CompletedNCT01952444Updated Apr 16, 2019Results posted

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

A Phase 1 interventional study of ETI-204 and Ciprofloxacin in Inhalational Anthrax, sponsored by Elusys Therapeutics. Completed at 1 site in United States. Open to participants aged 18 Years to 60 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2019-04-16.

Sponsored by Elusys Therapeutics · Phase 1, Interventional, and Other

Phase: Phase 1
Study type: Interventional
Enrollment: 40
Allocation: Randomized
Ages: 18 Years to 60 Years
Sex: All

Study summary

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

Read the detailed description

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.

Conditions studied

Inhalational Anthrax

Keywords

monoclonal antibody, ETI-204, ciprofloxacin, safety, PK

In context

Lead sponsor

Elusys Therapeutics is the lead sponsor of 7 studies on the registry; 1 is open to participants now.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 60 Years
Sexes eligible: All
Accepts healthy volunteers: Yes

Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.

Inclusion criteria

Females or males between 18 and 60 years of age
All females, regardless of , 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 or surgically sterile) must agree to practice abstinence or to use a medically accepted method of 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
Willing to comply with study restrictions (see Section 4.5.3 for a complete list of study restrictions)

Exclusion criteria

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 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 (surface antigen), , or (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 , 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 ( scale > I)
History of chronic liver disease
Calculated (CrCl) of \< 30 mL/min using the Cockcroft-Gault equation (see Section 5.1)
Any abnormality, in the Investigator's opinion, on (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 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 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:
1. Baseline prolongation of QTcF ≥ 500 msec
2. 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
3. The use of concomitant medications that prolong the QT interval within 30 days prior to Day 1

Terms in these criteria, in plain language(16)

Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.

Childbearing potential

Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).

Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.

Postmenopausal

Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).

Contraception

Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.

Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.

Informed consent

Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.

You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.

Investigational drug or device

A drug or device being studied in a clinical trial.

It may be new, or already approved and being studied for another use, dose or form. Criteria often leave out people who took part in another study of one within a recent period, commonly 30 days or five half-lives.

Hepatitis B tests

Hepatitis B is a virus that infects the liver. These are separate tests: HBsAg positive usually means a current infection (a recent vaccination can briefly cause it too); total anti-HBc (HBcAb) positive means an infection now or in the past; HBV DNA measures how much virus is in the blood.

Some studies accept a past infection if HBV DNA is undetectable, sometimes with antiviral medicine during the study. Check what this study allows.

Hepatitis C tests

Hepatitis C is a virus that infects the liver. An HCV antibody test can stay positive after an infection has cleared (and is occasionally positive without one); an HCV RNA test shows whether the virus is there now.

After treatment, hepatitis C counts as cured when HCV RNA is still undetectable 12 weeks or more after the treatment ended. Studies often accept people cured this way.

HIV

The human immunodeficiency virus, which weakens the immune system.

Many studies now accept people whose HIV is controlled on treatment, judged by the viral load and the CD4 count. Check the limits this study sets.

Corticosteroids (steroids)

Anti-inflammatory medicines such as prednisone, prednisolone and dexamethasone — not the anabolic steroids used for muscle.

Studies differ in what they allow: check which steroid medicines, routes (tablets, injections, creams, inhalers, eye drops) and doses this study accepts.

Immunosuppression

A weakened immune system. It can come from an illness, such as HIV or some blood cancers, or from medicines that turn the immune system down, for example after an organ transplant or for an autoimmune disease; steroids at higher doses count.

Read whether the line is about a condition or about medicines, and which medicines and doses it means.

NYHA class (heart failure)

The New York Heart Association’s four classes of how much heart failure limits physical activity.

I: No limits: ordinary activity causes no undue tiredness or breathlessness.
II: Slight limits: comfortable at rest, ordinary activity causes symptoms.
III: Marked limits: comfortable at rest, less than ordinary activity causes symptoms.
IV: Symptoms even at rest; any activity makes them worse.

Studies set their own limit — many outside heart failure leave out class III–IV, while heart failure studies may ask for a particular class. Check the class this study names.

Creatinine clearance (CrCl)

How quickly the kidneys clear creatinine, a waste product, from the blood. A study may estimate it from a blood test with age, weight and sex (often by the Cockcroft–Gault formula), or measure it using blood and urine collected over a set time. Given in mL/min; higher is better.

Clinically significant

Judged by the study doctor to matter for your health or for the study. It is a doctor’s decision, so ask the study team if you are unsure whether something counts.

ECG (electrocardiogram)

A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.

Hypersensitivity

An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.

QT and QTc

On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.

The study may name a correction formula and a limit in milliseconds, often around 450–480.

Study design

Phase: Phase 1
Primary purpose: Other
Allocation: Randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 40 participants (actual)

Study arms

Experimental
Group 1 ETI-204 and Ciprofloxacin
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 · Drug: Ciprofloxacin
Other
Group 2 ETI-204 Alone
Participants will receive a single IV dose of 16 mg/kg ETI-204 infused over 90 minutes on Day 1.
Biological: ETI-204

Interventions

BiologicalETI-204
A single IV infusion of 16 mg/kg ETI-204 over 90 minutes on Day 1
Also known as: Obiltoxaximab
DrugCiprofloxacin
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.

What researchers measure

Primary outcomes

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).
Time frame: 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 outcomes

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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: On Day 1 at predose and on Days 9, 29, 43, and 71.

Results

Posted Apr 8, 2019

Participant flow

Participant flow — Overall Study
Milestone	ETI-204	ETI-204 and Ciprofloxacin
Started	20	20
Completed	20	19
Not completed	0	1

Outcome measures

PrimaryNumber 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).

Time frame:: 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.
Reported as:: Count of participants · Participants

Number of Participants Who Experienced Adverse Events
Participants	ETI-204 + Ciprofloxacin	ETI-204
Number of Participants Who Experienced Adverse Events	14	13

SecondaryMaximum Observed Plasma Concentration of ETI-204 (Cmax)