Ciprofloxacin BioThrax Co-Administration Study

• Sponsor: Emergent BioSolutions (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01753115
• Collaborator: Department of Health and Human Services (U.S. Fed)
• Enrollment: 154
• Locations: 3
• Arms: 3
• Duration (Months): 8
• Patients Per Site: 51.3
• Patients Per Site Per Month: 6.4

Study Details

Study Description

Brief Summary

The purpose of this clinical trial is to determine whether there is any effect on the antibiotic, ciprofloxacin when taken before and after administration of a 3-dose series of BioThrax® (Anthrax Vaccine Adsorbed or AVA).

This study will be conducted in the United States (US) in 154 healthy male and female volunteer subjects ages 18 to 45.

The duration of study participation for each subject will be approximately 76 days (approximately 2.5 months)

Condition or Disease	Intervention/Treatment	Phase
Anthrax	Biological: BioThrax; Drug: Ciprofloxacin	Phase 2

Detailed Description

BioThrax is the only FDA-licensed vaccine for the prevention of anthrax infection. This is a randomized, open-label, Phase 2, multi-center trial to investigate the potential interactions of ciprofloxacin and BioThrax.

Study Design

• Study Type: Interventional
• Actual Enrollment: 154 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Study of The Effects of Co-Administering Ciprofloxacin and BioThrax on the Pharmacokinetics of Ciprofloxacin in Healthy Adults
• Study Start Date: Dec 1, 2012
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BioThrax + Ciprofloxacin PK BioThrax: route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule. Ciprofloxacin: 500 mg twice a day (Days 1-6, 19-21, 33-35, 40-48).	Biological: BioThrax; route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule; Other Names: Anthrax Vaccine Adsorbed AVA ; Drug: Ciprofloxacin; 500 mg twice a day (Days 1-6, 19-21, 33-35, 40-48).
Experimental: BioThrax + Ciprofloxacin no PK BioThrax: route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule. Ciprofloxacin: 500 mg twice a day (Days 1-6, 19-21, 33-35, 40-48).	Biological: BioThrax; route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule; Other Names: Anthrax Vaccine Adsorbed AVA ; Drug: Ciprofloxacin; 500 mg twice a day (Days 1-6, 19-21, 33-35, 40-48).
Experimental: BioThrax only BioThrax: route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule.	Biological: BioThrax; route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule; Other Names: Anthrax Vaccine Adsorbed AVA

Outcome Measures

Primary Outcome Measures

1. Ratios of Ciprofloxacin Area Under the Curve and Cmax (Day 5/Day 44) [Day 5 and Day 44 in Arm 1]

   Ratios of Area Under the Curve from zero to 12 hours (AUC0-12h) and maximum concentration (Cmax) achieved for ciprofloxacin (Day 5/Day 44).

Secondary Outcome Measures

1. Geometric Mean Titer (GMT) of Toxin Neutralizing Antibody (TNA) Levels [Two weeks after last vaccination]

   Blood was collected in arms 1 and 2 at day 48 ( 2 weeks following last vaccination) and in arm 3 at day 43 ( 2 weeks following last vaccination) for TNA assay to determine the NF50 antibody titer for calculating GMT.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Be between 18 and 45 years of age, at the time of enrollment

• Be in good health as determined by the investigator from medical history and a physical examination.

• If a pre-menopausal female, must be using acceptable methods of birth control.

• Be willing and able to return for all follow-up visits and blood and urine collections for the duration of the trial

• Be willing and able to complete a web-enabled electronic diary and report concomitant medications, adverse events, and BioThrax reactogenicity events during the trial

• Be able to understand and communicate in English.

Exclusion Criteria:

• Prior immunization with anthrax vaccine or known exposure to anthrax organisms

• Intend to enlist in the military during the study.

• Have a known allergy to aluminum hydroxide, formaldehyde, benzethonium chloride, or latex.

• Plan to receive experimental products 30 days prior to study entry or at any time during the study

• Have received a live vaccine in the 30 days before study entry

• Plan to receive a live vaccine at any time during the study.

