Botulinum Toxin Versus Placebo Injections to Temporalis and Masseter Muscles

NCT ID: NCT03223298

Last Updated: 2023-02-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-08-31
• Study Completion Date: 2020-03-13

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.

Conditions

Pain, Head; Pain Syndrome; Temporomandibular Disorder; Myofascial Pain Syndrome; Myofascial Pain

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Botulinum Toxin Type A

The intramuscular injections will be performed with the patient awake in the oral and maxillofacial surgery clinic. Three injection sites into bilateral masseter muscles and two injection sites into bilateral temporalis muscles will be identified by having the patient clench. The sites will be marked with a surgical pen prior to injections. The skin at the injection sites will be cleaned with an alcohol swab. Via a 1cc TB syringe and a 30-gauge needle, the subject will then receive 100 units of reconstituted botulinum toxin A. 37.5 units will be injected into each masseter muscle and 12.5 units into each temporalis muscle. A written post-operative instruction sheet will be provided to all patients.

Group Type: EXPERIMENTAL

Botulinum toxin type A

Intervention Type: DRUG

37.5 units injected into each masseter muscle and 12.5 units into each temporalis muscle

0.9% Sodium Chloride Injection

The intramuscular injections will be performed with the patient awake in the oral and maxillofacial surgery clinic. Three injection sites into bilateral masseter muscles and two injection sites into bilateral temporalis muscles will be identified by having the patient clench. The sites will be marked with a surgical pen prior to injections. The skin at the injection sites will be cleaned with an alcohol swab. Via a 1cc TB syringe and a 30-gauge needle, the subject will then receive unpreserved 0.9% sodium chloride. A written post-operative instruction sheet will be provided to all patients.

Group Type: PLACEBO_COMPARATOR

0.9% Sodium Chloride Injection

Intervention Type: DRUG

1cc syringe

Interventions

Botulinum toxin type A

37.5 units injected into each masseter muscle and 12.5 units into each temporalis muscle

Intervention Type: DRUG

0.9% Sodium Chloride Injection

1cc syringe

Intervention Type: DRUG

Other Intervention Names

Botulinum; Botox; Allergan; Botulinum Toxin A; Saline; Placebo

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

New York Presbyterian Hospital

OTHER

Sponsor Role: collaborator

Allergan

INDUSTRY

Sponsor Role: collaborator

Weill Medical College of Cornell University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Gwendolyn S Reeve, DMD

Role: PRINCIPAL_INVESTIGATOR

Weill Medical College of Cornell University

Michael Miloro, DMD

Role: PRINCIPAL_INVESTIGATOR

University of Illinois at Chicago

Locations

University of Illinois at Chicago

Chicago, Illinois, United States

Weill Cornell Medical College - NewYork-Presbyterian Hospital

New York, New York, United States

Countries

United States

References

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/

Reference Type: BACKGROUND

PMID: 25392894 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11010775 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 10437718 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22606852 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25062018 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12856249 (View on PubMed)

Reeve GS, Insel O, Thomas C, Houle AN, Miloro M. Does the Use of Botulinum Toxin in Treatment of Myofascial Pain Disorder of the Masseters and Temporalis Muscles Reduce Pain, Improve Function, or Enhance Quality of Life? J Oral Maxillofac Surg. 2024 Apr;82(4):393-401. doi: 10.1016/j.joms.2023.12.014. Epub 2023 Dec 28.

Reference Type: DERIVED

PMID: 38228287 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

1607017383

Identifier Type: -

Identifier Source: org_study_id