Oxymetazoline Drops for Acquired Blepharoptosis From Synkinesis

Study Overview
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Brief Summary
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After an episode of facial paralysis, as nerves recover, they aberrantly regenerate and send additional branches to the incorrect muscles in addition to the intended muscle. This leads to what is known as Aberrant Regeneration Syndrome, Post-paralysis Synkinesis, or Nonflaccid Facial Paralysis. It is characterized by poor facial symmetry and function, hypertonic facial muscles at rest, and abnormal facial movements. One sequela is acquired blepharoptosis causing a smaller ocular aperture, visual field obstruction, cosmetic deformity, and abnormal periocular spasms. This study aims to evaluate an FDA approved medication for acquired blepharoptosis due to synkinesis/hyperkinesis as an adjunct to treatment.

Detailed Description
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Broadly, synkinesis is a neuromuscular condition in which voluntary muscle contraction causes simultaneous involuntary contraction of other muscle groups e.g. pursing of the lips causes involuntary closure of the eye. It is a common sequelae of facial nerve paralysis with 55% or more of patients reporting synkinetic facial movement. 2 Additionally, patients may develop hyperkinesis due to continual firing of nerves that have aberrantly regenerated, thereby causing decreased movement due to antagonistic muscle hyperactivity, tightness, spasms, and pain. These together significant affect facial symmetry, aesthetics, and facial function. While the definitive pathophysiology of synkinesis is still unknown, the most supported theory describes neuronal miswiring (aberrant regeneration theory). It suggests that following injury to the facial nerve and Wallerian degeneration, axons from the facial nucleus in the brainstem regrow and form inappropriate connections to peripheral muscle groups (e.g. a nerve meant to control the orbicularis oris of the mouth connects to the orbicularis oculi of the eye as well). This results in involuntary facial movements during normal expression and can affect all muscles of facial expression. Furthermore, because of continual facial muscular tone or hypertonicity, this is not only a dynamic process, but a static one as well. Synkinesis and hypertonicity can cause facial asymmetry and a fixed immobile face (frozen facies) due to opposing muscles constantly contracting and limiting movement. The result can be unaesthetic: the eyes may look smaller, the commissure (corner) of the mouth may look deviated up and out, the nasolabial fold may look deeper, the base of the nose may be deviated, the chin may be twisted or dimpled, and a band may be seen in the neck. This also presents functional limitations, such as difficulties in articulation, biting of the lip/cheek, nasal obstruction, incomplete oral competency with drooling, watering of the eye (epiphora) and in controlling facial expressions. Patients notice pain, tightness, poor facial movement, and difficulty expressing emotions, loss of their smile, and embarrassment. These limitations decrease confidence and ultimately the patient's quality of life. Our study intends to look specifically at periocular synkinesis with orbicularis oculi muscle hypertonicity resulting in acquired blepharoptosis over time (i.e. drooping of the eyelid). Periocular synkinesis is partial closure of the eye due to inappropriate contraction of the orbicularis oculi muscle during other facial movement. Hypertonicity of the orbicularis oculi muscle results in the static narrowing of the palpebral fissure (acquired blepharoptosis) and may cause visual obstruction, asymmetry, and an aged appearance in the affected eye and can occur with both dynamic movement and static tone (hyperkinesis). This facial movement disorder has no cure. Treatments are intended to improve facial symmetry, decreased tightness/pain, improve function and improve quality of life. These include facial therapy, chemodenervation injections with neurotoxins, and a variety of surgeries. Patients require multimodal therapy. None of these treatments adequately address the acquired blepharoptosis from chronic hyperkinesis and synkinesis. Oxymetazoline was initially developed in 1961. It is a direct sympathomimetic, binding directly to alpha-1 and alpha-2 receptors. Currently, it is used as a nasal decongestant, in the treatment of epistaxis, and as a topical treatment for rosacea. Previously, an ophthalmic formulation was used to treat eye redness and irritation as it is FDA approved for the treatment of acquired blepharoptosis. However, this product line was discontinued when in July of 2020, oxymetazoline received Food and Drug Administration approval for treatment of cosmetic blepharoptosis. In the treatment of blepharoptosis, oxymetazoline acts on the superior tarsal muscle, Müller's muscle, to elevate the eyelid. The superior tarsal muscle is a sympathetically innervated muscle that is partially responsible for elevating the eyelid. 5 Previous cosmetic studies have shown oxymetazoline can serve as an adjunct to botulinum toxin in patients with acquired blepharoptosis. However, no study has been performed evaluating oxymetazoline's efficacy as an adjunct to botulinum toxin in patients with acquired blepharoptosis secondary to hypertonicity and synkinesis.