• Have ongoing drug abuse/dependence (including alcohol) issues and/or test positive in a urine drug screen for amphetamines, barbiturates, cocaine or opiates

• Have received immunosuppressive therapy (including systemic steroids) within 30 days prior to trial entry

• Have any other condition known to produce or be associated with immunosuppression

• Have received cytotoxic therapy in the previous 5 years

• A chronic condition that, in the opinion of the Investigator, would render vaccination unsafe or would interfere with trial evaluations or completion of the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Center for Pharmaceutical Research	Kansas City	Missouri	United States	64114
2	Meridian Clinical Research	Omaha	Nebraska	United States	68134
3	Research Across America	Dallas	Texas	United States	75234

Sponsors and Collaborators

• Emergent BioSolutions
• Department of Health and Human Services

Investigators

• Principal Investigator: Robert Hopkins, MD, MPH, TM, Emergent BioSolutions Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Emergent BioSolutions
• ClinicalTrials.gov Identifier: NCT01753115
• Other Study ID Numbers: EBS.AVA.009
• First Posted: Dec 20, 2012
• Last Update Posted: Nov 19, 2014
• Last Verified: Nov 1, 2014

• Keywords provided by Emergent BioSolutions: post-exposure prophylaxis; toxin neutralization assay
• Additional relevant MeSH terms: Anthrax; Ciprofloxacin

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled from 14 Dec 2012 to 04 Aug 2013 at 3 US sites.

Arm/Group Title	BioThrax + Ciprofloxacin PK	BioThrax + Ciprofloxacin no PK	BioThrax Only
Arm/Group Description	BioThrax: route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule Ciprofloxacin: 500 mg twice a day	BioThrax: route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule Ciprofloxacin: 500 mg twice a day	BioThrax: route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule
Period Title: Overall Study
STARTED	44	40	70
Treated	38	39	67
COMPLETED	32	25	56
NOT COMPLETED	12	15	14

Baseline Characteristics

Arm/Group Title	BioThrax + Ciprofloxacin PK	BioThrax + Ciprofloxacin no PK	BioThrax Only	Total
Arm/Group Description	BioThrax: route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule Ciprofloxacin: 500 mg twice a day	BioThrax: route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule Ciprofloxacin: 500 mg twice a day	BioThrax: route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule	Total of all reporting groups
Overall Participants	44	40	70	154
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	30.5 (8.76)	30.8 (8.05)	30.2 (7.29)	30.4 (7.88)
Age, Customized (participants) [Number]
18 - 30 years	22 50%	20 50%	35 50%	77 50%
31 - 45 years	22 50%	20 50%	35 50%	77 50%
Sex: Female, Male (Count of Participants)
Female	20 45.5%	20 50%	36 51.4%	76 49.4%
Male	24 54.5%	20 50%	34 48.6%	78 50.6%
Race/Ethnicity, Customized (participants) [Number]
White	24 54.5%	22 55%	33 47.1%	79 51.3%
Black or African America	20 45.5%	14 35%	34 48.6%	68 44.2%
Asian	0 0%	2 5%	1 1.4%	3 1.9%
American Indian or Alaskan Native	0 0%	1 2.5%	2 2.9%	3 1.9%
Multiple	0 0%	1 2.5%	0 0%	1 0.6%

Outcome Measures

1. Primary Outcome

Title	Ratios of Ciprofloxacin Area Under the Curve and Cmax (Day 5/Day 44)
Description	Ratios of Area Under the Curve from zero to 12 hours (AUC0-12h) and maximum concentration (Cmax) achieved for ciprofloxacin (Day 5/Day 44).
Time Frame	Day 5 and Day 44 in Arm 1

Outcome Measure Data

Analysis Population Description

Per protocol population: all subjects in arm 1 who received any dose of ciprofloxacin, had adequate PK data on Day 5 and Day 44, had received all three BioThrax doses, and who had no key protocol deviations (e.g., insufficient blood sample) that would be expected to affect the ciprofloxacin PK assessment.

Arm/Group Title	Arm 1 = BioThrax (0.5 mL) + Ciprofloxacin (500 mg Bid) + PK
Arm/Group Description	BioThrax: route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule Ciprofloxacin: 500 mg twice a day
Measure Participants	32
Ratio Cmax Day 44/Day 5	0.944
Ratio AUC0-12hr Day 44/Day 5	0.887

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1 = BioThrax (0.5 mL) + Ciprofloxacin (500 mg Bid) + PK
	Comments	Analysis of Ciprofloxacin Area Under the Curve at Day 5 and Day 44.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Equivalence margin is 0.80 - 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of AUC
	Estimated Value	0.887
	Confidence Interval	(2-Sided) 90%; 0.831 to 0.948
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm 1 = BioThrax (0.5 mL) + Ciprofloxacin (500 mg Bid) + PK
	Comments	Analysis of Cmax at Day 5 and Day 44
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Equivalence margin is 0.80 - 1.25.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of Cmax
	Estimated Value	0.944
	Confidence Interval	(2-Sided) 90%; 0.852 to 1.046
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Geometric Mean Titer (GMT) of Toxin Neutralizing Antibody (TNA) Levels
Description	Blood was collected in arms 1 and 2 at day 48 ( 2 weeks following last vaccination) and in arm 3 at day 43 ( 2 weeks following last vaccination) for TNA assay to determine the NF50 antibody titer for calculating GMT.
Time Frame	Two weeks after last vaccination

