Erenumab-aooe for Temporomandibular Disorders Management: TMD Cgrp Antibody RElief (TMD CARE)

Study Overview
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Brief Summary
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Evaluate erenumab- aooe efficacy as a therapeutic approach, for the management of painful chronic temporomandibular disorders (TMD). The study will be a randomized, double blind, placebo-controlled trial comparing erenumab-aooe vs Placebo. A total of 60 patients (30 per each arm) aged 18-65 years old of either sex, and any race or ethnicity presenting chronic temporomandibular disorders (TMD), (meeting the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for Clinical and Research Applications of chronic TMD (myalgia +/- arthralgia) will be randomly assigned in a 1:1 parallel, double-blind clinical trial, to receive either erenumab-aooe or placebo. Participants will attend 6 clinic visits (Visit 0-Visit 5) over a period of 21 weeks (20 +/- 1 weeks). Changes in pain intensity and other pain outcomes related to TMD will be assessed. Blood samples will be collected, and participants will need to keep a daily symptom diary and answer some other questionnaires.

Detailed Description
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Chronic TMD is a considerable burden and affects significantly the quality of life of the sufferer. For some patients, TMD has a tendency to remit or improve pain symptomatology over time but for others, TMD have the potential to become chronic and to lead to persistent dysfunction. Different classes of medications from anti-inflammatories, muscle relaxants, anxiolytics, antidepressants, anticonvulsants and a β-blocker have indicated to be beneficial for some patients as well as in clinical studies, but tolerability and side effects may be present for some patients. Furthermore, the indications of these drugs are for other disorders, so it is unclear their mechanism of action in TMD pathophysiology. Currently there is no medication specifically indicated for the management of TMD based on its molecular pathophysiology. However, there is evidence showing that CGRP has a role in TMD pathophysiology. CGRP is a key molecule in migraine pathophysiology. Erenumab-aooe is the first antibody therapeutic targeting the CGRP and has shown efficacy, to be well tolerated and with a safety profile similar to placebo for the prevention of migraine. The scientific premise for this study is that inhibiting CGRP in chronic TMD will decrease pain, pain related outcomes and improve TMJ biomechanics (function) in a safe and well tolerated manner for this patient population. Potential participants will be pre-screened at the Brotman Facial Pain clinic and the Oral and Maxillofacial Surgery Clinic both at the University of Maryland, School of Dentistry or by telephone; those willing to participate will be scheduled for a screening and baseline visit (Visit 0). During this visit potential participants will be evaluated for eligibility (meeting the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for Clinical and Research Applications) of chronic TMD (myalgia +/- arthralgia) and written informed consent will be obtained. The screening and baseline procedures include medical history review, clinical examinations, tests and administration of questionnaires. After screening, eligible participants will start Visit 0/Day 0 which is the start of the baseline period with a duration of 28 days/4 weeks. Instructions will be given for the completion of a Daily Symptom Diary (DSD) and other questionnaires at home or online. Participants who show 80% compliance with the DSD and who meet the pain score (inclusion criteria) during the baseline period, will be randomly assigned to one of two groups either the investigational drug or placebo and will be scheduled for Visit 1. Visit 1 can occur within 7 days/1 week after the baseline period (+/- 7 days). The study drug is erenumab-aooe 70mg, SC injection. Participants will attend 6 clinic visits (Visit 0-Visit 5) over a period of 21 weeks (20 +/- 1 weeks) or 140 +/- 7 days. After randomization and on Visit 1 (Week 4/Day 28), the participant will receive the drug or placebo. This same treatment will be administered once a month for 3 months (3 cycles/12 weeks). It will be administered on Visit 1/Day 28/Week 4; Visit 2/Day 56/Week 8; and Visit 3/Day 84/week 12. On Visit 0 (baseline) and on Visit 1, Visit 2, Visit 3, Visit 4/Day 112/Week 16 and visit 5/Day 140/Week 20, visits will include review of compliance with inclusion criteria, medical history review, review and collection of any adverse event, clinical examinations, questionnaires, tests, blood sample collection on Baseline/Visit 0 and Visit 4; and instruction to complete the DSD and questionnaires.

