22 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 35 |
| other Total, other adverse events | 30 / 35 | 31 / 35 |
| serious Total, serious adverse events | 0 / 35 | 1 / 35 |
Outcome results
Primary
Number of Participants Who Experienced Adverse Events
Safety was assessed for all subjects in the safety population by collecting and monitoring vital signs, laboratory tests, ECGs, physical examinations, skin assessments, infusion site assessments and adverse events.
Time frame: Up to 191 days or 221 days (30 days after the final study visit) for subjects with ongoing adverse events at the final study visit, for each arm.
Population: The safety population consisted of all subjects who received at least a partial dose of ETI 204 or placebo, whether prematurely withdrawn from the study or not
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sequence A | Number of Participants Who Experienced Adverse Events | 30 Participants |
| Sequence B | Number of Participants Who Experienced Adverse Events | 31 Participants |
Secondary
Area Under the Concentration-Time Curve From Time Zero to 120 Days (AUC0-120days) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B)
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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Day 1 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: One subjects in Sequence B was missing the final 3 or more scheduled samples (subject withdrew from the study on Day 8 due to conflict with work schedule) and therefore AUC and lamda z-based parameters were not reported. AUC0-120days was not calculated for Sequence A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence B | Area Under the Concentration-Time Curve From Time Zero to 120 Days (AUC0-120days) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) | 4560 µg.day/mL | Standard Deviation 1220 |
Secondary
Area Under the Concentration-Time Curve From Time Zero to 191 Days (AUC0-191days) After a Dose of 16 mg/kg ETI-204 on Days 1 and 14 (Sequence A)
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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Days 1 and 14 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: PK parameters for 1 subject in Sequence A were excluded because the subject did not rec a 2nd dose of ETI-204 due to AEs after the 1st dose. 2 subjects in Sequence A were missing the final 3 or more scheduled samples and therefore AUC and lambda z-based parameters were not reported. AUC0-191days was not calculated for Sequence B.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence A | Area Under the Concentration-Time Curve From Time Zero to 191 Days (AUC0-191days) After a Dose of 16 mg/kg ETI-204 on Days 1 and 14 (Sequence A) | 10,300 µg.day/mL | Standard Deviation 2480 |
Secondary
Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B)
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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Day 120 prepose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: 4 subjects in Sequence B were excluded because they did not receive the 2nd dose of ETI-204 on Day 120. For 4 subjects in Sequence B the AUC and lambda z-based parameters were excluded from descriptive statistics for Day 120 (1 for missing the final 3 or more scheduled samples, 3 because the t1/2 values were \>50% of the sample collection interval).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence B | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B) | 4400 µg.day/mL | Standard Deviation 796 |
Secondary
Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A)
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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Days 1 and 14 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: PK parameters for 1 subject in Sequence A were excluded because the subject was discontinued after the 1st dose of ETI-204 because of AEs and did not receive the 2nd dose. 2 subjects in Sequence A and 1 subject in Sequence B were missing the final 3 or more scheduled samples and therefore AUC and lambda z-based parameters were not reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence A | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | 10,300 µg.day/mL | Standard Deviation 2530 |
| Sequence B | Area Under the Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | 4690 µg.day/mL | Standard Deviation 1370 |
Secondary
Area Under the Concentration-Time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B)
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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Day 120 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: 4 subjects in Sequence B were excluded because the subjects did not receive the 2nd dose of ETI-204 on Day 120 (1 due to AEs after 1st dose, 1 withdrew consent , 1 lost to follow-up, 1 protocol violation). 1 subjects in Sequence B was missing the final 3 or more scheduled samples and therefore AUC and lambda z-based parameters were not reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence B | Area Under the Concentration-Time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B) | 4300 µg.day/mL | Standard Deviation 1010 |
Secondary
Area Under the Concentration-Time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A)
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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Days 1 and 14 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: PK parameters for 1 subject in Sequence A were excluded because the subject was discontinued after the 1st dose of ETI-204 because of AEs and did not receive the 2nd dose. 2 subjects in Sequence A and 1 subject in Sequence B (Day 1) were missing the final 3 or more scheduled samples and therefore AUC and lambda z-based parameters were not reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence A | Area Under the Concentration-Time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | 10,200 µg.day/mL | — |
