Assessment of the Effect of Botulinum Toxin in Extensor Digitorum Brevis Via Strain Gauge and Nerve Conduction Studies

Strain Gauge Feasibility Assessment & Correlation With Compound Muscle Action Potential & Surface Electromyogram Parameters Before & After a Single Intramuscular Injection of Botulinum Toxin Type A Into Extensor Digitorum Brevis Muscle

The purpose of this feasibility study is to determine if temporary weakness of a small foot muscle caused by local injection of botulinum toxin into that muscle can be measured with a strain gauge in addition to the previously known valid measurements via nerve conduction studies and surface electromyogram.

Study Overview

• Status: Completed
• Conditions: Muscle Strength; Botulinum Toxins, Type A
• Intervention / Treatment: Drug: Botulinum Toxin, Type A; Drug: Botulinum Toxin, Type A; Drug: Saline

Detailed Description

Purpose/Hypothesis:

Verify the validity and reliability of strain gauge assessment of strength of extensor digitorum brevis (EDB) muscle compared to compound muscle action potential (CMAP) size from EDB and surface electromyography (SEMG) data from EDB after injection of botulinum toxin into EDB

1. Primary Outcome Measure:

   Change in measured strength (using strain gauges) of dorsiflexion of digits 3 and 4 ("strength of EDB") after vs. before botulinum toxin injection into EDB

2. Secondary Outcome Measures:

   1. Change in CMAP (with standard reference electrode location and with an "inactive" reference electrode location) from EDB after vs. before botulinum toxin injection into EDB;
   2. Change in SEMG parameters from EDB, tibialis anterior (TA), and extensor digitorum longus (EDL) after vs. before botulinum toxin injection into EDB

STUDY DESIGN:

1. Overview:

   Single intramuscular injection of botulinum toxin or placebo (placebo or BOTOX 2 units or BOTOX 20 units, each with a total volume of 0.1 ml) intramuscular into right EDB on Day 0. Strain gauge data and SEMG data from TA and EDL are obtained at each evaluation time: Baseline (3 separate times prior to Day 0 after at least 5 separate training sessions for the strain gauges); Day 1; Day 2; Day 4 (during anticipated rapid change); Day 14 (+/-1 day) (at clinical nadir); Day 21 (+/-1 day) (another day at clinical nadir); and Month 4 (when clinical recovery from the effect of BOTOX should have occurred); CMAP & SEMG data from EDB are obtained at Baseline; Day 4 (close to nadir of CAMP); Day 14 (at nadir of CAMP) and/or Day 21 (at nadir of CAMP); and Month 4 (when clinical recovery from the effect of BOTOX should have occurred but CMAP should not have recovered).

2. Protocol:

Single-center, Double-Blind, Randomized, Pilot Trial Total Sample Size: 12-15

Treatment Groups:

BOTOX Single Dose 20 units IM in EDB in 0.1 ml BOTOX Single Dose 2 units IM in EDB in 0.1 ml Placebo (Saline) Single Dose IM in EDB in 0.1 ml

Estimated Time to Enroll:

0-3 months

Estimated Study Duration:

4-6 months

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Loma Linda, California, United States, 92354
      • Loma Linda University
    • Loma Linda, California, United States, 92354
      • Electromyography Laboratory, Loma Linda University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 54 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Normal, healthy, male or female subjects, 18 to 54 years of age.
• Written informed consent has been obtained.
• Females with child-bearing potential have a negative urine pregnancy test and agree to use a reliable form of contraception during the study.
• Ability to follow study instructions and likely to complete all required visits.
• Written authorization for Use and Release of Health and Research Study Information has been obtained.

