Safety Study of 7 Botulinum Antitoxin Serotypes Derived From Horses

Pharmacokinetics of a Heptavalent Equine-derived Botulinum Antitoxin (NP-018)

The primary purpose of the study is to evaluate the safety of the 7 Botulinum Antitoxin Serotypes derived from horses using various laboratory measurements, clinical examinations and adverse events. In addition, following intravenous (injected into the vein) administration assessing how much 7 Botulinum Antitoxin remains in the body.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Biological: Botulinum Antitoxin Heptavalent (A B C D E F G) - (EQUINE)

Detailed Description

Clostridial toxins are amongst the most toxic substances known to science (Middlebrook, 1995). In the United States and other countries, human exposure to Clostridium botulinum toxins usually occurs through food poisoning, wound botulism and colonizing infections in neonates. Recent events have heightened concern about the possibility of botulinum toxins being used in a bioterrorist attack. In order to be prepared for a biological attack as well as the usual human exposures, numerous therapeutic products have been or currently are undergoing development to treat or prevent botulism, including the use of human or equine derived antibodies for post-exposure prophylaxis of botulinum toxin exposure (Gelzleichter et al, 1999; Hibbs et al, 1996; Metzger and Lewis, 1979 and Keller and Stiehm, 2000).

Botulinum antitoxins have been in use to treat adult exposure to botulinum toxin for at least 40 years (Cupo et al, 2001). The use of botulinum antitoxins to treat individuals exposed to botulinum toxin is similar to the use of passive immune therapy with immune globulins collected from immunized or convalescing human donors to treat a wide range of bacterial and viral infectious diseases (Chippaux et al, 1998).

NP-018 (heptavalent equine-derived botulinum antitoxin) is prepared from plasma obtained from horses that have been immunized with a specific subtype of botulinum toxoid and toxin. Each individual horse is immunized against a single botulinum toxin subtype. Plasma is pooled from horses that have been immunized with the same botulinum toxin subtype. For each antitoxin serotype (A-G), a despeciated product will be produced by pepsin digestion of the IgG monomer in the equine plasma, yielding predominantly F(ab¢)2 fragment. Following the formulation, the seven antitoxin serotypes will be blended into a heptavalent product and filled into single-use vials.

The present clinical study is intended to assess the pharmacokinetics and safety of NP 018 following intravenous administration. The pharmacokinetics of NP 018 will be comparable to other equine derived antitoxin products. NP 018 will be safe to administer to normal healthy volunteers.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85044
      • MDS Pharma Services

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Body-mass index of 20 to 30 with minimum body weight of 111 lb (50 kg).
• For female subjects that are not surgically sterilized, willingness to use an effective method of contraception throughout the trial including:
• Using hormonal contraception (oral or injectable or implant) continuously for 3 months prior to the start of the trial and willing to continue to use hormonal contraception throughout the entire trial.
• IUD inserted at least 2 months prior to dosing.
• For female subjects who are postmenopausal less than 2 years an FSH >= 40 mIU/mL must be obtained. IF the FSH is < 40 mIU/mL the subject must agree to use an acceptable form of contraception (see above for acceptable forms of contraception.
• Normal and healthy as determined by medical history, physical examination, ECG, vital signs and test of liver, kidney and hematological functions.
• Written Informed Consent

Exclusion Criteria:

• Any known or documented allergies to horses (e.g. rash, wheezing, rhinitis etc. after exposure to horses)
• Any known or documented allergies to horse serum (observation of adverse events after treatment with any kind of products containing horse serum)
• Any severe food allergies, seasonal allergies or hay fever requiring therapy such as treatment with immunosuppressive drugs
• Known acute or chronic asthma requiring treatment with immunosuppressive drugs
• History of hypersensitivity to blood products derived from a human or equine source
• Heavy smokers (>10 cigarettes a day)
• Use of nicotine containing products
• Use of any investigational product within the past 30 days
• Pregnancy or lactation
• Positive serological test for HIV, HBV, or HCV
• History of, or suspected substance abuse problem (including alcohol) or failure of alcohol or drug screen at screening or at baseline
• Individuals with a history of allergy to latex or rubber
• Hemoglobin level of < 12 g/dL.
• Significant blood loss or blood donation within 56 days prior to dosing.
• Any plasma donation within 7 days prior to dosing.
• Demonstrated potential for allergic reaction to NP-018 based on positive horse dander (E3) IgE test or positive NP-018 skin sensitivity test prior to dosing

