Botulinum Toxin Versus Placebo Injections to Temporalis and Masseter Muscles
Condition: Pain, Head; Pain Syndrome; Temporomandibular Disorder; Myofascial Pain Syndrome; Myofascial Pain
MeSH terms: Myofascial Pain Syndromes; Temporomandibular Joint Disorders; Temporomandibular Joint Dysfunction Syndrome; Fibromyalgia; Syndrome; Headache; Somatoform Disorders
Study type: Interventional
Phase: Phase 3

Summary: 
      This study aims to determine whether the injection of botulinum toxin A or placebo
      (unpreserved 0.9% sodium chloride) into the masseter and temporalis muscles provides pain
      relief and improved jaw function in those who suffer from myofascial pain disorder. The study
      hypothesis is that botulinum toxin A injection is superior to placebo. The specific research
      questions are:

        1. Is the injection of botulinum toxin A superior to placebo for the improvement in pain?

        2. Is the injection of botulinum toxin A superior to placebo for the improvement in
           function or quality of life (QOL)?

        3. Are there any adverse effects that result from injection of botulinum toxin A or placebo
           into the masseters and temporalis muscles? Limited data exists to support the use of
           botulinum toxin A in the management of myofascial pain disorder of the masticatory
           region. Botulinum toxin A is not FDA approved for intra-muscular injection within the
           masticatory region. Its use in the masticatory region is considered off-label but
           performed without significant known complications. This study will provide the
           opportunity to quantitate and qualitate any complications in a large prospective sample
           of patients.
    

Detailed description: 
      Myofascial pain is classically used to describe pain experienced in the masticatory muscles
      and its associated structures (Freund 1999). It afflicts nearly 10% of Americans (Freund
      2000). There have been many described treatments such as the use of oral appliances,
      non-steroidal anti-inflammatory medications, physiotherapy, behavioral therapy and
      counseling, acupuncture, and botulinum toxin injections (Freund 2000). However, no single
      treatment has been found to be significantly superior to the others (Freund 2000).

      This is a randomized, double-blind, placebo-controlled multicenter study. Subjects will be
      recruited from the divisions of Oral and Maxillofacial Surgery from all sites. Patients aged
      18-65 years with myofascial pain involving the temporalis and masseters are eligible to enter
      the study. A complete history and physical examination will be performed for all patients in
      order to make an accurate diagnosis. The research diagnostic criteria (RDC/TMD) will be used
      to assign a diagnosis of myofascial pain of the masticatory region. All investigators and
      site-specific data collectors will be trained and calibrated in physical examination
      techniques and data collection to ensure uniformity between sites. Patients will complete a
      visual analog scale regarding pain during their screening appointment. To participate in the
      study, the subject must have greater than or equal to 3.5/10 on the visual analog scale of
      pain. Informed written consent will be obtained from all patients. Any patient lacking the
      capacity to make medical decisions will be excluded from the study, although they will be
      treated as deemed medically necessary. Consent will be written at the sixth grade level, and
      all potential subjects will be asked to verbally repeat the purpose, methods, and required
      follow-up to ensure adequate understanding.

      The site specific PI will educate fellow faculty and referring departments that the study is
      enrolling new subjects, advertising is anticipated, and referring physicians will not receive
      any financial compensation. The intent is to enroll a total of 110 subjects from all sites.
      The study participants will be reimbursed $25 per treatment visit for their participation.

      Previous studies have demonstrated a reduction of pain as indicated on the visual analogue
      scale of 45% and 32% with the use of intramuscular botulinum toxin A injections into masseter
      and temporalis (Freund 1999, Guarda-Nardini 2012). Von Lindern et. al. found a mean reduction
      of 3.2 points on a visual analog scale in the verum group. Based on the preliminary data and
      the sample size calculations estimating a difference in mean pre-post VAS change between
      groups of 1 point or greater (on a scale of 1-10), we plan to enroll a total of 110 subjects.
      With 50 patients in the botulinum toxin A injection group and 50 patients in the placebo
      group (N=100), the study will have more than 90% power to detect a difference in mean in
      pre-post change between groups of 1.0 point or greater on VAS, using a two-sided t-test and
      assuming a standard deviation of 1.5 for the mean difference. This calculation allows for 10%
      attrition rate. An intent-to-treat design will be followed and all subjects will have
      scheduled outcome evaluations until the end of the study, death of the subject, or subject
      refusal. Subjects will be withdrawn from their randomly assigned treatment for considerations
      of subject safety only.