Outcome Measure Data

Analysis Population Description

BioThrax immunogenicity population: received 3 vaccinations and had samples taken within the study-specified windows; had a valid immunogenicity result within 2 wks of the last vaccination; had no evidence of previous anthrax vaccination and received the correct BioThrax dose at all 3 times; received vaccine maintained at the proper temperature.

Arm/Group Title	BioThrax + Ciprofloxacin (Arms 1 + 2)	BioThrax Only (Arm 3)
Arm/Group Description	BioThrax: route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule Ciprofloxacin: 500 mg twice a day	BioThrax: route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule
Measure Participants	50	50
Geometric Mean (95% Confidence Interval) [titer]	1.170	0.923

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 1 = BioThrax (0.5 mL) + Ciprofloxacin (500 mg Bid) + PK, BioThrax Only (Arm 3)
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority margin is 0.67.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Ratio of GMT
	Estimated Value	1.267
	Confidence Interval	(2-Sided) 95%; 0.898 to 1.787
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Arm 1: enrollment, Days 0-5, 20, 34, 39-44, 48, or the early withdrawal visit (EWV) for a max of 16 visits. Arm 2: enrollment, Days 1, 5, 20, 34, 48, or EWV for a max of 6 visits. Arm 3: enrollment, Days 1, 15, 29, 43, or EWV for a max of 5 visits.
Adverse Event Reporting Description	Subjects in the safety (treated) population were asked about adverse event (AEs) at each visit. Severe (Grade 3) injection site and systemic reactions recorded in subject diaries were also recorded as AEs in the eCRF. Abnormal lab results, vital signs, and physical examination findings considered clinically significant were also recorded as AEs.
Arm/Group Title	BioThrax + Ciprofloxacin PK		BioThrax + Ciprofloxacin no PK		BioThrax Only
Arm/Group Description	BioThrax: route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule Ciprofloxacin: 500 mg twice a day		BioThrax: route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule Ciprofloxacin: 500 mg twice a day		BioThrax: route of administration/schedule- 0.5 mL subcutaneous (SC) injection / 0-2-4 week schedule
All Cause Mortality
	BioThrax + Ciprofloxacin PK		BioThrax + Ciprofloxacin no PK		BioThrax Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	BioThrax + Ciprofloxacin PK		BioThrax + Ciprofloxacin no PK		BioThrax Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		0/39 (0%)		0/67 (0%)
Other (Not Including Serious) Adverse Events
	BioThrax + Ciprofloxacin PK		BioThrax + Ciprofloxacin no PK		BioThrax Only
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/38 (15.8%)		7/39 (17.9%)		14/67 (20.9%)
Gastrointestinal disorders
Nausea	1/38 (2.6%)	1	1/39 (2.6%)	1	5/67 (7.5%)	9
General disorders
Fatigue	0/38 (0%)	0	2/39 (5.1%)	4	3/67 (4.5%)	4
Injection site erythema	2/38 (5.3%)	2	0/39 (0%)	0	2/67 (3%)	3
Injection site mass	0/38 (0%)	0	0/39 (0%)	0	4/67 (6%)	5
Injection site pain	0/38 (0%)	0	0/39 (0%)	0	4/67 (6%)	6
Infections and infestations
Upper respiratory tract infection	1/38 (2.6%)	1	2/39 (5.1%)	2	3/67 (4.5%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	2/38 (5.3%)	2	0/39 (0%)	0	1/67 (1.5%)	1
Myalgia	0/38 (0%)	0	0/39 (0%)	0	5/67 (7.5%)	6
Nervous system disorders
Headache	3/38 (7.9%)	3	4/39 (10.3%)	4	4/67 (6%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor is responsible for public disclosure of study data. Any proposed publication is subject to review agreed between the Biomedical Advanced Research & Development Authority (BARDA) and Emergent; between Emergent and the contract research organizations (CROs)/vendors; and between the CROs and the site Principal Investigator. Data are the property of the sponsor and cannot be published without prior authorization from the sponsor, but data and publication thereof will not be unduly withheld.