Official Title
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Evaluation of Ophthalmic Oxymetazoline as an Adjunct Treatment for Acquired Blepharoptosis Due to Periocular Synkinesis.

Conditions
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Blepharoptosis, Synkinesis, Hyperkinesis, Facial Paralysis

Intervention / Treatment
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* Drug: Oxymetazoline 0.1% (Pf) Oph Soln Ud
* Other: Preservative free lubricating drops


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Over 18 years of age Primary diagnosis of nonflaccid facial paralysis (aberrant regeneration syndrome) and acquired blepharoptosis. Exclusion Criteria: Patients under the age of 18 Patients on cardiac glycosides Patients on MAO inhibitors Patients with angle closure glaucoma Patients who experience asymmetrical eye opening due to weakness (e.g. lagophthalmos).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Blinded, randomized, cross-over trial that will analyze and compare the efficacy of oxymetazoline drops alone, oxymetazoline drops adjunct with botulinum toxin, botulinum toxin alone, and no treatment.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oxymetazoline 0.1% ophthalmic drops<br>Patients will use once daily in affected eye. Drops are provided in single use vials. | Drug: Oxymetazoline 0.1% (Pf) Oph Soln Ud<br>* Oxymetazoline was initially developed in 1961. It is a direct sympathomimetic, binding directly to alpha-1 and alpha-2 receptors. Currently, it is used as a nasal decongestant, in the treatment of epistaxis, and as a topical treatment for rosacea. Previously, an ophthalmic formulation was used to treat eye redness and irritation as it is FDA approved for the treatment of acquired blepharoptosis. However, this product line was discontinued when in July of 2020, oxymetazoline received Food and Drug Administration approval for treatment of cosmetic blepharoptosis. In the treatment of blepharoptosis, oxymetazoline acts on the superior tarsal muscle, Müller's muscle, to elevate the eyelid. The superior tarsal muscle is a sympathetically innervated muscle that is partially responsible for elevating the eyelid. Previous cosmetic studies have shown oxymetazoline can serve as an adjunct to botulinum toxin in patients with acquired blepharoptosis.<br>* Other names: Upneeq;|
| Placebo Comparator: Preservative free lubricating drops<br>Patients will use once daily in affected eye. Drops are provided in single use vials. | Other: Preservative free lubricating drops<br>* Over the counter ophthalmic lubricating drop.<br>* Other names: soothe;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference from baseline to end of study in Sunnybrook Grading Score | Clinician-graded outcome measure | 6 months | 
| Difference from baseline to end of study Synkinesis Assessment Questionnaire | Patient reported outcome measure | 6 months | 
| Difference from baseline to end of study in Facial Disability Index | Disease-specific quality of life measure | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in MRD-1 from baseline to when medication is being used | Objective assessment of eyelid position relative to the pupillary light reflex as measured by clinician | 6 months | 
| Difference in palpebral height from baseline to when medication is being used | Width of ocular aperture from upper to lower eyelid | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acquired blepharoptosis, hyperkinesis, synkinesis, facial paralysis, aberrant regeneration syndrome, post-paralysis synkinesis, nonflaccid facial paralysis