Study Comparing Short Term Efficacy of Dysport and Dysport NG to Placebo, and to Assess Efficacy and Safety of Dysport NG of Subjects With Cervical Dystonia

A Phase III, Randomised, Double-blind and Open Label Phase, Active and Placebo Controlled Study Comparing the Short-term Efficacy of Two Formulations of Clostridium Botulinum Type A Toxin (Dysport and Dysport NG) to Placebo, and Assessing the Short and Long Term Efficacy and Safety of Dysport NG Following Repeated Treatments of Subjects With Cervical Dystonia

The purpose of this study is to evaluate how well a new drug called Dysport NG works and how safe it is, when it is used for the treatment of cervical dystonia. Dysport NG will be compared to an approved drug called Dysport.

Study Overview

• Status: Completed
• Conditions: Cervical Dystonia
• Intervention / Treatment: Biological: Botulinum toxin type A; Biological: Botulinum toxin type A; Drug: Placebo

Detailed Description

The primary study objectives will be assessed in terms of improvement of the subject's CD at a pre-defined time point after treatment. The primary study objectives are to demonstrate the superiority of Dysport NG to placebo in terms of efficacy and to test the non-inferior efficacy of Dysport NG, when compared to Dysport, in CD subjects. In addition to testing for the primary study objectives, the superiority in terms of efficacy of Dysport versus placebo, will be assessed.

This clinical study was designed and implemented and reported in accordance with the International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and with the ethical principles laid down in the Declaration of Helsinki.

A large body of evidence demonstrates the safety and efficacy of Dysport across several clinical indications. This study was the first use of Dysport NG in humans with CD. The active substance (BTX-A-HAC) in Dysport NG was the same as in the currently marketed Dysport product and had the same mechanism of action. Dysport NG was, therefore, expected to have the same efficacy and safety profile in humans as Dysport, with the advantage of eliminating the potential risk of transmission of infective agents, by the substitution of plant and synthetic products for human and animal-derived products. However, due to the change of excipient, thorough assessment of the safety and efficacy of Dysport NG is necessary. Previous clinical studies indicate that the maximum effect of Dysport and maximum improvements in CD are observed approximately 4 weeks post treatment, after which there is a gradual return to baseline disease status. The Week 4 follow up visit after the first treatment cycle was therefore, chosen as the primary time point of interest. Retreatment is necessary in order to maintain the beneficial effect and the long term treatment of CD. Previously conducted long term studies demonstrate the maintenance of the therapeutic effect of Dysport following repeated treatments, with a favourable short and long term safety and immunogenicity profile.

