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

This study has been completed.
Sponsor:
Collaborator:
Department of Health and Human Services
Information provided by:
Cangene Corporation
ClinicalTrials.gov Identifier:
NCT00636519
First received: March 11, 2008
Last updated: February 22, 2011
Last verified: February 2011
History of Changes
  Purpose

The primary purpose of this study is:

  1. 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.
  2. 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.

Condition Intervention Phase
Healthy Volunteers
 Biological: Botulism Antitoxin Bivalent (Equine) Types A and B
Biological: Botulism Antitoxin Heptavalent (Equine) Types A-G
 Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Single Group Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Botulism Antitoxin Effects on Paralysis Induced by Type A and Type B Botulinum Neurotoxins in the Extensor Digitorum Brevis Muscle

Resource links provided by NLM:

MedlinePlus related topics: Botulism Paralysis
U.S. FDA Resources

Further study details as provided by Cangene Corporation:

Primary Outcome Measures:
  • Nerve Conduction Study [ Time Frame: Screening, Baseline (Day 0, -3 hrs), Day 1 (-1 hr), Day 3, Day 4, Day 7, Day 14, Day 21, Day 28 or Early Withdrawal ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Hematology [ Time Frame: Screening, Baseline (Day 0, -3 hr), Day 7, Day 14, Day 21, Day 28 or Early Withdrawal ] [ Designated as safety issue: Yes ]
  • Blood Chemistry [ Time Frame: Screening, Baseline (Day 0, -3 hr), Day 7, Day 14, Day 21, Day 28 or Early Withdrawal ] [ Designated as safety issue: Yes ]
  • Urinalysis [ Time Frame: Screening, Baseline (Day 0, -3 hr), Day 7, Day 14, Day 21, Day 28 or Early Withdrawal ] [ Designated as safety issue: Yes ]
  • Serum anti-Botulism Antitoxin Reactivity [ Time Frame: Baseline, Day 28 or Early Withdrawal ] [ Designated as safety issue: Yes ]
  • Adverse Events [ Time Frame: Day 0, Day 1( -1 hr), Day 1, Day 3, Day 4, Day 7, Day 14, Day 21, and Day 28 or Early Withdrawal ] [ Designated as safety issue: Yes ]
  • Vital Signs [ Time Frame: Screening, Day 0 (-3 hrs), Day 0, Day 1 (-1 hr), Day 1, Day 3, Day 4, Day 7, Day 14, Day 21, and Day 28 or Early Withdrawal ] [ Designated as safety issue: Yes ]
  • Physical Examination [ Time Frame: Screening, Baseline (Day 0, -3 hrs), Day 1 (-1 hr), Day 3, Day 4, Day 7, Day 21 and Day 28 or Early Withdrawal ] [ Designated as safety issue: Yes ]
  • 12-lead ECG [ Time Frame: Screening/ Day 28 or Early Withdrawal ] [ Designated as safety issue: Yes ]

Enrollment: 36
Study Start Date: February 2008
Study Completion Date: October 2009
Primary Completion Date: October 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Stage A
Botulism Antitoxin Bivalent (Equine) Types A and B Vs. Placebo
 Biological: Botulism Antitoxin Bivalent (Equine) Types A and B
One vial of Botulism Antitoxin Bivalent(Equine) Types A and B (1:10 in saline) or an Equivalent Volume of Placebo on Day 0 in Stage A
Experimental: Stage B
Botulism Antitoxin Heptavalent (Equine) Types A-G Vs. Placebo
 Biological: Botulism Antitoxin Heptavalent (Equine) Types A-G
One vial of Heptavalent Botulism Antitoxin (1:10 in saline) or an Equivalent Volume of Placebo on Day 0 in Stage B

Detailed 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.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00636519

Locations
United States, California
Dr. Gordon Peterson
Loma Linda, California, United States, 92354
United States, Washington
R. Richard Sloop, M. D.
Yakima, Washington, United States, 98902
Sponsors and Collaborators
Cangene Corporation
Department of Health and Human Services
Investigators
Principal Investigator: Richard Sloop, M. D. R. Richard Sloop, M. D.
Principal Investigator: Gordon Peterson, Dr. Faculty Physicains & Surgeons of Loma Linda University School of Medicine, Department of Neurology
  More Information

Publications:

Responsible Party: Christine Hall, Ph.D./ Manager, Clinical Science & Acting Manager, Clinical Operations, Cangene Corporation
ClinicalTrials.gov Identifier: NCT00636519     History of Changes
Other Study ID Numbers: BT002
Study First Received: March 11, 2008
Last Updated: February 22, 2011
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Cangene Corporation:
Botulism Antitoxin,Heptavalent,Bivalent,EDB Muscle,Paralysis

Additional relevant MeSH terms:
Botulism
Paralysis
Clostridium Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Neuromuscular Junction Diseases
Neuromuscular Diseases
Nervous System Diseases
Neurotoxicity Syndromes
Foodborne Diseases
 Poisoning
Substance-Related Disorders
Neurologic Manifestations
Signs and Symptoms
Antitoxins
Botulinum Antitoxin
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 16, 2013