DaxibotulinumtoxinA for Blepharospasm

Phase 2Not Yet RecruitingNCT07489430

University of Pennsylvania20 enrolled

Overview

This study aims to provide real-world information about the duration, safety, and overall benefit of DaxibotulinumtoxinA (also called DAXI) treatment for adults living with blepharospasm (BSP), a condition that causes uncontrolled blinking or muscle spasms around the eyes, which can interfere with vision and daily activities. Specifically, it is being done to learn more about how well and how long DAXI works for treating adults with blepharospasm. This is a single-center, open-label, single-arm study, meaning everyone in the study will receive DAXI, and both participants and researchers will know what treatment is being given. The study will include 20 adult participants. Participants may receive two to three treatment cycles of DAXI injections over about 12 months. The timing between treatments will depend on how long each injection works for each person. Injections will be given at least every 90 days (3 months) but no later than every 180 days (6 months). Participants and their doctors will decide when another injection is needed based on symptom control using a tool called the Blepharospasm Severity Tracker Form (BSTF). To make the injections more comfortable, participants may use topical lidocaine cream, cooling spray, or another local anesthetic before injection. DAXI will be prepared by the injecting clinician or trained staff right before use. The medication is made by mixing a measured amount of DAXI powder with a small amount of sterile saline solution (salt water) to reach the correct concentration. The exact injection technique (including the dose, location, and number of injection sites) will be chosen by the injector based on each participant's needs, but treatment will only be given in specific facial muscles (corrugator, procerus, orbicularis oculi, and nasalis). The use of imaging tools such as electromyography (EMG) or ultrasound is optional and typically not required for injections around the eyes. The starting DAXI dose will be based on each participant's current or previous botulinum toxin treatment: * If the participant was previously treated with onabotulinumtoxinA (Botox®), the same number of "units" will be used for DAXI (a 1:1 conversion). * If the participant was previously treated with incobotulinumtoxinA (Xeomin®), the DAXI dose will be adjusted to about two-thirds of the previous incobotulinumtoxinA dose (a 1.5:1 conversion). If a participant experienced side effects such as droopy eyelids (ptosis), double vision (diplopia), or dry eyes with prior treatments, that information will help guide dosing decisions. For later injection cycles, the injector may adjust the dose or injection pattern based on how well the participant responds. Whenever possible, the same injector will perform all of a participant's treatments to keep results consistent. Participants will come to the clinic for in-person visits for most study assessments. After each DAXI injection, the peak effect (best response) will be evaluated about one month later, guided by the BSTF. These visits may be done remotely (via phone or video) when appropriate. The same schedule will be followed for future cycles. For the final treatment, this one-month check will occur unless the participant reports that the treatment's full effect happened sooner. The main goal (primary endpoint) of the study is to measure how long DAXI's effects last, specifically by tracking the median time until the next injection is needed. Other key goals (secondary endpoints) include: * How long participants feel the treatment works * How severe their blepharospasm symptoms are over time * What side effects or safety concerns occur (adverse events)