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NP-018 - 1 vial; Subjects received one vials of NP-018 administered intravenously.	Biological: Botulinum Antitoxin Heptavalent (A B C D E F G) - (EQUINE); Biological/Vaccine NP-018 (heptavalent equine-derived botulinum antitoxin) is prepared from pooled plasma obtained from horses that have been immunized against one of seven botulinum antitoxins (A-G). .; Other Names: Botulism Antitoxin (BAT)
Experimental: NP-018 - 2 vials; Subjects receive two vials of NP-018 administered intravenously.	Biological: Botulinum Antitoxin Heptavalent (A B C D E F G) - (EQUINE); Biological/Vaccine NP-018 (heptavalent equine-derived botulinum antitoxin) is prepared from pooled plasma obtained from horses that have been immunized against one of seven botulinum antitoxins (A-G). .; Other Names: Botulism Antitoxin (BAT)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjects with adverse events over the course of the study	Number of subjects with AEs and severity of AEs up to Day 28	From Screening Day 1 to Day 28 or early withdrawal
Subjects with serious adverse events over the course of the study	Number of subjects with SAEs up to Day 28	From Screening Day 1 to Day 28 or early withdrawal

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PK analysis for all 7 botulinum antitoxins: AUC0-t	AUC0-t (area under the serum concentration versus time curve, from time 0 to the last measurable concentration, as calculated by the linear trapezoidal method) will be calculated for all 7 botulinum antitoxins for each subject after NP-018 administration	Day Screening 2, Day 0 -30 minutes, 4 hours, 8 hours, Day 1 [24 hours], Day 3, Day 7, Day 14, Day 21, Day 28 or early withdrawal
PK analysis for all 7 botulinum antitoxins: AUC0-inf	AUC0-inf (area under the serum concentration versus time curve from time 0 to infinity) will be calculated for all 7 botulinum antitoxins for each subject after NP-018 administration	Screening Day 2, Day 0- 30 minutes, 4 hours, 8 hours, Day 1 [24 hours], Day 3, Day 7, Day 14, Day 21, Day 28 or early withdrawal
PK analysis for all 7 botulinum antitoxins: AUC0-t/AUC0-inf	AUC0-t/AUC0-inf (ratio of AUC0-t to AUC0-inf) will be calculated for all 7 botulinum antitoxins for each subject after NP-018 administration	Screening Day 2, Day 0- 30 minutes, 4 hours, 8 hours, Day 1 [24 hours], Day 3, Day 7, Day 14, Day 21, Day 28 or early withdrawal
PK analysis for all 7 botulinum antitoxins: Cmax	Cmax (maximum measured serum concentration over the time span specified) will be calculated for all 7 botulinum antitoxins for each subject after NP-018 administration	Screening Day 2, Day 0- 30 minutes, 4 hours, 8 hours, Day 1 [24 hours], Day 3, Day 7, Day 14, Day 21, Day 28 or early withdrawal
PK analysis for all 7 botulinum antitoxins: Tmax	Tmax (time of the maximum measured serum concentration) will be calculated for all 7 botulinum antitoxins for each subject after NP-018 administration	Screening Day 2, Day 0- 30 minutes, 4 hours, 8 hours, Day 1 [24 hours], Day 3, Day 7, Day 14, Day 21, Day 28 or early withdrawal
PK analysis for all 7 botulinum antitoxins: t½	t½ (apparent first-order terminal elimination half-life) will be calculated for all 7 botulinum antitoxins for each subject after NP-018 administration	Screening Day 2, Day 0- 30 minutes, 4 hours, 8 hours, Day 1 [24 hours], Day 3, Day 7, Day 14, Day 21, Day 28 or early withdrawal
PK analysis for all 7 botulinum antitoxins: Cl	Cl (clearance of NP-018) will be calculated for all 7 botulinum antitoxins for each subject after NP-018 administration	Screening Day 2, Day 0- 30 minutes, 4 hours, 8 hours, Day 1 [24 hours], Day 3, Day 7, Day 14, Day 21, Day 28 or early withdrawal
PK analysis for all 7 botulinum antitoxins: Vd	Vd (initial volume of distribution) will be calculated for all 7 botulinum antitoxins for each subject after NP-018 administration	Screening Day 2, Day 0- 30 minutes, 4 hours, 8 hours, Day 1 [24 hours], Day 3, Day 7, Day 14, Day 21, Day 28 or early withdrawal

