Erenumab-aooe for the Management of Trigeminal Neuropathic Pain.

Study Overview
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Brief Summary
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This study is a single center, placebo-controlled, double blind, randomized, phase II pilot to evaluate the efficacy of erenumab-aooe in the management of trigeminal neuropathic pain comparing erenumab-aooe vs Placebo. A total of 40 patients (20 each arm) aged 18-65 years old of either sex, and any race or ethnicity, presenting trigeminal neuropathic pain will be randomly assigned in a 1:1 parallel, double-blind clinical trial, to receive either Erenumab or placebo. Participants will attend 6 clinic visits (Visit 0-Visit 5) over a period of 21 weeks. Changes in pain intensity and other pain related outcomes of trigeminal neuropathic pain 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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TNP are a considerable burden and affects significantly the quality of life of the sufferer. There are medications for their management but while they may work for some patients, may not work for the others; in addition, side effects may be present for some patients with the need to decrease dosage to not optimal levels. Furthermore, the indications of these drugs are for other neuropathic pain disorders and currently there is no medication specifically indicated for the management of TNP based on its molecular pathophysiology. The calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in migraine pathophysiology. There is evidence showing that CGRP has a role in other disorders mediated by the trigeminal system in addition to migraine; CGRP has shown to have a role in orofacial pain such as in TMD and in trigeminal neuropathic pain. Erenumab-aooe is the first antibody therapeutic targeting the CGRP receptor with FDA approval for migraine prevention that is well tolerated and with a good safety profile. Therefore, the scientific premise for this study is that inhibiting the CGRP pathway in trigeminal neuropathic pain will decrease pain and pain related outcomes in a safe and well tolerated manner for this patient population. Potential participants will be pre-screened at the Brotman Facial Pain clinic, at the Oral and Maxillofacial Surgery Clinic both at the University of Maryland, School of Dentistry, at the Pain Medicine Clinic at the University of Maryland, School of Medicine 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 for trigeminal neuropathic pain (subjects with diagnosis based on the International classification of headache disorders ICHD-3 and International classification of Orofacial Pains ICOP of idiopathic trigeminal neuralgia with concomitant continuous pain, painful posttraumatic trigeminal neuropathy or idiopathic painful trigeminal neuropathy) and written informed consent will be obtained. The screening and baseline procedures include medical history review, clinical examinations, tests and administration of questionnaires. Instructions will be given for the completion of a Daily Symptom Diary (DSD) and other questionnaires at home or online. Participants who show compliance with 80 % completion of the DSD and who meet the pain score (inclusion criteria) for 4 weeks/28 days during the baseline period from Visit 0, will be randomly assigned to one of two groups either the investigational drug or placebo and will be scheduled for Visit 1. The study drug is Erenumab 140 mg, SC injection. Participants will attend 6 clinic visits (Visit 0-Visit 5). After randomization and on Visit 1, the participant will receive the drug or placebo. This same treatment will be administered once a month for 3 months (3 cycles/12weeks).

Official Title
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Erenumab as a Therapeutic Approach for the Management of Trigeminal Neuropathic Pain (TNP)

Conditions
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Trigeminal Neuropathy