      Descriptive statistics including mean, standard deviation, median, range, frequency, and
      percent will be calculated for the entire cohort as well as by the study arm (botulinum toxin
      A and unpreserved 0.9% sodium chloride) to assess the results of randomization and identify
      potential confounders. The primary analyses of the data will be performed according to
      subjects' original treatment assignment (i.e., intention-to-treat analyses) and the inclusion
      of all data from all subjects randomized in the final analysis. To assess the primary
      endpoint of improvement of pain on a visual analog scale (VAS) between pre-op, 1, 2, and
      month post-op, and 3 months post-op, a repeated measure of analysis of variance will be
      performed with one between subject factor (botulinum toxin A versus placebo) and one within
      subject factor (time). This analysis will also be used for the secondary endpoints: function
      (MIO/jaw limitation scale) and quality of life (SF12). In the event of significant loss to
      follow-up, we will explore the use of a linear mixed model to assess the independent effect
      of the study group on VAS over the study visits. The paired t-test, or the signed-rank test
      as appropriate, will be used to assess change in pain, function, and QOL between pairs of
      relevant time points for both study arms. To assess the difference in proportion of adverse
      events between the botulinum toxin A and placebo groups, either the chi-square or Fisher's
      exact test will be used, as appropriate. All p-values will be two-sided with statistical
      significance evaluated at the 0.05 alpha level. Ninety-five percent confidence intervals (95%
      CI) will be calculated to assess the precision of the obtained estimates. All analyses will
      be performed in SAS Version 9.4 (SAS Institute Inc., Cary, NC). Note: This section was
      drafted in conjunction with Dr. Paul Christos and Gulce Askin, MPH in the Division of
      Biostatistics and Epidemiology, Department of Healthcare Policy and Research. They will be
      aiding in protocol design and development, data management, study implementation, study
      monitoring, and data analysis and reporting.

      Adverse events will be reported to the Data and Safety Monitoring Board every six months. The
      participants will be provided with the phone number of the primary investigator and
      co-investigators for use in reporting any adverse events. The study participants will also be
      questioned at one, two, and and three months post-treatment for the occurrence of any adverse
      events. The report of any such events will provide details including severity, relationship
      to treatment, onset, duration, and outcome. The Data and Safety Monitoring Board will
      regularly review these reports, and should any trend develop that suggests significant
      adverse outcomes, the study will be discontinued. If any serious adverse events occur (death,
      life-threatening, those involving prolonged hospitalization or disability), the independent
      study monitor, other study sites, IRBs, and DSMB will be notified with 24 hours in the case
      of death or 72 hours in the event of other serious adverse events.

      IRB approval for this study is currently in process (assigned protocol number 1607017383).
      Pending approval from the IRB for each involved site, research investigators will honor their
      responsibility to safeguard the rights and welfare of individuals who are or may become
      subjects of research. Investigators will also maintain compliance with Department of Health
      and Human Services regulations. All requirements and determinations made by the IRB will be
      followed to minimize unnecessary risks to subjects. The investigators will abide by
      procedures consistent with sound research design. Botulinum toxin A is currently not FDA
      approved for use in myofascial pain disorder of the masticatory region. If the IRB deems its
      use a "subject risk," an application for investigational new drug (IND) will be submitted to
      the FDA under the research or noncommercial category. This requirement is not anticipated
      given the routine use of botulinum toxin A, previous studies demonstrating benefit with
      minimal risk, and its existing FDA approval for use in the masseter and temporalis muscles
      for orofacial dystonia/dyskinesia.
    

Intervention name(s): Botulinum toxin type A; 0.9% Sodium Chloride Injection
Intervention type(s): Drug; Drug
Intervention description(s): 37.5 units injected into each masseter muscle and 12.5 units into each temporalis muscle; 1cc syringe
Other intervention name(s): Botulinum; Botox; Allergan; Botulinum Toxin A; Saline; Placebo
Intervention MeSH terms: Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Study participants will be randomly allocated to one of two treatment arms (injection of botulinum versus placebo). Blocked randomization will be performed at each of the participating sites. They will be stratified based on study site.
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Myofascial Pain; Myofascial Pain Disorder; Maxillofacial Pain; Masseter Muscle; Temporalis Muscle; Botulinum Toxin