Safety Study of 7 Botulinum Antitoxin Serotypes Derived From Horses

Study Overview
=================
Brief Summary
-----------------
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.

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.

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

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Biological: Botulinum Antitoxin Heptavalent (A B C D E F G) - (EQUINE)


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: NP-018<br>Subjects received one or two vials of NP-018 administered intravenously. | Biological: Botulinum Antitoxin Heptavalent (A B C D E F G) - (EQUINE)<br>* Biological/Vaccine NP-018 Experimental with 8 Cohorts of 5 Subjects each evaluating 2 Dosage levels of 1 or 2 vials of NP-018 administered intravenously.<br>* Other names: Botulism Antitoxin (BAT);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum for Antitoxins and Pk analysis |  | (Day 2 Screening, 30 minutes, 4 hours, 8 hours, Day 1 [24 hours], Day 3, Day 7, Day 14, Day 21, Day 28 or early withdrawal) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Chemistry Assessment |  | (Day 1 Screening, Baseline, Day 7 and Day 28 or early withdrawal) | 
| Urinalysis Assessment ( |  | Day 1 Screening, Baseline, Day 7 and Day 28 or early withdrawal) | 
| Physical Examination |  | (Day 1 Screening, Day 28 or early withdrawal) | 
| Concomitant Medications |  | (Day 1 Screening, Day 2 Screening, Baseline, Day 0 [Time 0], 30 minutes, 4 hours, 8 hours, Day 1 [24 hours], Day 3, Day 7, Day 14, Day 21, Day 28 or early withdrawal) | 
| Vital Signs |  | (Day 1 Screening, Baseline, Day 0 [Time 0], 30 minutes, 4 hours, 8 hours, Day 1 [24 hours], Day 7, Day 28 or early withdrawal) | 
| Adverse Events |  | (Day 1 Screening, Day 2 Screening, Baseline, Day 0 [Time 0], 30 minutes, 4 hours, 8 hours, Day 1 [24 hours], Day 3, Day 7, Day 14, Day 21, Day 28 or early withdrawal) | 
| Hematology Assessment |  | (Day 1 Screening, Baseline, Day 3, Day 7, Day 14, Day 21, Day 28 or early withdrawal) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Clinical Trials, Investigational Drug, Healthy Volunteers, Botulinum Antitoxin, Phoenix, Arizona