Exclusion Criteria:

• Abnormality by focused history and examination including the presence of foot deformity.
• Abnormal (as determined by the investigator) screening nerve conduction studies of the lower limbs.
• Identification of anomalous innervation of right EDB via screening nerve conduction studies.
• The subject having a foot which does not adequately fit in the modified ankle-foot orthosis used with the strain gauge.
• The subject having a foot in which anatomic bone landmarks cannot be adequately identified.
• Body mass index (BMI) greater than 30.
• History of significant (as determined by the investigator) lower limb injury or lower limb surgery
• Any uncontrolled clinically significant medical condition.
• Known allergy or sensitivity to any of the components in the study medication.
• Females with a positive pregnancy test, or who are breast-feeding, planning a pregnancy during the study, who think that they may be pregnant at the start of the study, or females of childbearing potential who are unable or unwilling to use a reliable form of contraception during the study.
• Concurrent participation in another investigational drug or device study or participation within 3 months prior to study.
• Treatment with botulinum toxin of any serotype prior to enrollment in study or prior clinical botulism.
• Any medical condition that may put the subject at increased risk with exposure to BOTOX including diagnosed myasthenia gravis, Lambert-Eaton myasthenic syndrome, amyotrophic lateral sclerosis, or any other disorder that might interfere with neuromuscular function.
• Evidence of alcohol abuse, drug abuse, or other relevant neuropsychiatric condition.
• Infection or skin disorder at an anticipated injection site.
• Any condition or situation that, in the investigator's opinion, may put the subject at significant risk, confound the study results (e.g. variable strength on serial testing during screening examination; or foot, toe, or ankle pain that may limit full participation in muscle strength testing), or interfere significantly with the subject's participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Botulinum toxin type A, 20 units; Single intramuscular (into extensor digitorum brevis muscle of the foot) dose of Botulinum toxin type A, 20 units	Drug: Botulinum Toxin, Type A; 20 units, single dose, intramuscular in right EDB muscle; Other Names: BOTOX; Drug: Botulinum Toxin, Type A; 2 units, single dose, intramuscular to right EDB muscle; Other Names: BOTOX
EXPERIMENTAL: Botulinum toxin, type A, 2 units; Single intramuscular (into extensor digitorum brevis muscle of the foot) dose of Botulinum toxin type A, 2 units	Drug: Botulinum Toxin, Type A; 20 units, single dose, intramuscular in right EDB muscle; Other Names: BOTOX; Drug: Botulinum Toxin, Type A; 2 units, single dose, intramuscular to right EDB muscle; Other Names: BOTOX
PLACEBO_COMPARATOR: Placebo; Saline, Single dose, Intramuscular injection into right EDB	Drug: Saline; Single Dose, Intramuscular into right EDB muscle; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Measured Force (Change From Baseline) (Using Strain Gauges) of Dorsiflexion of Digits 2 and 3 ("Force of EDB") After vs. Before Botulinum Toxin Injection Into EDB	The force of dorsiflexion of the combination of digits 2 and 3 (at the same time using a single loop) of the foot were measured using a strain gauge after and before the administration of Botulinum Neurotoxin type A (BoNT/A) or placebo. The baseline value was the mean of the 3 values for force obtained prior to injection of BoNT/A. The baseline was compared with the subsequent values.	Baseline (3 times) then following single injection of botulinum toxin into EDB with testing at Day 1, Day 2, Day 4, Day 14, Day 21, and Month 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stability of Baseline Measurements of Force	The force of dorsiflexion of the combination of digits 2 and 3 (at the same time using a single loop) of the foot were measured using a strain gauge on three different days prior to injection of BoNT/A or placebo. On each of the three days of baseline testing, the force was defined as the mean of three different measurements, separated by at least 1 minute from another measurement.	Baseline 1 (mean of 3 measurement on the same day of testing) compared with Baseline 2 (mean of 3 measurement on the same day of testing) on a second day compared with Baseline 3 (mean of 3 measurement on the same day of testing)
Difference in Force From Day 14 to Day 21	The force of dorsiflexion of the combination of digits 2 and 3 (at the same time using a single loop) of the foot were measured using a strain gauge after and before the administration of Botulinum Neurotoxin type A (BoNT/A). The force at each day of testing was the mean of the 3 values for force obtained on that day. Value is percent change from baseline. Comparison is made between the percent change from baseline force and the force on Day 14 in each group vs. the percent change from baseline force and the force on Day 21 in each group.	Force measured at Day 14 after BoNT/A injction into EDB and Force measured at Day 21 after BoNT/A injction into EDB.
