Botulism Antitoxin Effects on Paralysis Induced by Botulinum Neurotoxins in the EDB Muscle

Emergent BioSolutions

Status and phase

Completed

Phase 1

Conditions

Healthy Volunteers

Treatments

Biological: Botulism Antitoxin Heptavalent (Equine) Types A-G

Biological: Botulism Antitoxin Bivalent (Equine) Types A and B

Study type

Interventional

Funder types

Industry

Other U.S. Federal agency

Identifiers

NCT00636519

BT002

Details and patient eligibility

About

The primary purpose of this study is:

To evaluate the model determined by the ability of botulism antitoxin (bivalent, Aventis) to neutralize Botulinum toxin in the Extensor Digitorum Brevis model of muscle paralysis in Stage A.
To assess the ability of botulism antitoxin (heptavalent, Cangene) to neutralize Botulinum toxin in the Extensor Digitorum Brevis model of muscle paralysis in Stage B.

Full description

Botulism is a rare disease; however Botulinum toxins (neurotoxins) may be used as biological weapon especially in the form of aerosol. Botulism is caused by neurotoxins that are produced by the obligate anaerobic, gram-positive, spore-forming bacterium Clostridium botulinum (1). C. botulinum produces 8 serologically distinct neurotoxins identified as serotypes A, B, C1, C2, D, E, F, and G (2).

Therapy for botulism includes supportive care and passive immunization with antitoxin. Antitoxin should be administered to patients with neurologic signs of botulism as soon as possible after clinical diagnosis (3). Botulism antitoxin is prepared from plasma obtained from horses that have been immunized with a specific subtype of botulism toxoid and toxin.

The BT-002 is an exploratory pharmacodynamic study that is being performed to evaluate the effect of Botulism Antitoxins in preventing paralysis of extensor digitorum brevis muscle following BOTOX®/ MYOBLOC® administration. This study will compare bivalent and heptavalent products to a placebo. Safety data will be collected.

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. '

This research study will be conducted in two stages - Stage A and Stage B. If enrolled in the Stage A of the study, the subject will have an equal chance of getting either bivalent botulism antitoxin or placebo. If enrolled in Stage B of the study, the subject will have an equal chance of getting heptavalent botulism antitoxin (NP-018) or placebo. The subject will be receiving injections of Botox and Myobloc on the next day after the antitoxin administration in the left and right foot respectively. The subject's participation in this study will be for maximum of 57 days.

Enrollment

36 patients

Sex

All

Ages

18 to 55 years old

Volunteers

Accepts Healthy Volunteers

Inclusion criteria

Male or female
Age 18 - 55 years
Body-mass index 19-30
Normal and healthy as determined by medical history, physical examination, ECG, NCS, vital signs and tests of liver, kidney and hematological functions
Adequate form of contraception for female subjects
- For women with child-bearing potential-using hormonal contraception (oral, injectable or implant) continuously for 3 months prior to the start of the study and willing to continue to use hormonal contraception throughout the entire study. IUD inserted or use of condoms for at least 2 months prior to dosing
- Other forms of contraception may be considered as adequate at physician's discretion
- Surgically-sterilized female subjects
- For female subjects who are postmenopausal, an FSH ≥ than 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)
Signed written Informed Consent

Exclusion criteria

Previously injected with BOTOX®, BOTOX® COSMETIC or MYOBLOC®
Any known or documented Botulinum infection/intoxication
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 product containing horse serum)
Any moderate or severe food allergies, seasonal allergies or hay fever requiring treatment with peroral or parenteral immunosuppressive drug
Any known or documented hypersensitivity to blood products derived from a human or equine source
Any known or documented hypersensitivity to albumin
Positive result for Botulism Antitoxin skin sensitivity testing
Any known or documented allergy to rubber, latex or plastic
Known acute or chronic moderate or severe asthma requiring treatment with peroral and / or parenteral immunosuppressive drugs
Previously diagnosed or currently suspected Multiple Sclerosis or other neuromuscular degenerative disorder
Previously diagnosed or currently suspected motor neuron disease
Previously or currently diagnosed peripheral neuropathy of lower extremities' nerves
Current infection of the skin / skin problems at the injection site (foot)
Scar tissue or tattoo of the skin over the extensor digitorum brevis muscles.
Previously diagnosed or currently suspected diabetes
Previously diagnosed or currently suspected coagulopathies
Previously diagnosed or currently suspected vasculitis
Current treatment or treatment in the past 7 days with aminoglycosides, clindamycin, quinolines or aminopyridine
Heavy smokers (>10 cigarettes/day)
History of, or suspected substance abuse (including alcohol) or failure of drug screen at screening or at baseline
Use of any investigational product within the past 30 days (prior to screening)
Pregnancy or lactation
Positive serological test for diagnosis of HIV infection, HBV hepatitis, or HCV hepatitis
Abnormal (based on principle investigator assessment) nerve conduction study (NCS) results