Abobotulinum Toxin and Neubotulinum Toxin Injection in Cerivical Dystonia

Study Overview
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Brief Summary
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A 48-Week Prospective, Double-Blinded, Randomized, Cross-over design in Multicenter Study of, 250 unit of Abobotulinum Toxin Type A (Dysport) and 50 unit of Neubotulinum Toxin Type A (Neuronox) injection for Cervical Dystonia in patient diagnosed with cervical dystonia according to clinical diagnosis. It was designed to evaluate the efficacy, safety, tolerability, quality of life and the comparesion the improvement after treatment by of Abobotulinum Toxin Type A (Dysport) injection versus Neubotulinum Toxin Type A (Neuronox)Injection.

Detailed Description
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Abobotulinum neurotoxin type A, abo-BoNT/A, (Dysport®) is the most potent biological toxin produced from Clostridium botulinum. In 1920, Dr Hermann Sommer of the Hooper Foundation at the University of California made the first attempt to purify the botulinum toxin. His work paved the way for further studies at Cam (Fort) Detrick on botulinum toxin type B, C, D, and E, particularly during the World War II. In 1946, Dr Carl Lammanna first crystalised the botulinum toxin type A and found it was composed of toxic units bound to non-toxic unit proteins. Dr Vernon Brooks, suggested that the botulinum toxin type A might be use to reduce the activity of hyperactive muscle in 1950s (9). In 1970-1971 Dr Alan B. Scott evolved an elegant electrophysiology EMG-guided technique to inject small doses of various agents to produce weakening of extraocular muscle for non-surgical treatment of strabismus. By 1973, he demonstrated in animal experiments that botulinum can be used for the treatment of strabismus and suggested that it might be of benefit for treating blepharospasm. In 1977, the U.S.FDA approved the botulinum toxin for human study and the result of the first clinical trial of botulinum toxin for strabismus was published in 1980. The U.S. FDA approved the botulinum toxin treatment in various movement disorders in 1990. In 1991, the United Kingdom authorized the licence of Dysport®, and was commercially marketed by Speywood Pharmacuticals Ltd (previously Porton Products Ltd). After it's initial success in the treatment of strabismus, Botulinum toxin was used to treat other ophthalmological conditions, such as dysthyroid ophthalmopathy (1) and nystagmus (2) blepharospasm (3), focal abnormal movement such as hemifacial spasm, spasmodic torticollis, spasticity such as dystonia and pain such as cervical and lumbar pain (4). There has been a steady stream of ideas for other uses, such as urinary, rectal, gastroesophageal sphincter and sphincter of Oddi disturbances, cosmetic (reduction of wrinkle) and eventually tension-type headache. In the past few years, some clinical observation from Brin, MasKop reported that patients who had been injected with botulinum toxin for wrinkle had some benefit for relieving headache. Three documented studies showed the clinical use of botulinum toxin for migraine prophylaxis.(26) Neubotulinum Toxin Type A, (Neu-BoNT/A), (Neuronox® ) (Medytox Inc, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungcheongbuk-do, Republic of Korea), also known as Meditoxin in Korea, is a newly manufactured BoNT-A (Neu-BoNT/A) that was developed to provide features close to onabotulinum toxin A (5). Neuronox was tested in a murine model, and its effect on muscle force generation was equivalent to Botox® (ona-BoNT/A) (6). A previous multicenter randomized controlled trial showed that Neuronox and Botox® have equivalent efficacy and safety for the treatment of spastic equinus in children with cerebral palsy (6). However, Neuronox has not yet been investigated in post-stroke upper limb spasticity and cervical dystonia. STUDYOBJECTIVES Primary Objective Comparesion of pre- and post- treatment after 12 and 24 week TWSTRS and CDIP-58 scale with 50 unit of Neubotulinum Toxin Type A (Neuronox) and 250 unit of Abobotulinum Toxin Type A (Dysport) incervical dystonia patients 8.2 Secondary Objective Comparesion the