Number of Participants With Serious Adverse Effects to onabotulinumtoxinA (Botulinum Type A Neurotoxin)		At each visit for nerve conduction studies following injection of onabotulinumtoxinA (botulinum type A neurotoxin) into EDB (Day 0; Day 4; Day 14; Month 4)
Correlation in Percent Change of the CMAP (With Standard Reference Electrode Location) From EDB After vs. Before Botulinum Toxin Injection Into EDB vs. Percent Change Surface Electromyography (as Measured by Root Mean Squared With 1000 ms Window).	Measure the percent change of the Compound Muscle Action Potential (CMAP) Amplitude from extensor digitorum brevis (EDB) with the reference electrode in the standard location at the base of the ipsilateral 5th toe after injection of BoNT/A into EDB compared with before injection of BoNT/A. Each CMAP represents the mean of 3 individual measurements of the CMAP at that timepoint. In order to facilitate comparison from one subject to the next, the CMAP is then converted into percent change from baseline for that subject. CMAP percent change is then correlated with the percent change in the Surface Electromyography as measured by the Root Mean Squared with 1000 millisecond window at the same time points after injection. Group with injection of 20 units BoNT/A is used.	Mean of 3 measurements on the same day of testing following single injection of botulinum toxin into EDB with testing at Day 4; Day 14; and Month 4 each compared with Baseline measurement
Percent Change of the Surface Electromyogram (SEMG) MRV-500 From EDB After vs. Before Botulinum Toxin Injection Into EDB.	Measure the percent change of the Surface Electromyogram (SEMG) as measured by the Mean Rectified Voltage (MRV) with a window of 500 ms from extensor digitorum brevis (EDB) with the reference electrode in the standard location at the base of the ipsilateral 5th toe after injection of BoNT/A into EDB compared with before injection of BoNT/A or placebo. Each MRV represents the mean of 3 individual measurements of the MRV at that timepoint with measurements at least 60 seconds apart. In order to facilitate comparison from one subject to the next, the MRV is then converted into percent change from baseline for that subject.	Baseline (mean of 3 measurement on the same day of testing) then following single injection of botulinum toxin into EDB with testing at Day 4; Day 14; and Month 4
Correlation in Percent Change of the CMAP (With Standard Reference Electrode Location) From EDB After vs. Before Botulinum Toxin Injection Into EDB vs. Percent Change Surface Electromyography (as Measured by Root Mean Squared With 500 ms Window).	Measure the percent change of the Compound Muscle Action Potential (CMAP) Amplitude from extensor digitorum brevis (EDB) with the reference electrode in the standard location at the base of the ipsilateral 5th toe after injection of BoNT/A into EDB compared with before injection of BoNT/A. Each CMAP represents the mean of 3 individual measurements of the CMAP at that timepoint. In order to facilitate comparison from one subject to the next, the CMAP is then converted into percent change from baseline for that subject. CMAP percent change is then correlated with the percent change in the Surface Electromyography as measured by the Root Mean Squared with 500 millisecond window at the same time points after injection. Group with injection of 20 units BoNT/A is used.	Mean of 3 measurements on the same day of testing following single injection of botulinum toxin into EDB with testing at Day 4; Day 14; and Month 4 each compared with Baseline measurement
Correlation in Percent Change of the CMAP (With Standard Reference Electrode Location) From EDB After vs. Before Botulinum Toxin Injection Into EDB vs. Percent Change Surface Electromyography (as Measured by Root Mean Squared With 200 ms Window).	Measure the percent change of the Compound Muscle Action Potential (CMAP) Amplitude from extensor digitorum brevis (EDB) with the reference electrode in the standard location at the base of the ipsilateral 5th toe after injection of BoNT/A into EDB compared with before injection of BoNT/A. Each CMAP represents the mean of 3 individual measurements of the CMAP at that timepoint. In order to facilitate comparison from one subject to the next, the CMAP is then converted into percent change from baseline for that subject. CMAP percent change is then correlated with the percent change in the Surface Electromyography as measured by the Root Mean Squared with 200 millisecond window at the same time points after injection. Group with injection of 20 units BoNT/A is used.	Mean of 3 measurements on the same day of testing following single injection of botulinum toxin into EDB with testing at Day 4; Day 14; and Month 4 each compared with Baseline measurement