This study is an open-label, single-center, single-arm, longitudinal clinical trial designed to evaluate the use of daxibotulinumtoxinA (DAXI) for injection in twenty adult participants with blepharospasm (BSP). Each subject will be eligible to receive between two and three treatment cycles with DAXI over a twelve-month period. The timing of reinjection will depend on each participant's duration of benefit, as determined using the Blepharospasm Severity Tracker Form (BSTF). Treatments must be spaced at least ninety days apart but not more than one hundred eighty days. Participants will decide when to receive another injection and may use topical lidocaine cream, cooling spray, or other anesthetic methods to reduce pain during the procedure. The study will enroll adults of any race or gender, aged eighteen or older, who are in generally good health and have a clinical diagnosis of blepharospasm. Eligible participants may have either isolated blepharospasm, which could be focal or part of segmental or generalized dystonia, or blepharospasm as a complication of a parkinsonian condition. To qualify, participants must have a baseline blepharospasm severity rating of at least two points on the Blepharospasm Severity Rating Scale (BSRS) and must already be receiving either onabotulinumtoxinA or incobotulinumtoxinA with less than twelve weeks of benefit from that treatment. For each injection session, the study drug will be prepared by the injector or a qualified staff member by diluting one milliliter of Bacteriostatic Sodium Chloride Injection (0.9%) with one hundred units of DAXI to create a final concentration of ten units per 0.1 milliliter for intramuscular injection. The specific dose, muscles injected, and number of injection sites will be determined by the injector. Only four muscles may be treated: the corrugators, procerus, orbicularis oculi, and nasalis. Use of electromyography or ultrasonography for guidance is optional but generally unnecessary for facial injections. The initial DAXI dose will be based on the participant's previous injection cycle. Those currently treated with onabotulinumtoxinA will convert on a one-to-one unit basis, while those treated with incobotulinumtoxinA will use a 1.5:1 conversion ratio, meaning 1.5 units of incobotulinumtoxinA is equivalent to one unit of DAXI. If the previous dose resulted in excessive weakness or related side effects such as eyelid drooping, double vision, or dry eye, dosing will be adjusted accordingly. Subsequent DAXI dosing may be further modified at the injector's discretion, and efforts will be made for each subject to be treated by the same injector throughout the study. Following each treatment, efficacy will be evaluated at the time of peak response, which typically occurs about one month after injection. The first DAXI administration occurs around day ninety-five (visit three), and this timing determines when follow-up evaluations, usually by remote visit, are performed. Future injection cycles will follow similar timing, although exact intervals will vary depending on individual responses. The overall study period for each subject spans roughly one year, ending with either an end-of-study or early-termination visit between days 365 and 460. The primary measure of efficacy is the median time to reinjection, serving as an indicator of the duration of DAXI's therapeutic effect. Secondary outcomes include the participant's perceived duration of benefit, changes in blepharospasm severity, quality-of-life improvements, and overall treatment satisfaction. Specific evaluation tools include the Blepharospasm Severity Tracking Form (BSTF), Blepharospasm Severity Rating Scale (BSRS), Craniocervical Dystonia Questionnaire (CDQ-24), Clinical Global Impression of Change (CGIC), Patient Global Impression of Change (PGIC), and a Treatment Satisfaction Questionnaire. Safety monitoring is a critical component of the trial. Assessments will include pregnancy testing for women of childbearing potential, physical and neurological examinations, the Columbia-Suicide Severity Rating Scale (C-SSRS), vital signs, and inspection of injection sites. Investigators will also record concomitant medications and monitor all adverse events, including any deemed to be of special interest.

Interventions

Botulinum Neurotoxin Type ADRUG

DaxibotulinumtoxinA (DAXI) for injection is a sterile, lyophilized powder containing 100 units of active daxibotulinumtoxinA per vial, along with inactive ingredients including RTP004, trehalose dihydrate, L-histidine, L-histidine hydrochloride, and polysorbate 20. It is reconstituted with Bacteriostatic Sodium Chloride Injection 0.9% (Pfizer) and stored at 2-8°C. DAXI will be prepared by trained injectors or staff, with all preparations documented. Experienced movement disorder neurologists will administer injections, primarily from UPenn's Parkinson's Disease and Movement Disorders Center. Dosing will follow prior treatment patterns using a 1:1 conversion from onabotulinumtoxinA or 1.5:1 from incobotulinumtoxinA, adjusted for prior adverse effects. Injection sites will be selected based on clinical presentation, with optional EMG or imaging guidance.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Adults (18 years of age, or older) * Clinical diagnosis of Blepharospasm that is disruptive enough to warrant ongoing clinical botulinum toxin injections and scoring ≥2 on the BSRS during screening. Blepharospasm may be focal (i.e. Benign essential blepharospasm), associated with non-drug-induced secondary cause (e.g., typical or atypical parkinsonism) or as part of a diagnosis of segmental or generalized dystonia involving the upper cranial region, if blepharospasm is the only indication requiring botulinum toxin injections. * Currently receiving onabotulinumtoxinA or incobotulinumtoxinA for the treatment of blepharospasm with: 1) documented duration of benefit \<12 weeks from most recent injection; and 2) no further dose escalation possible or advised due to side effect risk (e.g., ptosis, diplopia, etc.), as determined by treating neurologist; and 3) ability to provide informed consent and comply with study procedures, or subject has a reliable caregiver/proxy. * Written informed consent including authorization to release health information. Exclusion Criteria: * Tardive or medication-induced blepharospasm, as well as psychogenic/functional blepharospasm. * Active ocular pathology interfering with evaluation or injection safety. * Neuromuscular junction or motor neuron disorders (e.g., myasthenia gravis, Lambert-Eaton Myasthenic Syndrome, Amyotrophic Lateral Sclerosis, etc.). * Known hypersensitivity to botulinum toxin or formulation components. * Pregnant or breastfeeding women (including those who are found to be pregnant after a positive pregnancy test at Screening), women who are hoping to get pregnant over the upcoming 15 months, or women of childbearing potential who are unwilling to use contraception while enrolled in the BLEXI study. * Any signal suggestive of active suicidality, as per C-SSRS at screening. * Subjects who have undergone Deep Brain Stimulation (DBS) surgery for the management of blepharospasm and are not willing to keep the DBS settings unchanged for the duration of the trial. * History of primary or secondary non-response to BoNT-A injections, particularly those known to have neutralizing antibodies to BoNT-A. * Subjects on oral medications for dystonia (e.g., anticholinergics, muscle relaxants, benzodiazepines, dopamine depleter) who have not been stable on their regimen for at least 4 weeks prior to Screening, or who are not willing to keep them stable for the duration of the trial. * Use of aminoglycoside antibiotics, polymyxins, lincosamides (e.g., clindamycin), or other agents that might interfere with neuromuscular transmission (e.g., curare-like drugs, quinidine, magnesium sulfate, anticholinesterases, succinylcholine chloride) within 14 days prior to Screening. * History of severe (stage 3) chronic obstructive pulmonary disease, or unstable pulmonary disease within 30 days prior to Screening. * History of chronic or recurrent hypokalemia. * History of congestive heart failure (New York Heart Association Class III or IV), Torsade de Pointe (TdP), and/or Long QT Syndrome. * Subjects in an investigational drug or device study within the last 30 days prior to Screening. * Active skin infections at the injection sites which would put the subject at increased risk of morbidity with BoNT injections * History of blood coagulation disorder that makes facial injection an absolute contraindication * Any acute illnesses or medical conditions including cognitive impairment (e.g., dementia), significant psychiatric illnesses (e.g., major depressive or bipolar disorder) or symptoms (e.g., suicidal ideation, psychosis) that are not stable, and in the Investigator's opinion, could put the subject at increased risk of morbidity, confound the study results, or interfere significantly with the subject's participation in the study.

