Safety, Tolerability and PK of Intravenous (IV) ETI-204 Alone and in Presence of Ciprofloxacin in Adult Volunteers

Study Overview
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Brief Summary
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Evaluate the safety, tolerability and pharmacokinetics (PK) of intravenous (IV) ETI-204 alone and in the presence of IV and oral ciprofloxacin

Detailed Description
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An open-label, randomized, parallel group study of IV ETI-204 administered alone and in the presence of IV and oral ciprofloxacin in 40 adult volunteers. Subjects will be randomized to two groups of 20 subjects each in a 1:1 ratio. Group 1 will receive a single IV dose of ETI-204 16 mg/kg followed immediately at the end of the infusion by a single dose of IV ciprofloxacin (400 mg), followed by oral ciprofloxacin (750 mg) every 12 hours on Days 2-8 with the final oral dose on the morning of Day 9. Group 2 will receive IV ETI-204 (16 mg/kg) only. The total duration of the study for each subject will be approximately 100 days divided as follows:Screening: Days -28 to -2; In-Unit Phases: Days -1, 1 and 2 [all subjects]; Days 8, 9 and 10 [Group 1 only]; Out-of-Unit Visits: Day 9 [Group 2 only]; Day 16 (+/- 3 days); Day 29 (+/- 3 days); Day 43 (+/- 3 days); Final Visit: Day 71 (+/- 3 days). Following completion of a Screening visit subjects will arrive at the clinical research unit (CRU) on Day -1 following at least a 10-hour fast. On Day 1, subjects who qualify for entry into the study will be randomized to receive either ETI-204 plus IV and oral ciprofloxacin (Group 1) or ETI-204 only (Group 2) in a 1:1 ratio according to the randomization treatment assignment. On Day 1, all subjects will receive 50 mg oral diphenhydramine approximately 30 minutes prior to ETI-204 infusion. Subjects in Group 1 will receive IV ETI-204 16 mg/kg infused over 90 minutes, immediately followed by IV ciprofloxacin 400 mg infused over 60 minutes. Subjects in Group 2 will receive IV ETI-204 16 mg/kg infused over 90 minutes. All subjects will be discharged from the CRU on Day 2. On Days 2 through 8, subjects in Group 1 will receive oral ciprofloxacin (750 mg every 12 hours); the final dose will be received on the morning of Day 9. Oral ciprofloxacin dosing begins 24 hours after the initiation of the ciprofloxacin infusion on Day 1. Subjects in Group 1 will return to the CRU on Day 8 and will be discharged from the unit following completion of PK sampling on Day 10. Subjects in Group 2 will return to the unit for an out-patient visit on Day 9 but will not be re-admitted to the CRU for an overnight stay. All subjects will return to the CRU for out-patient visits on Days 16, 29, 43, and 71.

Official Title
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An Open-Label, Randomized, Parallel Group Study to Assess the Safety, Tolerability and Pharmacokinetics of ETI-204 Alone and in the Presence of Ciprofloxacin in Adult Volunteers

Conditions
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Inhalational Anthrax

Intervention / Treatment
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* Biological: ETI-204
* Drug: Ciprofloxacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Females or males between 18 and 60 years of age All females, regardless of childbearing potential, must have a negative serum beta human chorionic gonadotropin (β-hCG) pregnancy test at Screening and Day -1 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 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 Females who have undergone surgical sterilization, including hysterectomy, bilateral oophorectomy, bilateral salpingectomy, tubal ligation, or tubal essure ≥ 3 months prior to Screening. Tubal essure requires radiological confirmation of occlusion of the fallopian tubes. Subjects who cannot provide documentation may participate if they agree to follow the methods of contraception specified in Inclusion Criterion #3 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. Note this does not apply to males who have undergone a vasectomy and can provide documentation of confirmatory sperm count 3 months post procedure. Provide written informed consent Willing to comply with study restrictions (see Section 4.5.3 for a complete list of study restrictions) Exclusion Criteria: Pregnant or lactating woman Clinically-significant comorbidity that would interfere with completion of the study procedures or objectives or compromise the subject's safety Supine systolic blood pressure (BP) ≥ 150 mmHg or ≤ 90 mmHg or diastolic BP ≥ 95 mmHg Use of H1 receptor antagonists (i.e. antihistamines) within 5 days prior to Day 1 Evidence of drug or alcohol abuse as determined by the Investigator, within 6 months of Day 1 Positive test result for drugs of abuse (with the exception of medically prescribed drugs) at Screening or on Day -1 Positive test for alcohol at Screening or Day -1 Treatment with an investigational agent within 30 days or five half-lives of the investigational agent at Day 1 (whichever is longer)- Congenital or acquired immunodeficiency syndrome Prior solid organ or bone marrow transplant Positive test for Hepatitis B (surface antigen), Hepatitis C, or human immunodeficiency virus (HIV) at Screening History of prior treatment for anthrax exposure or prior anthrax infection Prior immunization with any approved or investigational anthrax vaccine or prior treatment with an investigational anthrax treatment (i.e., ETI-204, raxibacumab, or anthrax immune globulin) 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 Therapeutic 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 Donation or loss of > 500 mL of blood within 30 days or plasma within 7 days of Day 1 Prior stroke, epilepsy, relapsing or degenerative CNS disease, or relapsing or degenerative ocular disease Myocardial infarction or acute coronary syndrome in the past 5 years, active angina pectoris, or heart failure (New York Heart Association scale > I) History of chronic liver disease Calculated creatinine clearance (CrCl) of < 30 mL/min using the Cockcroft-Gault equation (see Section 5.1) 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 History of allergic or hypersensitivity reactions to other therapeutic antibodies or immunoglobulins 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 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 Exclusion Criteria Specific to the Use of Ciprofloxacin Hypersensitivity to any fluoroquinolone At increased risk of Clostridium. difficile (C. difficile) infection (e.g., prior systemic antibiotic therapy or in-hospital stay of greater than 2 nights over the past 6 months, abdominal surgery within 3 months prior to Day 1, a chronic inflammatory bowel disease or prior C. difficile infection) Any medical condition that may require repeat courses of antibiotics, e.g., recurrent urinary tract or respiratory infections. A short course (i.e.≤ 10 days) of antibiotics within 6 months prior to Day 1 is not exclusionary. A history of any tendon rupture Subjects who smoke or have used tobacco or nicotine containing products within 3 months of Day 1. Use of cation-containing drugs or food supplements within 2 days prior to Day 1 Use of protheophylline, theophylline, methylxanthine, tizanidine, or other drugs metabolized via cytochrome P450 1A (CYP1A) within 30 days prior to Day 1 Use of glyburide, cyclosporine, didanosine, methotrexate, or probenecid and medications that prolong the QT interval within 30 days prior to Day 1 or within 5 half-lives of Day 1, whichever is longer Subjects at high risk for QT prolongation, including: Baseline prolongation of QTcF ≥ 500 msec Risk factors for Torsade de Pointes, including hypocalcemia, hypokalemia, sudden death of unknown cause in a close family member (i.e. biological mother, father or siblings), a near drowning episode, a family history of either Romano-Ward syndrome or Jervell and Lange-Nielson syndrome The use of concomitant medications that prolong the QT interval within 30 days prior to Day 1