• Study Type: Interventional
• Enrollment (Actual): 382
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Clayton, Australia
    • Monash Medical Centre
  • Heidelberg, Australia
    • Austin Hospital
  • Prahran, Australia
    • Department of Neurosciences Alfred Hospital
  • Westmead, Australia
    • Westmead Hospital
• Austria
  • Innsbruck, Austria
    • Univ.-Klinik für Neurologie
  • Wien, Austria
    • Univ.-Klinik für Neurologie
• Belgium
  • Brugge, Belgium
    • AZ St. Jan
  • Edegem, Belgium
    • Universitair Ziekenhuis Antwerpen
  • Gent, Belgium
    • AZ Sint Lucas
  • Liège, Belgium
    • Centre Hospitalier Universitaire de Liege
  • Roeselare, Belgium
    • HH Ziekenhuis
• Czechia
  • Brno, Czechia
    • Fakultni Nemocnice Brno
  • Pardubice, Czechia
    • Pardubicka krajska nemocnice
  • Plzen, Czechia
    • Research Site s.r.o.
  • Praha, Czechia
    • Vseobecna Fakultni Nemocnice V Praze
• France
  • Amiens, France
    • CHU Amiens
  • Bron, France
    • Hôpital Neurologique
  • Nîmes, France
    • CHU Caremeau
  • Pessac, France
    • CHU Bordeaux
  • Strasbourg, France
    • CHU Strasbourg
  • Toulouse, France
    • Hôpital Purpan
• Germany
  • Berlin, Germany
    • Neurologische Klinik u. Poliklinik
  • Bonn, Germany
    • Neurologische Klinik u. Poliklinik
  • Düsseldorf, Germany
    • Neurologische Klinik
  • Halle, Germany
    • Neurologische Klinik
  • Hannover, Germany
    • Neurologische Klinik
  • Leipzig, Germany
    • Neurologische Klinik
  • München, Germany
    • Neurologische Klinik
  • Tübingen, Germany
    • Neurologische Klinik
  • Wiesbaden, Germany
    • Neurologische Klinik
  • Würzburg, Germany
    • Neurologische Klinik
• Hungary
  • Budapest, Hungary
    • Semmelweis Egyetem
  • Nyíregyháza, Hungary
    • Jósa András Oktató Kórház Nonprofit Kft.
  • Pécs, Hungary
    • Pecsi Tudomanyegyetem
  • Szeged, Hungary
    • Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ
• Poland
  • Gdansk, Poland
    • Pomorskie Centrum Traumatologii im. M. Kopernika w Gdansku
  • Katowice, Poland
    • Specjalistyczna Praktyka Lekarska
  • Krakow, Poland
    • Malopolskie Centrum Medyczne
  • Lodz, Poland
    • Gabinet Lekarski
  • Poznan, Poland
    • Niepubliczny Zaklad Opieki Zdrowotnej
  • Warszawa, Poland
    • Samodzielny Publiczny Centralny Szpital Kliniczny
• Portugal
  • Lisboa, Portugal
    • Hospital Santa Maria
  • Porto, Portugal
    • Hospital Geral de Santo Antonio
• Russian Federation
  • Kazan, Russian Federation
    • Research Medical Complex "Vashe Zdorovie"
  • Moscow, Russian Federation
    • Research Center of Neurology of RAMS
  • Nizhniy Novgorod, Russian Federation
    • Nizhniy Novgorod Research Institute for Traumatology and Orthopaedics
  • Samara, Russian Federation
    • Samara Regional Clinical Hospital
  • Smolensk, Russian Federation
    • Smolensk State Medical Academy Smolensk Regional Clinical Hospital
  • St. Petersburg, Russian Federation
    • Russian Medical Military Academy n.a. S.M.Kirov
• Ukraine
  • Chernivtsi, Ukraine
    • Bukovinian Medical State University
  • Dnipropetrovsk, Ukraine
    • Ukrainian State Institute of Medical and Social Problems of Disability
  • Donetsk, Ukraine
    • Donetsk Railroad Clinical Hospital
  • Kharkiv, Ukraine
    • Institute of Neurology, Psychiatry and Narcology AMS of Ukraine
  • Lviv, Ukraine
    • Lviv Regional Clinical Hospital
  • Odessa, Ukraine
    • Municipal Institution "Odesa Regional Clinical Hospital"
  • Uzhgorod, Ukraine
    • Uzhgorod National University
  • Vinnytsya, Ukraine
    • Vinnytsya National Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Dystonia with at least 18 months duration since onset.
• Previously untreated with Botulinum toxin-A (BTX-A) or -B or a minimum of 14 weeks since the last injection.
• TWSTRS score at baseline of: Total score ≥ 30, Severity Sub-Scale score ≥ 15, Disability Sub-Scale score ≥ 3, Pain Sub-Scale score ≥ 2.

Exclusion Criteria:

• Known hypersensitivity to Botulinum toxin (BTX) or related compounds or any component in the study drug formulation (including cow milk protein).
• Pure anterocollis or pure retrocollis.
• In apparent remission from Cervical Dystonia.
• Known clinically significant underlying swallowing or respiratory abnormality which might be exacerbated by BTX treatment.
• Previous poor response to BTX treatment or known presence of BTX neutralising antibodies.
• Previous phenol or alcohol injections into the neck muscles.
• Previous myotomy or denervation surgery involving the neck or shoulder region.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dysport NG; 500U (1mL) administered as intramuscular injection on day 1 of treatment cycle 1 and 2. 250U (0.5mL), 500U (1mL) or 750U (1.5mL) administered as intramuscular injection on day 1 of treatment cycle 3. 250U (0.5mL), 500U (1mL), 750U (1.5mL) or 1000U (2mL) administered as intramuscular injection on day 1 of treatment cycle 4 and 5.	Biological: Botulinum toxin type A; I.M. (in the muscle) injection on day 1 of up to 5 treatment cycles.; Other Names: AbobotulinumtoxinA (DysportRU®); Biological: Botulinum toxin type A; I.M. injection on day 1 of treatment cycle 1.; Other Names: AbobotulinumtoxinA (Dysport®)
Active Comparator: Dysport; 500U (1mL) injected as intramuscular injection on day 1 of treatment cycle 1.	Biological: Botulinum toxin type A; I.M. (in the muscle) injection on day 1 of up to 5 treatment cycles.; Other Names: AbobotulinumtoxinA (DysportRU®); Biological: Botulinum toxin type A; I.M. injection on day 1 of treatment cycle 1.; Other Names: AbobotulinumtoxinA (Dysport®)
Placebo Comparator: Placebo; 1mL administered as, intramuscular injection on day 1 of treatment cycle 1.	Drug: Placebo; I.M. injection on day 1 of treatment cycle 1.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score Following First Treatment Cycle	TWSTRS measures the degree of CD and is comprised of three different components, namely Severity, Disability and Pain subscales. There is an ordinal scale score and range for each component. Severity scores range from 0 (absence of severity) to 35 (maximum severity), Disability scores range from 0 (no disability) to 30 (maximum disability) and Pain scores range from 0 (no pain) to 20 (maximum pain). TWSTRS Total score is the sum of the 3 component scores ranging from 0 to a maximum of 85, with higher scores denoting worse outcome. If the change from baseline is negative, this represents an improvement in symptoms.	Baseline and Week 4

