Efficacy and Safety of GSK1358820 (Botulinum Toxin Type A) in Patients With Strabismus

Study Overview
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Brief Summary
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Primary objective is to evaluate the efficacy of single-dose treatment with GSK1358820 compared with non-treatment in patients with strabismus based on angles of strabismus in the primary position.

Detailed Description
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Primary objective is to evaluate the efficacy of single-dose treatment with GSK1358820 compared with non-treatment in patients with strabismus based on angles of strabismus in the primary position. Secondary objective is to evaluate the efficacy and safety of repeated-dose treatment with GSK1358820 in patients with strabismus.

Official Title
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A Multicenter, Randomized, Evaluator-masked, Parallel-group, Non-treatment-controlled Study Followed by an Open-label Study to Evaluate Efficacy and Safety of GSK1358820 (Botulinum Toxin Type A) in Patients With Strabismus

Conditions
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Strabismus

Intervention / Treatment
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* Drug: GSK1358820


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: <At the start of screening period> Paralytic or concomitant strabismus. Subjects with paralytic strabismus will be eligible for inclusion only if paralysis has persisted for at least 3 months and strabismus has been developed at one eye Horizontal deviations (esotropia or exotropia) Strabismus with the (absolute) strabismus angles at both distance and near of primary position >-10 PD and <50 PD Age>-12 years at the time of giving informed consent The subject has to be capable of giving written informed consent of their own will. For subjects aged less than 20 years, the subject and his/her legally acceptable representative (person in parental authority or guardian) have to give written informed consent Either sex. Males have to agree to practice contraception during the study period. Females of child-bearing potential will be eligible for inclusion in this study. However, they have to have negative pregnancy test both at the screening visit and just before initial injection and agree to practice reliable methods of contraception QTc <450 msec; for patients with Bundle Branch Block, QTc <480 msec based on average QTc value of triplicate ECGs <At the start of treatment period > Strabismus with the (absolute) strabismus angles at both distance and near of primary position >-10 PD and <50 PD ALT at the screening visit <2 x ULN and alkaline phosphatase and bilirubin <-1.5 x ULN Exclusion Criteria: <At the start of screening period> Secondary strabismus caused by prior surgical recession of the antagonist in past surgical treatment of strabismus Strabismus due to abnormal innervations Strabismus with thyroid-associated ophthalmopathy Strabismus with strong motor limitation of extraocular muscles Mechanical limitations of ocular movement due to periorbital disease or due to past surgical treatment other than strabismus Blepharoptosis Conjunctival pathology Systemic neuromuscular junction dysfunction Systemic neuromuscular disease Past treatment with botulinum toxin Planned injections of botulinum toxin for other indication(s) or for cosmetic purpose during the study period Known hypersensitivity to any of the drugs to be used in the study or history of allergy Treatment with antibiotics with neuromuscular junction inhibitory action such as aminoglycosides, polypeptides, tetracyclines and lincomycins, except those contained in topical antibacterial formulations Treatment with muscle relaxants or drugs with muscle relaxant action Chronic respiratory disorder Severe muscle weakness or atrophy Angle-closure glaucoma or its predisposing factors Severe cardiac, hepatic or renal impairment. The severity refers to Grade 3 according to the Classification of the Severity of Adverse Experiences (MHLW PAB/SD Notification No. 80, dated 29 June 1992). Surgical operation or hospitalization to be needed during the study period Female subjects who are pregnant or lactating, who may be pregnant, or who plan for pregnancy during the study period Participation in another clinical study within 6 months prior to enrollment in this study or planned participation in another clinical study after enrollment in this study Psychiatric disorder or impairment of intellectual function that may affect the subject's ability to give informed consent or to comply with the trial procedures History of alcohol dependence or drug abuse Subjects whom the investigator (or sub-investigator) considers ineligible for the study

Ages Eligible for Study
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Minimum Age: 12 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Non-treatment (10-20 PD)<br>Receive no treatment on Week 0 | |
| Active Comparator: GSK1358820 1.25 U (10-20 PD)<br>Receive 1.25 U of GSK1358820 on Week 0 | Drug: GSK1358820<br>* IM injection of Botulinum Toxin Type A<br>* Other names: Botulinum Toxin Type A;|
| Active Comparator: GSK1358820 2.5 U (10-20 PD)<br>Receive 2.5 U of GSK1358820 on Week 0 | Drug: GSK1358820<br>* IM injection of Botulinum Toxin Type A<br>* Other names: Botulinum Toxin Type A;|
| No Intervention: Non-treatment (20-50 PD)<br>Receive no treatment on Week 0 | |
| Active Comparator: GSK1358820 2.5 U (20-50 PD)<br>Receive 2.5 U of GSK1358820 on Week 0 | Drug: GSK1358820<br>* IM injection of Botulinum Toxin Type A<br>* Other names: Botulinum Toxin Type A;|
| Active Comparator: GSK1358820 5.0 U (20-50 PD)<br>Receive 5.0 U of GSK1358820 on Week 0 | Drug: GSK1358820<br>* IM injection of Botulinum Toxin Type A<br>* Other names: Botulinum Toxin Type A;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Strabismus Angle Prism Dioptre (PD) in the Primary Position at Week 4 of the FTP in Observed Cases (OC) | The strabismus angle in the primary position was measured using the alternative prism cover test (APCT). The strabismus angle was evaluated as the mean value of the distant-view strabismus angle (measured at a distance of 5 meters [m]) and the near-view strabismus angle (measured at a distance of 33 centimeters [cm]). Every participant's evaluation was performed in the same affected eye (left or right) throughout the study period. Change from Baseline was calculated as the value at Week 4 minus the value at Baseline. | Baseline and Week 4 of the FTP | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Strabismus Angle Prism Dioptre (PD) in the Primary Position at Week 1 After the Initial Injection of the FTP in Observed Cases (OC) | The strabismus angle in the primary position was measured using the APCT. The strabismus angle was evaluated as the mean value of the distant-view strabismus angle (measured at a distance of 5 m) and the near-view strabismus angle (measured at a distance of 33 cm). Every participant's evaluation was performed in the same affected eye (left or right) throughout the study period. Change from Baseline was calculated as the value at Week 1minus the value at Baseline. | Baseline and Week 1 of the FTP | 
| Change From Baseline in the Strabismus Angle PD in the Primary Position at Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 After the Final Injection of the FTP | The strabismus angle in the primary position was measured using the APCT. The strabismus angle was evaluated as the mean value of the distant-view strabismus angle (measured at a distance of 5 m) and the near-view strabismus angle (measured at a distance of 33 cm). Every participant's evaluation was performed in the same affected eye (left or right) throughout the study period. The values were summarized for the observed cases for the change in the strabismus angle in the primary position from Baseline at Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48 (before reinjection of the second treatment period if applicable) after the final injection of the FTP (after randomization in the non-treatment groups). Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline and Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 after the final injection of the FTP | 
| Change From Baseline in the Strabismus Angle PD in the Primary Position at Weeks 1, 4, 8, 12, 16, 20, and 24 of the Second Treatment Period (STP) | The strabismus angle in the primary position was measured using the APCT. The strabismus angle was evaluated as the mean value of the distant-view strabismus angle (measured at a distance of 5 m) and the near-view strabismus angle (measured at a distance of 33 cm). Every participant's evaluation was performed in the same affected eye (left or right) throughout the study period. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline and Weeks 1, 4, 8, 12, 16, 20, and 24 of the STP (up to Study Week 52) | 
| Absolute Strabismus Angle in the Primary Position at Weeks 1 and 4 of the FTP | The strabismus angle in the primary position was measured using the APCT. The strabismus angle was evaluated as the mean value of the distant-view strabismus angle (measured at a distance of 5 m) and the near-view strabismus angle (measured at a distance of 33 cm). Every participant's evaluation was performed in the same affected eye (left or right) throughout the study period. The absolute values of the strabismus angle in the primary position at Week 1 and Week 4 of the FTP were summarized for observed cases without imputation of missing values. | Weeks 1 and 4 of the FTP | 
| Absolute Strabismus Angle in the Primary Position at Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 After the Final Injection of the FTP | The strabismus angle in the primary position was measured using the APCT. The strabismus angle was evaluated as the mean value of the distant-view strabismus angle (measured at a distance of 5 m) and the near-view strabismus angle (measured at a distance of 33 cm). Every participant's evaluation was performed in the same affected eye (left or right) throughout the study period. The absolute values of the strabismus angle in the primary position were summarized for observed cases at Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 (before reinjection of the second treatment period if applicable) after the final injection of the FTP (after randomization in the non-treatment groups). | Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 after the final injection of the FTP | 
| Absolute Strabismus Angle in the Primary Position at Weeks 1, 4, 8, 12, 16, 20, and 24 of the STP | The strabismus angle in the primary position was measured using the APCT. The strabismus angle was evaluated as the mean value of the distant-view strabismus angle (measured at a distance of 5 m) and the near-view strabismus angle (measured at a distance of 33 cm). Every participant's evaluation was performed in the same affected eye (left or right) throughout the study period. | Weeks 1, 4, 8, 12, 16, 20, and 24 of the STP (up to Study Week 52) | 
| Percent Change From Baseline in the Strabismus Angle in the Primary Position at Week 1 and Week 4 in Observed Cases (OC) of the FTP | The strabismus angle in the primary position was measured using the APCT. The strabismus angle was evaluated as the mean value of the distant-view strabismus angle (measured at a distance of 5 m) and the near-view strabismus angle (measured at a distance of 33 cm). Every participant's evaluation was performed in the same affected eye (left or right) throughout the study period. The values were summarized for observed cases for the percent change from Baseline in the strabismus angle in the primary position at Week 1and Week 4 after the initial injection in the FTP. Percent change from Baseline in the strabismus angle was calculated as: absolute angle ([strabismus angle at Baseline minus strabismus angle after the final injection] divided by the absolute strabismus angle at Baseline) multiplied by 100. | Baseline and Weeks 1 and 4 of the FTP | 
| Percent Change From Baseline in the Strabismus Angle in the Primary Position at Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 After the Final Injection of the FTP | The strabismus angle in the primary position was measured using the APCT. The strabismus angle was evaluated as the mean value of the distant-view strabismus angle (measured at a distance of 5 m) and the near-view strabismus angle (measured at a distance of 33 cm). Every participant's evaluation was performed in the same affected eye (left or right) throughout the study period. The values were summarized for observed cases for percent change from Baseline in the strabismus angle in the primary position at Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 (before reinjection of the second treatment period if applicable) after the final injection of the FTP (after randomization in non-treatment groups; up to a maximum of 52 weeks of the FTP). Percent change from Baseline in the strabismus angle was calculated as: (absolute angle [strabismus angle at Baseline minus the strabismus angle after the final injection] divided by the absolute strabismus angle at Baseline) multiplied by | Baseline and Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 of the FTP | 
| Percent Change From Baseline in the Strabismus Angle in the Primary Position at Weeks 1, 4, 8, 12, 16, 20, and 24 of the STP | The strabismus angle in the primary position was measured using the APCT. The strabismus angle was evaluated as the mean value of the distant-view strabismus angle (measured at a distance of 5 m) and the near-view strabismus angle (measured at a distance of 33 cm). Every participant's evaluation was performed in the same affected eye (left or right) throughout the study period. Percent change from Baseline in the strabismus angle was calculated as: (absolute angle [strabismus angle at Baseline minus the strabismus angle after the final injection] divided by the absolute strabismus angle at Baseline) multiplied by 100. | Baseline and Weeks 1, 4, 8, 12, 16, 20, and 24 of the STP (up to Study Week 52) | 
| Duration of Effect | Duration of effect is defined as the number of days after the final injection of the FTP (after randomization in the non-treatment groups) until the date of the first recording of a value smaller than 50% in percent correction compared to the maximum change in the strabismus angle in the primary position. The strabismus angle in the primary position was measured using the APCT. The strabismus angle was evaluated as the mean value of the distant-view strabismus angle (measured at a distance of 5 m) and the near-view strabismus angle (measured at a distance of 33 cm). Percent correction compared to the maximum change in the strabismus angle was calculated as: (absolute angle [strabismus angle at Baseline minus the strabismus angle after injection]/absolute angle [strabismus angle at Baseline minus the strabismus angle at maximum change]) multiplied by 100. | Up to Week 48 after the final injection of the FTP (up to Study Week 52) | 
| Severity of Duction Limitation at Weeks 1 and 4 of the FTP | The severity of duction limitation was calculated for participants with paralytic strabismus. For each evaluable participant, assessment was done by taking a frontal photo of the condition of the affected eye to determine the maximum movement toward the direction to which duction is limited while the non-affected eye was masked with eye-patch. The evaluation was performed in the same eye (left or right) throughout the study period. Based on the photos, the severity of the duction limitation was assessed on a 6-point scale, with scores ranging from 0=no duction limitation to -5=cannot rotate eye to midline. | Week 1 and Week 4 of the FTP | 
| Severity of Duction Limitation at Weeks 1, 4, 8, 12, 16, 20, and 24 After the Final Injection of the FTP | The severity of duction limitation was calculated for participants with paralytic strabismus. For each evaluable participant, assessment was done by taking a frontal photo of the condition of the affected eye to determine the maximum movement toward the direction to which duction is limited while the non-affected eye was masked with eye-patch. The evaluation was performed in the same eye (left or right) throughout the study period. Based on the photos, the severity of the duction limitation was assessed on a 6-point scale, with scores ranging from 0=no duction limitation to -5=cannot rotate eye to midline. | Weeks 1, 4, 8, 12, 16, 20, and 24 after the final injection of the FTP (up to a maximum of 52 weeks of the FTP) | 
| Severity of Duction Limitation at Weeks 1, 4, 8, 12, 16, 20, and 24 of the STP | The severity of duction limitation was calculated for participants with paralytic strabismus. For each evaluable participant, assessment was done by taking a frontal photo of the condition of the affected eye to determine the maximum movement toward the direction to which duction was limited while the non-affected eye was masked with eye-patch. The evaluation was performed in the same eye (left or right) throughout the study period. Based on the photos, the severity of the duction limitation was assessed on a 6-point scale, with scores ranging from 0=no duction limitation to -5=cannot rotate eye to midline. All participants with paralytic strabismus did not receive a second injection so there were no participants to analyse for this outcome measure. | Weeks 1, 4, 8, 12, 16, 20, and 24 of the STP (up to Study Week 52) | 
| Change From Baseline in the Severity of Duction Limitation at Weeks 1 and 4 of the FTP | The severity of duction limitation was calculated for participants with paralytic strabismus. For each evaluable participant, assessment was done by taking a frontal photo of the condition of the affected eye to determine the maximum movement toward the direction to which duction was limited while the non-affected eye was masked with eye-patch. The evaluation was performed in the same eye (left or right) throughout the study period. Based on the photos, the severity of the duction limitation was assessed on a 6-point scale, with scores ranging from 0=no duction limitation to -5=cannot rotate eye to midline. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline and Weeks 1 and 4 of the FTP | 
| Change From Baseline in the Severity of Duction Limitation at Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 After the Final Injection of the FTP | The severity of duction limitation was calculated for participants with paralytic strabismus. For each evaluable participant, assessment was done by taking a frontal photo of the condition of the affected eye to determine the maximum movement toward the direction to which duction was limited while the non-affected eye was masked with eye-patch. The evaluation was performed in the same eye (left or right) throughout the study period. Based on the photos, the severity of the duction limitation was assessed on a 6-point scale, with scores ranging from 0=no duction limitation to -5=cannot rotate eye to midline. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. | Baseline and Weeks 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 after the final injection of the FTP (up to a maximum of 52 weeks of the FTP) | 
| Change From Baseline in the Severity of Duction Limitation at Weeks 1, 4, 8, 12, 16, 20, and 24 of the STP | The severity of duction limitation was calculated for participants with paralytic strabismus. For each evaluable participant, assessment was done by taking a frontal photo of the condition of the affected eye to determine the maximum movement toward the direction to which duction was limited while the non-affected eye was masked with eye-patch. The evaluation was performed in the same eye (left or right) throughout the study period. Based on the photos, the severity of the duction limitation was assessed on a 6-point scale, with scores ranging from 0=no duction limitation to -5=cannot rotate eye to midline. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. All participants with paralytic strabismus did not receive a second injection so there were no participants to analyse for this outcome measure. | Baseline and Weeks 1, 4, 8, 12, 16, 20, and 24 of the STP (up to Study Week 52) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuromuscular Agents, Strabismus, Botulinum Toxin Type A