Official Title
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Erenumab as a Therapeutic Approach for the Management of Painful Chronic Temporomandibular Disorders (TMD)

Conditions
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Temporomandibular Disorders

Intervention / Treatment
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* Drug: Erenumab-Aooe 70 MG in 1 mL Prefilled Syringe
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to be eligible to participate in this study, an individual must meet all of the following criteria: Provide signed and dated informed consent form Is between 18 and 65 years of age (inclusive; male or female and any race or ethnicity) Meets diagnostic criteria for TMD: Myalgia with or without arthralgia • The participant must meet 2 criteria relating: 1) reported pain, ache or tenderness in the face, jaw/mandible, pre-auricular area, inside the ear or temple that it is modified by TMJ biomechanics. 2) finding(s) of TMD myalgia according to the classification DC/TMD criteria. Has experienced facial pain and/or pain with TMJ biomechanics for the last 3 months episodically or unremitting Has experienced facial pain for at least 10 days of the last 30 days prior to Baseline Visit (Visit 0) Prior to randomization, has been compliant 80% with the entries in the Daily Symptom Diary within the baseline period and reported an average pain level ≥30 on a numerical rating scale (0-100) in the DSD, or has experienced a pain level ≥30 on the same scale for at least 3 days in the week prior to Visit 1. If taking a prescription medication daily for the management of pain (taken for at least 30 days before baseline), agrees to continue the daily use of the medication throughout the study at the same dosage. If taking prescription medication, opioid medication or OTC medications as needed or episodically for the management of TMD pain agrees to discontinue its use prior to the Screening and Baseline Visit. Rescue medications will be defined as allowable over-the-counter analgesics used for treatment of TMD pain. In case a patient presents pain during the study, only it is allowed the use of OTC medications as a rescue and as described on section 6.6.3: Participants use of short-acting non-prescription analgesics such as NSAIDs, acetaminophen or aspirin during the study, will be recorded and quantified at each visit, and the usage will be classified as either episodic or daily. Episodic use of non-prescription analgesics will be defined as use for no more than 2 consecutive days and for no more than 18 days from baseline to visit 4. This type of analgesics should not be used for more than 2 days a week prior to Baseline and a week prior to visit 4, when the exploratory outcome is assessed (cytokine release assay). If taking OTC pain medications daily agrees to continue its daily use at the same dosage throughout the study. • If a participant is taking an over-the-counter medication daily for management of other type of pain or for prophylaxis of myocardial infarction or stroke, the participant will be encouraged to continue the same usage of that medication throughout the study. Agrees to not start any new prescription medication for the management of pain throughout the study Agrees to not start any injection therapy for the management of TMD (trigger point injections, steroid injections, Botox) during the course of the study Agrees to not use acupuncture for the management of pain during the course of the study Agrees to not have Physical therapy for the management of TMD during the course of the study. Agrees to not start intraoral appliance therapy during the course of the study. If the patient has used a nightguard for more than one month before the study, agrees to continue use it only at night. Females of childbearing potential agree to use one of the following methods of contraception throughout the study: licensed hormonal method, intrauterine device, female or male condoms with contraceptive foam, abstinence, bilateral tubal ligation/occlusion, or vasectomy in partner (if postmenopausal, must not have menstruated for at least 12 consecutive months) Willing and able to understand and comply with all study procedures and be available for the duration of the study Exclusion Criteria: Participants with a history of congestive heart failure, rheumatoid arthritis or uncontrolled diabetes. Participants with serious hepatic, respiratory, hematologic or immunologic illnesses, an unstable cardiovascular disease, or any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with trial participation or Erenumab or may interfere with the interpretation of trial results and, in the judgment of the investigator, would make the participant inappropriate for entry into this trial Participants with high blood pressure, history of abnormal electrocardiograms, history of heart conductance defects, malignant disease, chronic constipation, IBSc or any other severe acute or chronic medical or psychiatric condition or laboratory finding that may increase the risk associated with trial participation with Erenumab Participants with active malignancy of any type or a history a malignancy (with exception of participants with malignancy surgically removed