Correlation in Percent Change of the CMAP (With Standard Reference Electrode Location) From EDB After vs. Before Botulinum Toxin Injection Into EDB vs. Percent Change Surface Electromyography (as Measured by Mean Rectified Voltage With 1000 ms Window).	Measure the percent change of the Compound Muscle Action Potential (CMAP) Amplitude from extensor digitorum brevis (EDB) with the reference electrode in the standard location at the base of the ipsilateral 5th toe after injection of BoNT/A into EDB compared with before injection of BoNT/A. Each CMAP represents the mean of 3 individual measurements of the CMAP at that timepoint. In order to facilitate comparison from one subject to the next, the CMAP is then converted into percent change from baseline for that subject. CMAP percent change is then correlated with the percent change in the Surface Electromyography as measured by the Mean Rectified Voltage with 1000 millisecond window at the same time points after injection. Group with injection of 20 units BoNT/A is used.	Mean of 3 measurements on the same day of testing following single injection of botulinum toxin into EDB with testing at Day 4; Day 14; and Month 4 each compared with Baseline measurement
Correlation in Percent Change of the CMAP (With Standard Reference Electrode Location) From EDB After vs. Before Botulinum Toxin Injection Into EDB vs. Percent Change Surface Electromyography (as Measured by Mean Rectified Voltage With 500 ms Window).	Measure the percent change of the Compound Muscle Action Potential (CMAP) Amplitude from extensor digitorum brevis (EDB) with the reference electrode in the standard location at the base of the ipsilateral 5th toe after injection of BoNT/A into EDB compared with before injection of BoNT/A. Each CMAP represents the mean of 3 individual measurements of the CMAP at that timepoint. In order to facilitate comparison from one subject to the next, the CMAP is then converted into percent change from baseline for that subject. CMAP percent change is then correlated with the percent change in the Surface Electromyography as measured by the Mean Rectified Voltage with 500 millisecond window at the same time points after injection. Group with injection of 20 units BoNT/A is used.	Mean of 3 measurements on the same day of testing following single injection of botulinum toxin into EDB with testing at Day 4; Day 14; and Month 4 each compared with Baseline measurement
Correlation in Percent Change of the CMAP (With Standard Reference Electrode Location) From EDB After vs. Before Botulinum Toxin Injection Into EDB vs. Percent Change Surface Electromyography (as Measured by Mean Rectified Voltage With 200 ms Window).	Measure the percent change of the Compound Muscle Action Potential (CMAP) Amplitude from extensor digitorum brevis (EDB) with the reference electrode in the standard location at the base of the ipsilateral 5th toe after injection of BoNT/A into EDB compared with before injection of BoNT/A. Each CMAP represents the mean of 3 individual measurements of the CMAP at that timepoint. In order to facilitate comparison from one subject to the next, the CMAP is then converted into percent change from baseline for that subject. CMAP percent change is then correlated with the percent change in the Surface Electromyography as measured by the Mean Rectified Voltage with 200 millisecond window at the same time points after injection. Group with injection of 20 units BoNT/A is used.	Mean of 3 measurements on the same day of testing following single injection of botulinum toxin into EDB with testing at Day 4; Day 14; and Month 4 each compared with Baseline measurement
Correlation in Percent Change of the CMAP (With "Inactive" Reference Electrode Location) From EDB After vs. Before Botulinum Toxin Injection Into EDB vs. Percent Change Surface Electromyography (as Measured by Root Mean Squared With 1000 ms Window).	Measure the percent change of the Compound Muscle Action Potential (CMAP) Amplitude from extensor digitorum brevis (EDB) with the reference electrode in an "inactive" location at the ipsilateral medial malleolus after injection of BoNT/A into EDB compared with before injection of BoNT/A. Each CMAP represents the mean of 3 individual measurements of the CMAP at that timepoint. In order to facilitate comparison from one subject to the next, the CMAP is then converted into percent change from baseline for that subject. CMAP percent change is then correlated with the percent change in the Surface Electromyography as measured by the Root Mean Squared with 1000 millisecond window at the same time points after injection. Group with injection of 20 units BoNT/A is used.	Mean of 3 measurements on the same day of testing following single injection of botulinum toxin into EDB with testing at Day 4; Day 14; and Month 4 each compared with Baseline measurement
Correlation in Percent Change of the CMAP (With "Inactive" Reference Electrode Location) From EDB After vs. Before Botulinum Toxin Injection Into EDB vs. Percent Change Surface Electromyography (as Measured by Root Mean Squared With 500 ms Window).	Measure the percent change of the Compound Muscle Action Potential (CMAP) Amplitude from extensor digitorum brevis (EDB) with the reference electrode in an "inactive" location at the ipsilateral medial malleolus after injection of BoNT/A into EDB compared with before injection of BoNT/A. Each CMAP represents the mean of 3 individual measurements of the CMAP at that timepoint. In order to facilitate comparison from one subject to the next, the CMAP is then converted into percent change from baseline for that subject. CMAP percent change is then correlated with the percent change in the Surface Electromyography as measured by the Root Mean Squared with 500 millisecond window at the same time points after injection. Group with injection of 20 units BoNT/A is used.	Mean of 3 measurements on the same day of testing following single injection of botulinum toxin into EDB with testing at Day 4; Day 14; and Month 4 each compared with Baseline measurement