quality of life (SF 36, CES-D) pre- and post- 12 and 24 week treatment with 50 unit of Neubotulinum Toxin Type A (Neuronox) and 250 unit of Abobotulinum Toxin Type A (Dysport) incervical dystonia patients There were two treatment arms in crossover designed study and the interest was only on the comparison of each pre- and post- treatment outcomes of (Dysport)and (Neuronox) , two pair- wise comparisons pre and post treatment after 12 and 24 week scale were carried out. For each of the pair-wise comparison, 2-sided p-value was used to ensure that the overall Type I error=0.05. Beta error 80% Multiple repeated analysis and general linear model will be analysed in the efficacy of treatment.Two-sided exact p-values were reported in the efficacy analyses. Demographic and safety analyses were based on the summary of descriptive statistics. At the screening visit and prior to performance of any study procedures, the investigators would explain the details of the study and the subject would have to sign on the written informed consent, exclusion criteria, and inclusion criteria Each subject who was willing to enrol into the study was asked about their medical history as well as their recent and current medications being taken. All enrolled subjects were asked to undertake an initial physical examination and had to satisfy the criteria for the inclusion /exclusion before being enrolled into the study. All patients were asked to complete physical examination, TWSTRS, CDIP-58, SF36, PHQ9 and CES-D . Laboratory blood (livers tests, haematology,) examinations, urine pregnancy test) were performed for safety reasons. 1Inclusion Criteria The subjects need to satisfy the following criteria before being allowed to participate in the study: The subject has to grant permission to enter into the study by signing and dating the informed consent form before completing any study-related procedure such as any assessment or evaluation not related to the normal medical care of the subject. Able to give written inform consent and retained one copy of the consent form • Male or female subject, aged between 18 - 100 years old. Subject diagnosed to be cervical dystonia. Female subject in good health and sexually active was instructed by the investigator to avoid pregnancy during the study and to use condom or other contraceptive measure if necessary. The subject was required to have a negative urine pregnancy test before being eligible for the study. (At each of the subsequent visit, a urine pregnancy test was performed). Subject judged to be reliable for compliance for taking medication and capable of recording the effects of the medication and motivated in receiving benefits from the treatment. Subject should undergo a normal physical and neurological examination TWSTRS, CDIP-58, SF36, and CES-D during the whole study period at will. 9.2.2 Exclusion Criteria The subject WERE NOT ALLOWED TO enter/continue into the study, if :. The subject was pregnant or lactating. The subject was a female at risk of pregnancy during the study and not taking adequate precautions against pregnancy. The subject had a known hypersensitivity to any of the test materials or related compounds. The subject was unable or unwilling to comply fully with the protocol. The subject received any unlicensed drug within the previous 6 months. Treatment with investigational drug (s) within 6 months before the screening visit. • The subject had previously entered in this study. Subject with past history of botulism, other neuromuscular disorder (e.g. myasthenia gravis, Lambert - Elton Syndrome) Subject with significant medical / neurological / psychiatric disorders such as blood dyscrasia, thrombocytopenia, rheumatoid arthritis, congestive heart failure, coronary artery heart diseases, dementia, psychosis, or other conditions which could influence the clinical trial. Known history of drug abuse (narcotic (s), cafergot, or others) or drug (botulinum toxin type A) allergy. Unable to cooperate fill-up TWSTRS, CDIP-58, SF36, and CES-D • Patient who planned to schedule elective surgery during the study. The used of aminoglycoside antibiotics and curare were not allowed during the study.

Official Title
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A 48-Week Prospective, Double-Blinded, Randomized, Cross-over Design in Multicenter Study of 250 Unit of Dysport Versus 50 Unit of Neuronox Injection For Cervical Dystonia in Thai Patients

Conditions
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Cervical Dystonia

Intervention / Treatment
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* Drug: Neuronox(R)
* Drug: Dysport (R)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subjects need to satisfy the following criteria before being allowed to participate in the study: The subject has to grant permission to enter into the study by signing and dating the informed consent form before completing any study-related procedure such as any assessment or evaluation not related to the normal medical care of the subject. Able to give written inform consent and retained one copy of the consent form • Male or female subject, aged between 18 - 100 years old. Subject diagnosed to be cervical dystonia. Female subject in good health and sexually active was instructed by the investigator to avoid pregnancy during the study and to use condom or other contraceptive measure if necessary. The subject was required to have a negative urine pregnancy test before being eligible for the study. (At each of the subsequent visit, a urine pregnancy test was performed). Subject judged to be reliable for compliance for taking medication and capable of recording the effects of the medication and motivated in receiving benefits from the treatment. Subject should undergo a normal physical and neurological examination TWSTRS, CDIP-58, SF36, and CES-D • during the whole study period Exclusion Criteria: - The subject WERE NOT ALLOWED TO enter/continue into the study, if :. The subject was pregnant or lactating. The subject was a female at risk of pregnancy during the study and not taking adequate precautions against pregnancy. The subject had a known hypersensitivity to any of the test materials or related compounds. The subject was unable or unwilling to comply fully with the protocol. The subject received any unlicensed drug within the previous 6 months. Treatment with investigational drug (s) within 6 months before the screening visit. • The subject had previously entered in this study. Subject with past history of botulism, other neuromuscular disorder (e.g. myasthenia gravis, Lambert - Elton Syndrome) Subject with significant medical / neurological / psychiatric disorders such as blood dyscrasia, thrombocytopenia, rheumatoid arthritis, congestive heart failure, coronary artery heart diseases, dementia, psychosis, or other conditions which could influence the clinical trial. Known history of drug abuse (narcotic (s), cafergot, or others) or drug (botulinum toxin type A) allergy. Unable to cooperate fill-up TWSTRS, CDIP-58, SF36, and CES-D • Patient who planned to schedule elective surgery during the study. The used of aminoglycoside antibiotics and curare were not allowed during the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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: Crossover Assignment
Interventional Model Description: Double Blind randomized controlled trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Neuronox(R) intramuscular injection<br>Neu-botulinum Toxin Type A (Neuronox(R) - botulinum toxin type A product by medyceles company , Korea) 50 units Intramuscular injection in the affected neck muscle that cause cervical dystonia every 12 weeks for 24 weeks ( 2 times , 12 week interval) | Drug: Neuronox(R)<br>* Injection botulinum toxin intramuscular for affected neck muscle<br>* Other names: Intramuscular injection;|
| Active Comparator: Dysport (R) intramuscular injection<br>Abo-botulinum Toxin Type A (Dysport (R) - botulinum toxin type A product by IPEN company, France ) 250 unit Intramuscular Injection in the affected neck muscle that cause cervical dystonia every 12 weeks for 24 weeks (2 times , 12 week interval) | Drug: Dysport (R)<br>* Intramuscular injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toronto Western Spasmodic Torticollis Rating scale ( TWSTRS) | TWSTRS ranged( 0-85 by summation of all 3 sub- scales ) higher represent a worse outcome TWSTRS Sub- scale includes TWSTRS-Total severity scale ( maximum 35 points) TWSTS-Disability scale (maximum 30 points) TWSTS-Pain scale (maximum 20 points) | 24 week | 
| Cervical Dystonia Impact Profile 58 ( CDIP-58) | ) Cervical Dystonia Impact Profile-58 items composed of 8 sub-scale Total score by summation of 8 subscale higher represent a worse outcome Analysis both total score (range 58-290 points) And sub-scale analysis composed of Head and neck symptoms ( 6 items ; 6-30 points) Pain and discomfort ( 5 items ; 5-25 points) Upper limb activity ( 9 items ; 9-45 points) Walking ( 9 items ; 9-45 points) Sleep ( 4 items ; 4-20 points) Annoyance ( 8 items ; 8-40 points) Mood (7 items ; 7-35 points) Psychosocial functioning ( 10 items ; 10-50 points) | 24 week | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparesion the quality of life 36 item ( SF 36) | Comparesion the quality of life (SF 36) pre- and post- 12 and 24 week ttreatment with 50 unit of Neubotulinum Toxin Type A (Neuronox) and 250 unit of Abobotulinum Toxin Type A (Dysport) this score has special formula calculation | 24 week | 
| Depression scale measured by Center of Epidemiologic Study of Depression 20 item ( CES-D 20) | Comparesion of CES-D pre- and post- 12 and 24 week treatment with 50 unit of Neubotulinum Toxin Type A (Neuronox) and 250 unit of Abobotulinum Toxin Type A (Dysport) Score ranged from 20-80 points higher represent a worse outcome | 24 week | 
| Depression scale measured by Patient Health Questionnaire Depression Scale (PHQ-9) | Comparesion of PHQ-9 pre- and post- 12 and 24 week treatment with 50 unit of Neubotulinum Toxin Type A (Neuronox) and 250 unit of Abobotulinum Toxin Type A (Dysport) There is the special scale calculation for diagnosis Major depressive disorder, Other depressive disorder and others,higher points /score represent a worse outcome ranged 0-27 points plus 3 points Total summation of 5-9 points indicate Minimal symptoms, 10-14 Minor depression ++ or Dysthymia* or Major depression, mild , 15-19 points Major depression, moderately severe ≥ 20 Major depression, severe | 24 week | 
| Clinical Global Impression of Changed ( CGIC) | Comparesion of CGIC pre- and post- 12 and 24 week treatment with 50 unit of Neubotulinum Toxin Type A (Neuronox) and 250 unit of Abobotulinum Toxin Type A (Dysport) | 24 week the scale compose of -3 to 3 higher represent a good outcome |