with no evidence of recurrence within 5 years before enrollment. History of facial trauma or orofacial or orthognathic surgery within the previous 6 months Patients with dental pain Patients with trigeminal neuralgia or other neuropathic pain in the craniofacial area Patients with degenerative joint disease in the TMJs, rheumatoid arthritis or any systemic arthritis Patients with chronic migraine with and w/o aura following the ICHD-3 criteria treated or not treated with medication • Without excluding headache attributed to TMD Participants currently taking or have previously taken Erenumab or other CGRP monoclonal antibody (mAmb) or currently taking a CGRP-Receptor antagonist (gepants) for migraine prevention. CGRP-Receptor antagonist (gepants) for acute use for migraine are allowed. Patients with hypersensitivity to Erenumab Patients who have received the Botox injection protocol in the masseters and/or Migraine protocol within 3 months prior screening and baseline visit. Used injections for management of TMD (trigger point injections, steroid injections) within 2 weeks prior to the Screening and Baseline Visit Has commenced a new daily prescription medication for the management of pain within 30 days prior to the Screening and Baseline Visit Has commenced intraoral appliance therapy for the management of facial pain within 30 days prior to the Screening and Baseline Visit Patient currently undergoing active orthodontic treatment (passive retainers are permitted) Treatment for drug or alcohol abuse within the last year Has been treated with another investigational drug or treatment within 30 days prior to the Screening and Baseline Visit Patients sensitive to Latex Patient is pregnant, planning to become pregnant or breastfeeding Anything that, in the opinion of the investigator, would place the participant at increased risk or impede the participant's full compliance with or completion of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Erenumab-aooe<br>Erenumab-aooe 70 mg/ml. Subcutaneous injection. Administered once every 4 weeks/28 days at visit 1, visit 2 and visit 3 for a total of 3 cycles. Other Name: Aimovig® | Drug: Erenumab-Aooe 70 MG in 1 mL Prefilled Syringe<br>* Administered once every 4 weeks/28 days at visit 1, visit 2 and visit 3 for a total of 3 cycles.<br>* Other names: Aimovig;|
| Placebo Comparator: Placebo<br>Placebo. Subcutaneous injection.Administered once every 4 weeks/28 days at visit 1, visit 2 and visit 3 for a total of 3 cycles. Other name: Placebo | Drug: Placebo<br>* Administered once every 4 weeks/28 days at visit 1, visit 2 and visit 3 for a total of 3 cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of >= 30% reduction in the monthly average pain score from baseline to Visit 4, compared to placebo. | Assessment of the efficacy of erenumab-aooe in the proportion of participants that achieve >=30% reduction (Yes/no) in monthly average pain score from baseline to Visit 4 (the end of last monthly treatment cycle), compared to placebo. The daily pain intensity score will be measured on a 0-100 numeric rating scale (NRS) and reported in the Daily Symptom Diary (DSD). The monthly mean pain intensity score will be determined from baseline, Visit 1/Day 28/Week 4, Visit 2/Day 56/Week 8, Visit 3/Day 84/week 12 and Visit 4/Day 112/Week 16. | From Visit 0 (Baseline phase/study day 0) to Visit 4 (study day 112) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of >= 50% reduction in monthly TMD pain days, compared to placebo. | Assessment of the efficacy of erenumab-aooe in the proportion of participants with at least a 50% reduction (Yes/No) in monthly TMD days from baseline to Visit 5 (follow up/final visit). Definition of TMD pain day: A TMD pain day was any calendar day in which the participant experienced pain, stiffness, soreness, tenderness, in the jaw or temple area or either side being brief or continuous; and/or pain with TMJ biomechanics (chewing, mouth opening or any jaw movement; and/or pain with jaw activities (yawning, kissing, talking); and/or pain with jaw habits (chewing gum, clenching, grinding). | From Visit 0 (Baseline phase/study day 0) to Visit 5 (study day 140 +/- 7) | 
| Change of >= 30% reduction in the monthly average pain score compared to placebo from baseline to Visit 5. | Assessment of the efficacy of erenumab-aooe in the proportion of participants who achieved a least 30% reduction in the monthly average daily pain score from baseline to Visit 5 (follow up and final study visit). The monthly mean pain intensity score will be determined from baseline, Visit 1/Day 28/Week 4, Visit 2/Day 56/Week 8, Visit 3/Day 84/week 12, Visit 4/Day 112/Week 16 and Visit 5/Day 140/Week 20. | From Visit 0 (Baseline phase/study day 0) to Visit 5 (Study day 140 +/- 7) | 
| Change in Pressure Pain Threshold (PPT) measurement in muscles of mastication (temporalis muscle) compared to placebo from baseline to Visit 5. | Assessments of pressure stimuli will be performed in the temporalis muscle and averaged to obtain a single pressure pain threshold value (kPa) per site. This assessment will be performed bilaterally in each temporalis muscle. A higher value means a better outcome. | Visit 0 (baseline/study day 0) to Visit 5/Week 20 (Study day 140 +/- 7) | 
