Clinical trial NCT03223298: Botulinum Toxin Versus Placebo Injections to Temporalis and Masseter Muscles
Official title: Comparison of Botulinum Toxin Versus Placebo Injections to Temporalis and Masseter Muscles in the Management of Myofascial Pain Disorder: A Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pain, Head
Pain Syndrome
Temporomandibular Disorder
Myofascial Pain Syndrome
Myofascial Pain
Keywords: Myofascial Pain
Myofascial Pain Disorder
Maxillofacial Pain
Masseter Muscle
Temporalis Muscle
Botulinum Toxin
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
Collaborators: name: New York Presbyterian Hospital
name: Allergan
First posted: 2017-07-21
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

* 18-65 years of age
* Ability to give informed consent
* Myofascial pain of masticatory muscles as defined according to the RDC/TMD criteria
* Baseline pain measured by the subject ≥3.5/10 on visual analog scale

Exclusion Criteria:

* Baseline pain measured by the subject \<3.5/10 on visual analog scale
* Central/Neuropathic pain disorder affecting the masticatory muscles
* Temporomandibular Joint Arthralgia that is more severe than the myofascial pain disorder affecting the masticatory muscles
* Previous Temporomandibular Joint Surgery
* Systemic arthropathies
* Fibromyalgia
* Allergy to study medications
* Traumatic injury of masticatory muscles or temporomandibular joint within last 12 months
* Mandibular fracture within last 12 months
* Pregnancy or breast feeding
* Cervical radiculopathy or surgery
* Prior botox injection in the masticatory muscles
* Initiation of additional treatment of MPD within the past 3 months

Primary outcomes:
measure: Change in Jaw Pain as Reported by Patient on Visual Analog Scale (VAS)
timeFrame: Pre-intervention, Change at 1 month post-intervention, Change at 2 months post-intervention, Change at 3 months post-intervention
Secondary outcomes:
measure: Jaw Function as Measured by Jaw Function Limitation Scale
timeFrame: Pre-intervention, 1 month post-intervention, 2 months post-intervention, 3 months post-intervention
measure: Change in Jaw Function as Measured by Maximum Interincisal Opening (MIO)
timeFrame: Pre-intervention, Change at 1 month post-intervention, Change at 2 months post-intervention, Change at 3 months post-intervention
measure: Change in Objectively Assessed Quality of Life as Measured by Short Form 36
timeFrame: Pre-intervention, Change at 1 month post-intervention, Change at 2 months post-intervention, Change at 3 months post-intervention
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Illinois at Chicago
state: Illinois
city: New York
country: United States
facility: Weill Cornell Medical College - NewYork-Presbyterian Hospital
state: New York
Study officials:
affiliation: Weill Medical College of Cornell University
name: Gwendolyn S Reeve, DMD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Illinois at Chicago
name: Michael Miloro, DMD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Botulinum Toxin A for Myofascial Pain Syndrome: A Review of the Clinical Effectiveness [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2014 Sep 22. Available from http://www.ncbi.nlm.nih.gov/books/NBK253364/
citation: Freund B, Schwartz M, Symington JM. Botulinum toxin: new treatment for temporomandibular disorders. Br J Oral Maxillofac Surg. 2000 Oct;38(5):466-71. doi: 10.1054/bjom.1999.0238.
citation: Freund B, Schwartz M, Symington JM. The use of botulinum toxin for the treatment of temporomandibular disorders: preliminary findings. J Oral Maxillofac Surg. 1999 Aug;57(8):916-20; discussion 920-1. doi: 10.1016/s0278-2391(99)90007-1.
citation: Guarda-Nardini L, Stecco A, Stecco C, Masiero S, Manfredini D. Myofascial pain of the jaw muscles: comparison of short-term effectiveness of botulinum toxin injections and fascial manipulation technique. Cranio. 2012 Apr;30(2):95-102. doi: 10.1179/crn.2012.014.
citation: Soares A, Andriolo RB, Atallah AN, da Silva EM. Botulinum toxin for myofascial pain syndromes in adults. Cochrane Database Syst Rev. 2014 Jul 25;2014(7):CD007533. doi: 10.1002/14651858.CD007533.pub3.
citation: von Lindern JJ, Niederhagen B, Berge S, Appel T. Type A botulinum toxin in the treatment of chronic facial pain associated with masticatory hyperactivity. J Oral Maxillofac Surg. 2003 Jul;61(7):774-8. doi: 10.1016/s0278-2391(03)00153-8.