| Sequence B | Area Under the Concentration-Time Curve From Time Zero to Time of Last Measurable Concentration (AUC0-last) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | 4550 µg.day/mL | Standard Deviation 1220 |
Secondary
Maximum Observed Plasma Concentration of ETI-204 (Cmax) After a Dose of 16 mg/kg on Day 120 (Sequence B)
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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Day 120 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: Four subjects in Sequence B were excluded because the subjects did not receive the 2nd dose of ETI-204 16 m/kg on Day 120 (one due to AEs after the 1st dose, one withdrew consent due to conflict with work, one was lost to follow-up on Day 43, and one was withdrawn by the investigator due to protocol violation (positive drug screen on Day 120).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence B | Maximum Observed Plasma Concentration of ETI-204 (Cmax) After a Dose of 16 mg/kg on Day 120 (Sequence B) | 402 µg/mL | Standard Deviation 134 |
Secondary
Maximum Observed Plasma Concentration of ETI-204 (Cmax) After a Dose of 16 mg/kg on Day 1(Sequence B) or Two Doses on Days 1 and 14 (Sequence A)
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.The PK parameter, Cmax, was derived from ETI-204 serum concentrations by sequence group and treatment period for the PK analysis population. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Days 1 and 14 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: One subject in Sequence A was prematurely discontinued from the study by the investigator after the 1st dose of ETI-204 because of AEs. This subject did not receive the 2nd dose of ETI-204 on Day 14 and therefore all PK parameters from this subject were excluded from descriptive statistics.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence A | Maximum Observed Plasma Concentration of ETI-204 (Cmax) After a Dose of 16 mg/kg on Day 1(Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | 506 µg/mL | Standard Deviation 102 |
| Sequence B | Maximum Observed Plasma Concentration of ETI-204 (Cmax) After a Dose of 16 mg/kg on Day 1(Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | 384 µg/mL | Standard Deviation 103 |
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.
Time frame: On Days 1,14, and 120 predose and on Days 8, 43, 85, 128, 163, and 191
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sequence A | Number of Participants With Anti-ETI-204 Antibodies | 3 Participants |
| Sequence B | Number of Participants With Anti-ETI-204 Antibodies | 1 Participants |
Secondary
Systemic Clearance (CL) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B)
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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Day 120 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: 4 subjects in Sequence B were excluded because they did not receive the 2nd dose of ETI-204 on Day 120. For 4 subjects in Sequence B the AUC and lambda z-based parameters were excluded from descriptive statistics for Day 120 (1 for missing the final 3 or more scheduled samples, 3 because the t1/2 values were \>50% of the sample collection interval).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence B | Systemic Clearance (CL) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B) | 0.313 Liters/day | Standard Deviation 0.076 |
Secondary
Systemic Clearance (CL) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A)
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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Days 1 and 14 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: PK parameters for 1 subject in Sequence A were excluded because the subject was discontinued after the1st dose of ETI-204 because of AEs and did not receive the 2nd dose. 2 subjects in Sequence A and 1 subject in Sequence B were missing the final 3 or more scheduled samples and therefore AUC and lambda z-based parameters were not reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence A | Systemic Clearance (CL) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | 0.274 Liters/day | Standard Deviation 0.0862 |
| Sequence B | Systemic Clearance (CL) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | 0.300 Liters/day | Standard Deviation 0.104 |
Secondary
Terminal Half-life (t1/2) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B)
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.The PK parameter, Cmax, was derived from ETI-204 serum concentrations by sequence group and treatment period for the PK analysis population. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Day 120 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: 4 subjects in Sequence B were excluded because they did not receive the 2nd dose of ETI-204 on Day 120. For 4 subjects in Sequence B the AUC and lambda z-based parameters were excluded from descriptive statistics for Day 120 (1 for missing the final 3 or more scheduled samples, 3 because the t1/2 values were \>50% of the sample collection interval).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence B | Terminal Half-life (t1/2) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B) | 18.6 days | Standard Deviation 3.43 |
Secondary
Terminal Half-life (t1/2) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A)
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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Days 1 and 14 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: PK parameters for 1 subject in Sequence A were excluded because the subject was discontinued after the 1st dose of ETI-204 because of AEs and did not receive the 2nd dose. 2 subjects in Sequence A and 1 subject in Sequence B were missing the final 3 or more scheduled samples and therefore AUC and lambda z-based parameters were not reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence A | Terminal Half-life (t1/2) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | 22.8 days | Standard Deviation 5.82 |