Outcomes

Primary Outcomes

First time to retreatment

Time to retreatment (in days) with DAXI between the first and second study injection cycle.

Time frame: Outcome will be assessed during Visit 5 (2nd study injection visit) and reported at study conclusion. Visit 5 will take place for each individual subject between days 180 and 280.

Final time to retreatment

For patients who receive 3 study injection cycles with DAXI over 12 months, a second primary endpoint will be the time to retreatment (in days) between the second-to-last and last injection cycle (i.e., between DAXI cycles 2 and 3).

Time frame: Outcome will be assessed during Visit 7 (3rd study injection visit) and reported at study conclusion. Visit 7 will take place for each individual study subject between days 270 and 280.

Secondary Outcomes

Difference in time to return of symptoms after first DAXI cycle

Change in time (in days) to return of baseline blepharospasm symptoms, as documented in the Blepharospasm Severity Tracker Form between data relating to the last clinical injection cycle prior to screening and the first DAXI study injection cycle.

Time frame: Outcome will be assessed during Visit 3 (1st study injection visit) and reported at study conclusion. Visit 3 will take place for each individual study subject between days 90 and 100.

Difference in time to return of symptoms after final DAXI cycle

Change in time (in days) to return of baseline BSP symptoms, as documented in the Blepharospasm Severity Tracker Form between data relating to the last clinical injection cycle prior to screening and the last DAXI study injection cycle.

Time frame: Outcome will be assessed during Visit 5 (days 180-280) for subjects only receiving 2 injections during study participation, and during Visit 7 (days 270-280) for subjects receiving 3. Outcomes will be reported at study conclusion.

Change in severity after first DAXI injection cycle

Change in the Blepharospasm Severity Rating Scale (BSRS) total score between Visit 2 (peak efficacy assessment of last clinical injection) and Visit 4 (peak efficacy assessment of first DAXI injection). The BSRS is a validated scale with scores ranging from 0 to 18, with higher numbers reflecting worsening blepharospasm severity.

Time frame: Outcome will be assessed during Visit 4 (1st study injection peak effect assessment) and reported at study conclusion. Visit 4 will take place for each individual study subject between days 114 and 156.

Change in severity after final DAXI injection cycle

Change in Blepharospasm Severity Rating Scale (BSRS) total score between Visit 2 (the peak efficacy assessment of the last clinical injection) and the peak efficacy assessment following the subject's final DAXI study injection (which may occur during either the second or third injection cycle, depending on how long the individual subject chooses to wait before reinjection with DAXI). The BSRS is a validated scale ranging from 0 to 18, with higher scores indicating greater blepharospasm severity.