Correlation in Percent Change of the CMAP (With "Inactive" Reference Electrode Location) From EDB After vs. Before Botulinum Toxin Injection Into EDB vs. Percent Change Surface Electromyography (as Measured by Root Mean Squared With 200 ms Window).	Measure the percent change of the Compound Muscle Action Potential (CMAP) Amplitude from extensor digitorum brevis (EDB) with the reference electrode in an "inactive" location at the ipsilateral medial malleolus after injection of BoNT/A into EDB compared with before injection of BoNT/A. Each CMAP represents the mean of 3 individual measurements of the CMAP at that timepoint. In order to facilitate comparison from one subject to the next, the CMAP is then converted into percent change from baseline for that subject. CMAP percent change is then correlated with the percent change in the Surface Electromyography as measured by the Root Mean Squared with 200 millisecond window at the same time points after injection. Group with injection of 20 units BoNT/A is used.	Mean of 3 measurements on the same day of testing following single injection of botulinum toxin into EDB with testing at Day 4; Day 14; and Month 4 each compared with Baseline measurement
Correlation in Percent Change of the CMAP (With "Inactive" Reference Electrode Location) From EDB After vs. Before Botulinum Toxin Injection Into EDB vs. Percent Change Surface Electromyography (as Measured by Mean Rectified Voltage With 1000 ms Window).	Measure the percent change of the Compound Muscle Action Potential (CMAP) Amplitude from extensor digitorum brevis (EDB) with the reference electrode in an "inactive" location at the ipsilateral medial malleolus after injection of BoNT/A into EDB compared with before injection of BoNT/A. Each CMAP represents the mean of 3 individual measurements of the CMAP at that timepoint. In order to facilitate comparison from one subject to the next, the CMAP is then converted into percent change from baseline for that subject. CMAP percent change is then correlated with the percent change in the Surface Electromyography as measured by the Mean Rectified Voltage with 1000 millisecond window at the same time points after injection. Group with injection of 20 units BoNT/A is used.	Mean of 3 measurements on the same day of testing following single injection of botulinum toxin into EDB with testing at Day 4; Day 14; and Month 4 each compared with Baseline measurement
Correlation in Percent Change of the CMAP (With "Inactive" Reference Electrode Location) From EDB After vs. Before Botulinum Toxin Injection Into EDB vs. Percent Change Surface Electromyography (as Measured by Mean Rectified Voltage With 500 ms Window).	Measure the percent change of the Compound Muscle Action Potential (CMAP) Amplitude from extensor digitorum brevis (EDB) with the reference electrode in an "inactive" location at the ipsilateral medial malleolus after injection of BoNT/A into EDB compared with before injection of BoNT/A. Each CMAP represents the mean of 3 individual measurements of the CMAP at that timepoint. In order to facilitate comparison from one subject to the next, the CMAP is then converted into percent change from baseline for that subject. CMAP percent change is then correlated with the percent change in the Surface Electromyography as measured by the Mean Rectified Voltage with 500 millisecond window at the same time points after injection. Group with injection of 20 units BoNT/A is used.	Mean of 3 measurements on the same day of testing following single injection of botulinum toxin into EDB with testing at Day 4; Day 14; and Month 4 each compared with Baseline measurement
Correlation in Percent Change of the CMAP (With "Inactive" Reference Electrode Location) From EDB After vs. Before Botulinum Toxin Injection Into EDB vs. Percent Change Surface Electromyography (as Measured by Mean Rectified Voltage With 200 ms Window).	Measure the percent change of the Compound Muscle Action Potential (CMAP) Amplitude from extensor digitorum brevis (EDB) with the reference electrode in an "inactive" location at the ipsilateral medial malleolus after injection of BoNT/A into EDB compared with before injection of BoNT/A. Each CMAP represents the mean of 3 individual measurements of the CMAP at that timepoint. In order to facilitate comparison from one subject to the next, the CMAP is then converted into percent change from baseline for that subject. CMAP percent change is then correlated with the percent change in the Surface Electromyography as measured by the Mean Rectified Voltage with 200 millisecond window at the same time points after injection. Group with injection of 20 units BoNT/A is used.	Mean of 3 measurements on the same day of testing following single injection of botulinum toxin into EDB with testing at Day 4; Day 14; and Month 4 each compared with Baseline measurement