Intervention / Treatment
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* Drug: Erenumab-Aooe
* Other: 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) Trigeminal neuropathic pain symptoms for a minimum of 3 months prior to randomization visit, localized in any trigeminal distribution (intraoral or extraoral). Meets diagnostic criteria for Trigeminal neuropathic pain with diagnosis based on the International classification of headache disorders ICHD-3 and International classification of Orofacial Pains ICOP. Diagnosed with idiopathic trigeminal neuralgia with concomitant continuous pain per ICDH-3. Diagnosed with Painful posttraumatic trigeminal neuropathy or idiopathic painful trigeminal neuropathy per ICOP. May include: Subjects with a history of persistent pain of idiopathic origin or after dental extractions, mandibular fracture, surgical procedure, implant procedure and root canal therapy. Participants must have a minimum mean of average daily pain intensity score of 4/10 in where 0= no pain and 10= maximum pain imaginable on a numerical rating scale (0-10), during the 4 weeks/28 days baseline period prior randomization. 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 pain agrees to discontinue its use prior to the Screening and Baseline Visit. 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. If subjects diagnosed with migraine, are allowed only if episodic, with attacks of duration up to 5 days/month and only using triptans or NSAIDs as an abortive medication. Agrees to not start any new prescription medication for the management of trigeminal neuropathic pain or other type of pain throughout the study. Agrees to not modify their prescription regimen for current trigeminal neuropathic pain or other types of pain throughout the study Agrees not to receive any injection therapy for the management of neuropathic pain or migraine (e.g. nerve blocks, SPG blocks, steroid injections, Botox) during the course of the study Agrees not to use any neuromodulatory device for the management of neuropathic pain or migraine during the course of the study Agrees not to undergo any surgical procedure for the management of neuropathic pain during the course of the study Agrees to not use cognitive behavioral therapy (CBT), biofeedback or acupuncture for the management of pain during the course of the study. 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 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, uncontrolled high blood pressure, malignant disease, chronic constipation, any malabsorption disorders such as IBSc or any other severe acute or chronic medical or psychiatric condition (major depression, schizophrenia, dementia) or laboratory finding that may increase the risk associated with trial participation with Erenumab, that in the judgement of the investigators would interfere with study assessments and/or would make the participant inappropriate for entry into this trial. 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. Participants with evidence or a history of drug or alcohol abuse within the past 12 months or has been diagnosed with a substance abuse disorder. Participants with dental pain (determined pain of odontogenic/periodontal origin). Participants with significant neurological disorders. 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. Patients with hypersensitivity to Erenumab Participants with trigeminal neuropathic pain taken medications for the management of trigeminal neuropathic pain in where daily dosage has been modified within three weeks before baseline. Neuroimaging showing the presence of neurovascular compression or AV malformation. Neuroimaging showing the presence of intracranial pathology (i.e. multiple sclerosis, tumor). Presence of extracranial pathology in the area of pain (tumor, lesion). Has been treated with another investigational drug or treatment within 30 days 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 Currently taking opioid medication whether episodically or daily, within 30 days prior to the Screening and Baseline Visit. Patients sensitive to Latex If planning to become pregnant, 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 140 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<br>* Administered once every 4weeks/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 andvisit 3 for a total of 3 cycles. Other name: Placebo | Other: Placebo<br>* Administered once every 4weeks/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 (28 days) 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 (28 days) average pain score from baseline to Visit 4 (the last monthly treatment cycle), compared to placebo. The daily pain intensity score will be measured on a 11-point (0-10) numeric rating scale (NPRS) and reported in the Daily Symptom Diary (DSD). The monthly mean pain intensity score will be determined from baseline (4 weeks/28 days), for each month during the 12 weeks of treatment. | From Visit 0 (Baseline phase/Study day 0) to Visit 4 (Study day 112 +/- 7) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of erenumab-aooe compared to placebo on the reduction in monthly average daily pain score from baseline to the end of 12-week treatment period. | Comparison of erenumab-aooe with placebo in the reduction of pain score from baseline continuously through to the end of 12 weeks (Visit 4). | From Visit 0 (Baseline phase/Study day 0) to Visit 4 (study day 112 +/- 7) | 
| Change of >= 30% reduction in the monthly (28 days) average pain score compared to placebo from baseline to Visit 5. | Assess the efficacy of erenumab-aooe compared to placebo on the proportion of subjects who achieved a least 30% reduction in the monthly average daily pain score from baseline to Visit 5 (follow-up/final visit). | From Visit 0 (Baseline phase/Study day 0) to Visit 5 ( study day 140 +/- 7) | 
| Change in participant ratings compared to placebo for improving physical function and health related quality of life in patients with trigeminal neuropathic pain measured by the Penn Facial Pain Scale-Revised. | Efficacy of erenumab-aooe compared to placebo in improvement on burden/disability of daily activities related to trigeminal neuropathic pain (e.g. chewing, eating, talking, touching) measured by the Penn Facial Pain Scale-Revised. 12 items. The higher the score the more pain and disability. | Visit 0 (baseline/study day 0), Visit 1 (study day 28), Visit 2 (study day 56), Visit 3 (study day 84), Visit 4 (study day 112) and Visit 5 (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), Visit 1 (study day 28), Visit 2 (study day 56), Visit 3 (study day 84), Visit 4 (study day 112) and Visit 5 (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), Visit 1 (study day 28), Visit 2 (study day 56), Visit 3 (study day 84), Visit 4 (study day 112) and Visit 5 (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), Visit 1 (study day 28), Visit 2 (study day 56), Visit 3 (study day 84), Visit 4 (study day 112) and Visit 5 (140) +/- 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trigeminal Nerve Injury, Trigeminal neuropathic pain, Idiopathic trigeminal neuralgia with continuous pain, Idiopathic painful trigeminal neuropathy, Trigeminal Nerve Diseases, Cranial Nerve Diseases, Calcitonin Gene-Related Peptide Receptor Antagonists, CGRP Receptor Antagonist, Erenumab, Neuralgia, Face Pain, Physiological effects of drugs, Trigeminal Nerve Trauma