Collaborators and Investigators

• Sponsor: Emergent BioSolutions
• Collaborators: Department of Health and Human Services
• Investigators: Principal Investigator: Mark J. Allison, M.D., MDS Pharma Services

Publications and helpful links

General Publications

• Keller MA, Stiehm ER. Passive immunity in prevention and treatment of infectious diseases. Clin Microbiol Rev. 2000 Oct;13(4):602-14. doi: 10.1128/CMR.13.4.602.
• Middlebrook JL. Protection strategies against botulinum toxin. Adv Exp Med Biol. 1995;383:93-8. doi: 10.1007/978-1-4615-1891-4_11. No abstract available.
• Gelzleichter TR, Myers MA, Menton RG, Niemuth NA, Matthews MC, Langford MJ. Protection against botulinum toxins provided by passive immunization with botulinum human immune globulin: evaluation using an inhalation model. J Appl Toxicol. 1999 Dec;19 Suppl 1:S35-8. doi: 10.1002/(sici)1099-1263(199912)19:1+3.0.co;2-9.
• Hibbs RG, Weber JT, Corwin A, Allos BM, Abd el Rehim MS, Sharkawy SE, Sarn JE, McKee KT Jr. Experience with the use of an investigational F(ab')2 heptavalent botulism immune globulin of equine origin during an outbreak of type E botulism in Egypt. Clin Infect Dis. 1996 Aug;23(2):337-40. doi: 10.1093/clinids/23.2.337.
• Metzger JF, Lewis GE Jr. Human-derived immune globulins for the treatment of botulism. Rev Infect Dis. 1979 Jul-Aug;1(4):689-92. doi: 10.1093/clinids/1.4.689.
• Cupo P, de Azevedo-Marques MM, Sarti W, Hering SE. Proposal of abolition of the skin sensitivity test before equine rabies immune globulin application. Rev Inst Med Trop Sao Paulo. 2001 Jan-Feb;43(1):51-3. doi: 10.1590/s0036-46652001000100010.
• Chippaux JP, Lang J, Eddine SA, Fagot P, Rage V, Peyrieux JC, Le Mener V. Clinical safety of a polyvalent F(ab')2 equine antivenom in 223 African snake envenomations: a field trial in Cameroon. VAO (Venin Afrique de l'Ouest) Investigators. Trans R Soc Trop Med Hyg. 1998 Nov-Dec;92(6):657-62. doi: 10.1016/s0035-9203(98)90802-1.

Study record dates

Study Major Dates

• Study Start: July 1, 2006
• Primary Completion (Actual): December 1, 2006
• Study Completion (Actual): April 1, 2010

Study Registration Dates

• First Submitted: July 19, 2006
• First Submitted That Met QC Criteria: August 3, 2006
• First Posted (Estimated): August 7, 2006

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Healthy Volunteers; Clinical Trials; Investigational Drug; Botulinum Antitoxin; Phoenix, Arizona
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Immunologic Factors; Antitoxins; Botulinum Antitoxin
• Other Study ID Numbers: AA24424 BT-001