| Sequence B | Terminal Half-life (t1/2) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | 21.5 days | Standard Deviation 6.73 |
Secondary
Time to Maximum Observed Plasma Concentration of ETI-204 (Tmax) After a Dose of 16 mg/kg on Day 120 (Sequence B)
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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Day 120 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: Four subjects in Sequence B were excluded because the subjects did not receive the 2nd dose of ETI-204 16 m/kg on Day 120 (one due to AEs after the 1st dose, one withdrew consent due to conflict with work, one was lost to follow-up on Day 43, and one was withdrawn by the investigator due to protocol violation (positive drug screen on Day 120).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sequence B | Time to Maximum Observed Plasma Concentration of ETI-204 (Tmax) After a Dose of 16 mg/kg on Day 120 (Sequence B) | 0.0743 days |
Secondary
Time to Maximum Observed Plasma Concentration of ETI-204 (Tmax) After a Dose of 16 mg/kg on Day 1(Sequence B) or Two Doses on Days 1 and 14 (Sequence A)
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.The PK parameter, Tmax, was derived from ETI-204 serum concentrations by sequence group and treatment period for the PK analysis population. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Days 1 and 14 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: One subject in Sequence A was prematurely discontinued from the study by the investigator afte the 1st dose of ETI-204 because of AEs. This subject did not receive the 2nd dose of ETI-204 on Day 14 and therefore all PK parameters from this subject were excluded from descriptive statistics.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sequence A | Time to Maximum Observed Plasma Concentration of ETI-204 (Tmax) After a Dose of 16 mg/kg on Day 1(Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | 13.1 days |
| Sequence B | Time to Maximum Observed Plasma Concentration of ETI-204 (Tmax) After a Dose of 16 mg/kg on Day 1(Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | 0.125 days |
Secondary
Volume of Distribution at Steady State (Vdss) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B)
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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Day 120 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: 4 subjects in Sequence B were excluded because they did not receive the 2nd dose of ETI-204 on Day 120. For 4 subjects in Sequence B the AUC and lambda z-based parameters were excluded from descriptive statistics for Day 120 (1 for missing the final 3 or more scheduled samples, 3 because the t1/2 values were \>50% of the sample collection interval).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence B | Volume of Distribution at Steady State (Vdss) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B) | 7.01 Liters | Standard Deviation 2.32 |
Secondary
Volume of Distribution at Steady State (Vdss) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B)
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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Day 1 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: One subject in Sequence B was missing the final 3 or more scheduled samples and therefore AUC and lambda z-based parameters were not reported. Vdss was not reported for Sequence A.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence B | Volume of Distribution at Steady State (Vdss) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) | 7.20 Liters | Standard Deviation 1.49 |
Secondary
Volume of Distribution (Vd) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B)
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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Day 120 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: 4 subjects in Sequence B were excluded because they did not receive the 2nd dose of ETI-204 on Day 120. For 4 subjects in Sequence B the AUC and lambda z-based parameters were excluded from descriptive statistics for Day 120 (1 for missing the final 3 or more scheduled samples, 3 because the t1/2 values were \>50% of the sample collection interval).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence B | Volume of Distribution (Vd) After a Dose of 16 mg/kg ETI-204 on Day 120 (Sequence B) | 8.33 Liters | Standard Deviation 2.39 |
Secondary
Volume of Distribution (Vd) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A)
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. Sequence A - there were insufficient serum concentration data to adequately characterize ETI 204 PK separately after each dose administration (Day 1 and Day 14), therefore it was treated as one 32 mg/kg dose split into two 16 mg/kg administrations. Sequence B was treated as 2 separate 16 mg/kg doses (Day 1 and Day 120). All 70 subjects who received ETI-204 were included in the PK population: 35 in Sequence A and 35 in Sequence B; however, the full complement of PK parameters could not be determined in all subjects.
Time frame: On Days 1 and 14 predose, at the end of infusion, and 3 and 8 hours after the start of infusion, and on Days 2, 8, 15, 28, 43, 71, 85, 121, 128, 134, 149, 163, and 191.
Population: PK parameters for 1 subject in Sequence A were excluded because the subject was discontinued after the 1st dose of ETI-204 because of AEs and did not receive the 2nd dose. 2 subjects in Sequence A and 1 subject in Sequence B were missing the final 3 or more scheduled samples and therefore AUC and lambda z-based parameters were not reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence A | Volume of Distribution (Vd) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | 8.69 Liters | Standard Deviation 2.65 |
| Sequence B | Volume of Distribution (Vd) After a Dose of 16 mg/kg ETI-204 on Day 1 (Sequence B) or Two Doses on Days 1 and 14 (Sequence A) | 8.75 Liters | Standard Deviation 2.09 |