| Change in Pressure Pain Threshold (PPT) measurement in muscles of mastication (masseter muscle) compared to placebo from baseline to Visit 5. | Assessments of pressure stimuli will be performed in the masseter muscle and averaged to obtain a single pressure pain threshold value (kPa) per site. This assessment will be performed bilaterally in each masseter muscle. A higher PPT value means a better outcome. | Visit 0 (baseline/study day 0) to Visit 5/Week 20 (Study day 140 +/- 7) | 
| Change in Pressure Pain Threshold (PPT) measurement in upper trapezius muscle compared to placebo from baseline to Visit 5. | Assessments of pressure stimuli will be performed in the upper trapezius muscle and averaged to obtain a single pressure pain threshold value (kPa) per site (R/L side). This assessment will be performed bilaterally. A higher PPT value means a better outcome. | Visit 0 (baseline/study day 0) to Visit 5/Week 20 (Study day 140 +/- 7) | 
| Change in Pressure Pain Threshold (PPT) measurement in the temporomandibular joint (TMJ) compared to placebo from baseline to Visit 5. | Assessments of pressure stimuli will be performed in the TMJ and averaged to obtain a single pressure pain threshold value (kPa) per site. This assessment will be performed bilaterally. A higher PPT value means a better outcome. | Visit 0 (baseline/study day 0) to Visit 5/Week 20 (Study day 140 +/- 7) | 
| Change in Pressure Pain Threshold (PPT) measurement at the lateral epicondyle compared to placebo from baseline to Visit 5. | Assessments of pressure stimuli will be applied bilaterally in the right and left lateral epicondyles and averaged to obtain a single pressure pain threshold value (kPa) per site. A higher PPT value means a better outcome. | Visit 0 (baseline/study day 0) to Visit 5/Week 20 (Study day 140 +/- 7) | 
| Change in maximum unassisted jaw opening during erenumab-aooe treatment, after treatment and compared to placebo. | Measured during TMD examination. A higher value means a better outcome | Visit 0 (baseline/study day 0) to Visit 5/Week 20 (Study day 140 +/- 7) | 
| Change in maximum pain free opening during erenumab-aooe treatment, after treatment and compared to placebo. | Measured during TMD examination. A higher value means a better outcome | Visit 0 (baseline/study day 0) to Visit 5/week 20 (Study day 140 +/- 7) | 
| Change in maximum assisted/active opening during erenumab-aooe treatment, after treatment and compared to placebo. | Measured during TMD examination. A higher value means a better outcome | Visit 0 (baseline/study day 0) to Visit 5/Week 20 (Study day 140 +/- 7) | 
| Change in the Jaw Functional Limitation Scale (JFLS) global score during erenumab-aooe treatment, after treatment and compared to placebo. | The JFLS is a 20-item instrument that measures limitations across 3 domains related to TMJ biomechanics: masticatory function, jaw opening (vertical mobility), and verbal and emotional expression. A degree of limitation is rated on a 0-10 scale from 0 (no limitation) to 10 (severe limitation) | Visit 0 (baseline/study day 0) to Visit 5/Week 20 (Study day 140 +/- 7) | 
| Change in the frequency of oral behaviors evaluated by the oral behaviors checklist (OBC) during erenumab-aooe treatment, after treatment and compared to placebo. | The Oral Behaviors Checklist (OBC) evaluates parafunctional behaviors and generates a single scale representing the frequency of 21 activities such as clenching, chewing gum, and holding objects between teeth, yawning. | Visit 0 (baseline/study day 0) to Visit 5/Week 20 (Study day 140 +/- 7) | 
| Change in Graded Chronic Pain Scale (GCPS) outcomes during erenumab-aooe treatment, after treatment and compared to placebo. | The GCPS includes 7 items and assesses 2 dimensions of pain, pain intensity and pain-related disability. A higher grade means a worse outcome. | Visit 0 (baseline/study day 0) to Visit 5/Week 20 (Study day 140 +/- 7) | 
| Change in impression of overall status measured by the Patient Global Impression of Change (PGIC) during erenumab-aooe treatment, after treatment and compared to placebo. | The PGIC measures change in participant's overall status on a scale ranging from 1 (very much improved) to 7 (very much worse). | Visit 0 (baseline/study day 0) to Visit 5/Week 20 (Study day 140 +/- 7) | 
| Change in the Hospital Anxiety and Depression Scale (HADS). Anxiety and Depression score change during erenumab-aooe treatment, after treatment and compared to placebo. | The HADS evaluates anxiety (7 items) and depression (7 items) with a 14-item instrument assessing symptoms on a 4-point scale rated from 0 not at all to 3 very often indeed. Responses provide separate scores for anxiety and depression. A higher score means a worse outcome. | Visit 0 (baseline/study day 0) to Visit 5/Week 20 (Study day 140 +/- 7) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Erenumab, Craniomandibular Disorders, Temporomandibular Joint Dysfunction Syndrome, Temporomandibular Joint Disorders, Myofascial Pain Syndromes, Physiological Effects of Drugs, Calcitonin Gene-Related Peptide Receptor Antagonists, Neuropeptides, CGRP Receptor Antagonist, Stomatognathic Diseases, Musculoskeletal Diseases