Collaborators and Investigators

• Sponsor: Loma Linda University
• Collaborators: Allergan
• Investigators: Principal Investigator: Gordon W Peterson, MD, Loma Linda University

Publications and helpful links

General Publications

• Sloop RR, Escutin RO, Matus JA, Cole BA, Peterson GW. Dose-response curve of human extensor digitorum brevis muscle function to intramuscularly injected botulinum toxin type A. Neurology. 1996 May;46(5):1382-6. doi: 10.1212/wnl.46.5.1382.
• Hamjian JA, Walker FO. Serial neurophysiological studies of intramuscular botulinum-A toxin in humans. Muscle Nerve. 1994 Dec;17(12):1385-92. doi: 10.1002/mus.880171207.

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (ACTUAL): March 1, 2009
• Study Completion (ACTUAL): July 1, 2015

Study Registration Dates

• First Submitted: January 12, 2009
• First Submitted That Met QC Criteria: January 13, 2009
• First Posted (ESTIMATE): January 14, 2009

Study Record Updates

• Last Update Posted (ACTUAL): September 5, 2018
• Last Update Submitted That Met QC Criteria: August 6, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Cholinergic Agents; Membrane Transport Modulators; Acetylcholine Release Inhibitors; Neuromuscular Agents; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
• Other Study ID Numbers: 58360

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO