Randomized, Double-Blind, Placebo-Controlled, Parallel, Group Dose-Response, Study of E2014 in Patients WIth Spasmodic Torticollis

Study Overview
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Brief Summary
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To evaluate efficacy and safety of E2014 (2500U, 5000U, 10000U, placebo) in a multicenter, randomized, double-blind, parallel group comparative study by intramuscularly administering to patients with spasmodic torticollis. Primary endpoint for efficacy evaluation is changes in TWSTRS total scores from baseline measured at Week 4 and the clinical recommended dose will be examined with Williams multiple comparison. For safety evaluation, an inter group comparison (active drug and placebo) will be performed mainly focusing on incidence of adverse events, adverse drug reactions, and abnormal changes in laboratory parameters.

Official Title
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Randomized, Double-Blind, Placebo-Controlled, Parallel, Group Dose-Response, Study of E2014 in Patients WIth Spasmodic Torticollis

Conditions
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Cervical Dystonia, Spasmodic Torticollis

Intervention / Treatment
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* Drug: BOTULINUM TOXIN TYPE B


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who can give written informed consent and aged between greater than or equal to 20 years and less than 75 years at the time of obtaining prior consent (irrespective of gender). Patients with dystonic symptoms at least 2 or more lesions in the following cervical muscles. Sternocleidomastoid Scalenus complex (scalenus anterior, scalenus medius, and scalenus posterior) Trapezius Levator scapulae Splenius capitis Semispinalis capitis Patients who persistently have symptoms in the above (2) for 1 year or longer. Patients weighing greater than or equal to 40 kg. Patients whose TWSTRS total score at baseline is greater than or equal to 20. Patients whose TWSTRS-severity score at baseline is greater than or equal to 10. Patients whose TWSTRS-disability score at baseline is greater than or equal to 3. Patients whose TWSTRS-pain score at baseline is greater than or equal to 1. Patients who are judged to be eligible for study entry by the investigator or subinvestigator based on their physical and neurological findings, laboratory parameters, and ECG results. Exclusion Criteria: Patients who are botulinum toxin-resistant in previous exposures (primary no-responder*) *If patients who were once responder to botulinum toxin treatment but thereafter became non-responder can be included in this study. Patients whose passive range of motion in the neck is significantly narrowed due to cervical contracture or spondylosis. Patients having only pure retrocollis- or anterocollis-associated symptoms. Patients who received botulinum toxin agents within 4 months prior to study treatment of E2014, or those who show carry-over effect of previous treatment with botulinum toxin at the time of starting study administration even though the previous treatment was given 4 months or earlier. Patients who were treated with narcotics or antibiotics that may potentiate effects of muscle relaxation (spectinomycin hydrochloride preparations, aminoglycosides, polypeptides, tetracyclines, lincomycins) within 4 months prior to study treatment. Patients who started or altered the dose levels of the following agents (musculoskeletal relaxants, antispasm drugs, strong tranquilizers, benzodiazepines including similar drugs, anticholinergic drugs, antiparkinsonian drugs, antidepressants) within 4 weeks prior to study treatment. Patients who received medical care(s) other than pharmacotherapies (surgical interventions, MAB, acupuncture, relaxation, etc.) prior to study treatment showing carry-over effect of these cares or unstable condition at the time of starting study treatment. Patients who have a history of myectomy or neurectomy in the neck and/or shoulder. Patients who have a history of hypersensitivity to E2014's ingredients (botulinum toxin type B, human serum albumin, sodium succinate buffer solution), or other type of botulinum toxins. Patients with complication(s) or history of serious neurological or musculoskeletal disease (myasthenia, amyotrophic lateral sclerosis, etc.), cardiovascular disease (acute myocardial infarction, etc.), respiratory disease (COPD, etc.), renal disease (acute or chronic renal failure, etc.), hepatic disease (cirrhosis, etc.), gastrointestinal disease (paralytic ileus, etc.), dermatological disease (toxic epidermal necrosis, etc.), psychiatric disease (schizophrenia, alcohol or drug dependence, etc.), hematological disease (aplastic anemia, etc.), and/or infectious disease (hepatitis, syphilis, AIDS, etc.). Patients with complication or history of malignant tumor(s). Patients who participated in another clinical study within 30 days prior to obtaining informed consent for this study. Women of pregnant, childbearing potential, childbearing intension during the study period, or lactating. Others who are judged to be ineligible for study entry by the investigator or subinvestigator

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 74 Years

Sexes Eligible for Study
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All

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: Double


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: BOTULINUM TOXIN TYPE B|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) -Total Score at Week 4 After Treatment | The TWSTRS-Total score is the sum of scores of the three components of the scale: TWSTRS-Severity score which ranges from 0 (=absence of severity) to 35 points (=maximum severity) TWSTRS-Pain score which ranges from 0 (=no pain) to 20 (=maximum pain) TWSTRS-Disability score which ranges from 0 (=no disability) to 30 (=maximum disability). The TWSTRS total score ranges from 0 (=best value) to 85 (=worst value). The change from baseline was calculated as the score at the corresponding visit minus the baseline score. | Baseline, Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Patient Global Assessment - Visual Analog Scale (PtGA-VAS) at Week 4 After Treatment | Change from Baseline in PtGA-VAS is computed as Week 4 value minus baseline value. A negative value in change from baseline indicates an improvement. Participants answered: Considering all the ways your cervical dystonia affects you, how are you feeling today? Participants responded by using a 0 - 100 mm VAS, where 0 mm = very well and 100 mm = very poorly. | Baseline, Week 4 | 
| Mean Change From Baseline in Physician Global Assessment Disease Assessment - Visual Analog Scale (PGA-VAS) at Week 4 After Treatment | Change from Baseline in PGA-VAS (0 to 100 mm visual analog scale, 0 being no symptoms and 100 being severe symptoms) is computed as Week 4 value minus baseline value. A negative value in change from baseline indicates an improvement. | Baseline, Week 4 | 
| Mean Change From Baseline in the TWSTRS - Functional Disability Score at Week 4 After Treatment | TWSTRS-Disability score which ranges from 0 (=no disability)to 30 (=maximum disability). The change from baseline was calculated as the score at the corresponding visit minus the baseline score. | Baseline, Week 4 | 
| Mean Change From Baseline in the TWSTRS - Pain Score at Week 4 After Treatment | TWSTRS-Pain score which ranges from 0 (=no pain) to 20 (=maximum pain). The change from baseline was calculated as the score at the corresponding visit minus the baseline score. | Baseline, Week 4 | 
| Mean Change From Baseline in the TWSTRS - Severity Score at Week 4 After Treatment | TWSTRS-Severity score which ranges from 0 (=absence of severity) to 35 points (=maximum severity). The change from baseline was calculated as the score at the corresponding visit minus the baseline score. | Baseline, Week 4 | 
| Mean Change From Baseline in Patient Pain Assessment (VAS) at Week 4 After Treatment | Change from Baseline in Patient's Pain Assessment-VAS is computed as Week 4 value minus baseline value. A negative value in change from baseline indicates an improvement. The patient's assessment of pain was performed using a 100 mm VAS)ranging from no pain (0) to unbearable pain (100). The distance in mm from the left edge of the scale was measured. A negative change from Baseline score indicates improvement in pain intensity. | Baseline, Week 4 |