Time frame: BSRS will be assessed during Visit 6 (days 200-340) for subjects only receiving 2 injections during study participation, and during Visit 8 (days 294-336) for subjects receiving 3. Outcomes will be reported at study conclusion.

First change in the Patient Global Impression of Change (PGIC)

Change in Patient Global Impression of Change (PGIC) score between V2 (peak efficacy assessment of last clinical injection) and V4 (peak efficacy assessment of first study DAXI injection). The PGIC is a patient-reported outcome that acts as a 7-point Likert scale, with values ranging from -3 (very much worse) to +3 (very much better).

Time frame: Outcome will be assessed during Visit 4 (peak efficacy assessment of first study DAXI injection) taking place on days 114-156, and reported at study conclusion.

Final change in the Patient Global Impression of Change (PGIC)

Change in Patient Global Impression of Change (PGIC) score between V2 (peak efficacy assessment of last clinical injection) and during the peak efficacy assessment of the study subject's final DAXI study injection (which may occur during either the second or third injection cycle, depending on how long the individual subject chooses to wait before reinjection with DAXI). The PGIC is a patient-reported outcome that acts as a 7-point Likert scale, with values ranging from -3 (very much worse) to +3 (very much better).

Time frame: PGIC will be assessed during Visit 6 (days 200-340) for subjects only receiving 2 injections during study participation, and during Visit 8 (days 294-336) for subjects receiving 3. Outcomes will be reported at study conclusion.

First change in the Clinical Global Impression of Change (CGIC)

Change in Clinical Global Impression of Change (CGIC) score between V2 (peak efficacy assessment of last clinical injection) and V4 (peak efficacy assessment of first DAXI injection). The CGIC is a validated clinical outcome measure that acts as a 7-point Likert scale, with values ranging from -3 (very much worse) to +3 (very much better).

Time frame: Outcome will be assessed during Visit 4 (peak efficacy assessment of first study DAXI injection) taking place on days 114-156, and reported at study conclusion.

Final change in the Clinical Global Impression of Change (CGIC)

Change in Clinical Global Impression of Change (CGIC) score between V2 (peak efficacy assessment of last clinical injection) and during the peak efficacy assessment of the study subject's final DAXI study injection (which may occur during either the second or third injection cycle, depending on how long the individual subject chooses to wait before reinjection with DAXI). The CGIC is a validated clinical outcome measure that acts as a 7-point Likert scale, with values ranging from -3 (very much worse) to +3 (very much better).

Time frame: CGIC will be assessed during Visit 6 (days 200-340) for subjects only receiving 2 injections during study participation, and during Visit 8 (days 294-336) for subjects receiving 3. Outcomes will be reported at study conclusion.

First change in satisfaction

Change in Treatment Satisfaction Questionnaire score between V3 (day of first DAXI study injection) and V5 (day of second DAXI study injection). The Treatment Satisfaction Questionnaire is a patient-reported outcome that acts as a 7-point Likert scale, with values ranging from -3 (very dissatisfied) to +3 (very satisfied).

Time frame: Outcome will be assessed during Visit 5 (days 180-280). Outcomes will be reported at study conclusion.

Final change in satisfaction

Change in Treatment Satisfaction Questionnaire (TSQ) score between V3 (day of first DAXI study injection) and EOS/ET (last day of study). The Treatment Satisfaction Questionnaire is a patient-reported outcome that acts as a 7-point Likert scale, with values ranging from -3 (very dissatisfied) to +3 (very satisfied).

Time frame: Outcome will be assessed during Visit 7 (days 270-280) and Visit 9 (days 365-460). Outcomes will be reported at study conclusion.

Incidence of Treatment-Emergent Adverse Events (suicidality, toxin-related side effects and injection site reactions)

Safety, which includes screening for suicidality (C-SSRS) and adverse events (AEs), particularly adverse events of special interest: diplopia (or other visual disturbances), dry eyes, ptosis, injection site reactions and toxin effect spread to the lower face.

Time frame: Outcomes will be assessed during Visit 1 (day 0), Visit 2 (day 30 +/-5), Visit 3 (day 95 +/-5), Visit 4 (day 135 +/- 21), Visit 5 (day 180-280), Visit 6 (day 200-340), Visit 7 (day 275 +/-5), Visit 8 (day 315 +/- 21), Visit 9 (day 365-460).