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 ETI-204 and Ciprofloxacin<br>Participants will receive a single IV dose of 16 mg/kg ETI-204 infused over 90 minutes on Day 1, immediately followed by an IV dose of ciprofloxacin 400 mg infused over 60 minutes, followed by oral doses of ciprofloxacin (750 mg every 12 hours) from Day 2 to Day 8 and a final dose on the morning of Day 9. | Biological: ETI-204<br>* A single IV infusion of 16 mg/kg ETI-204 over 90 minutes on Day 1<br>* Other names: Obiltoxaximab;Drug: Ciprofloxacin<br>* A single IV Infusion of 400 mg Ciprofloxacin over 60 minutes immediately following the infusion of ETI-204 on Day 1, followed by oral Ciprofloxacin (750 mg every 12 hours) on Days 2-8, and a final oral dose on the morning of Day 9.<br>|
| Other: Group 2 ETI-204 Alone<br>Participants will receive a single IV dose of 16 mg/kg ETI-204 infused over 90 minutes on Day 1. | Biological: ETI-204<br>* A single IV infusion of 16 mg/kg ETI-204 over 90 minutes on Day 1<br>* Other names: Obiltoxaximab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 assessments, skin assessments, infusion site assessments, and adverse events (AEs). | 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. | 

Secondary Outcome Measures

| Outcome Measure | 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 at predose, at the end of ETI-204 infusion, 2.5, 4.5 and 7.5 hours after the start of the ETI-204 infusion, and on Days 2 (24 hours), 9, 16, 29, 43, and 71. | 
| 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 at predose, at the end of ETI-204 infusion, 2.5, 4.5 and 7.5 hours after the start of the ETI-204 infusion, and on Days 2 (24 hours), 9, 16, 29, 43, and 71. | 
| Area Under the Concentration-Time Curve From Time 0 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 at predose, at the end of ETI-204 infusion, 2.5, 4.5 and 7.5 hours after the start of the ETI-204 infusion, and on Days 2 (24 hours), 9, 16, 29, 43, and 71. | 
| Area Under the Concentration-Time Curve From Time 0 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 at predose, at the end of ETI-204 infusion, 2.5, 4.5 and 7.5 hours after the start of the ETI-204 infusion, and on Days 2 (24 hours), 9, 16, 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 at predose, at the end of ETI-204 infusion, 2.5, 4.5 and 7.5 hours after the start of the ETI-204 infusion, and on Days 2 (24 hours), 9, 16, 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 at predose, at the end of ETI-204 infusion, 2.5, 4.5 and 7.5 hours after the start of the ETI-204 infusion, and on Days 2 (24 hours), 9, 16, 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 at predose, at the end of ETI-204 infusion, 2.5, 4.5 and 7.5 hours after the start of the ETI-204 infusion, and on Days 2 (24 hours), 9, 16, 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 at predose, at the end of ETI-204 infusion, 2.5, 4.5 and 7.5 hours after the start of the ETI-204 infusion, and on Days 2 (24 hours), 9, 16, 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 at predose and on Days 9, 29, 43, and 71. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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monoclonal antibody, ETI-204, ciprofloxacin, safety, PK