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Subscale Score Following First Treatment Cycle	TWSTRS measures the degree of CD and comprises three different components, one of which is the Severity subscale. TWSTRS Severity subscale scores range from 0 (absence of severity) to 35 (maximum severity). If the change from baseline is negative, this represents an improvement in symptoms.	Baseline and Week 4
Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Subscale Score Following First Treatment Cycle	TWSTRS measures the degree of CD and comprises three different components, one of which is the Disability subscale. TWSTRS Disability subscale scores range from 0 (no disability) to 30 (maximum disability). If the change from baseline is negative, this represents an improvement in symptoms.	Baseline and Week 4
Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score Following First Treatment Cycle	TWSTRS measures the degree of CD and comprises three different components, one of which is the Pain subscale. TWSTRS Pain subscale scores range from 0 (no pain) to 20 (maximum pain). If the change from baseline is negative, this represents an improvement in symptoms.	Baseline and Week 4
Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia Following First Treatment Cycle	The assessment was made on a continuous 100-mm horizontal line with a scale range of 0 mm (no pain) to 100 mm (worst possible pain).	Baseline and Week 4
Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia Following First Treatment Cycle	The assessment was made on a continuous 100-mm horizontal line with a scale range of 0 mm (no symptoms) to 100 mm (worst possible symptoms).	Baseline and Week 4
Percentage of Treatment Responders Following First Treatment Cycle	A treatment responder was defined as a patient with >30% improvement in TWSTRS Total score compared to baseline. TWSTRS measures the degree of CD and is comprised of three different components, namely Severity, Disability and Pain subscales. There is an ordinal scale score and range for each component. Severity scores range from 0 (absence of severity) to 35 (maximum severity), Disability scores range from 0 (no disability) to 30 (maximum disability) and Pain scores range from 0 (no pain) to 20 (maximum pain). TWSTRS Total score is the sum of the 3 component scores ranging from 0 to a maximum of 85, with higher scores denoting worse outcome. If the change from baseline is negative, this represents an improvement in symptoms.	Baseline and Week 4
Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Total Score for Treatment Cycles 2 to 5	TWSTRS measures the degree of CD and is comprised of three different components, namely Severity, Disability and Pain subscales. There is an ordinal scale score and range for each component. Severity scores range from 0 (absence of severity) to 35 (maximum severity), Disability scores range from 0 (no disability) to 30 (maximum disability) and Pain scores range from 0 (no pain) to 20 (maximum pain). TWSTRS Total score is the sum of the 3 component scores ranging from 0 to a maximum of 85, with higher scores denoting worse outcome. If the change from baseline is negative, this represents an improvement in symptoms.	Treatment cycle Baseline and Week 4
Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Severity Score for Treatment Cycles 2 to 5	TWSTRS measures the degree of CD and comprises three different components, one of which is the Severity subscale. TWSTRS Severity subscale scores range from 0 (absence of severity) to 35 (maximum severity). If the change from baseline is negative, this represents an improvement in symptoms.	Treatment cycle Baseline and Week 4
Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Disability Score for Treatment Cycles 2 to 5	TWSTRS measures the degree of CD and comprises three different components, one of which is the Disability subscale. TWSTRS Disability subscale scores range from 0 (no disability) to 30 (maximum disability). If the change from baseline is negative, this represents an improvement in symptoms.	Treatment cycle Baseline and Week 4
Change From Baseline in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) Pain Subscale Score for Treatment Cycles 2 to 5	TWSTRS measures the degree of CD and comprises three different components, one of which is the Pain subscale. TWSTRS Pain subscale scores range from 0 (no pain) to 20 (maximum pain). If the change from baseline is negative, this represents an improvement in symptoms.	Treatment cycle Baseline and Week 4
Change From Baseline in Subject Visual Analogue Score (VAS) for Pain From Cervical Dystonia for Treatment Cycles 2 to 5	The assessment was made on a continuous 100-mm horizontal line with a scale range of 0 mm (no pain) to 100 mm (worst possible pain).	Treatment cycle Baseline and Week 4
Change From Baseline in Subject Visual Analogue Score (VAS) for Symptoms of Cervical Dystonia for Treatment Cycles 2 to 5	The assessment was made on a continuous 100-mm horizontal line with a scale of 0 mm (no symptoms) to 100 mm (worst possible symptoms).	Treatment cycle Baseline and Week 4
Percentage of Treatment Responders for Treatment Cycles 2 to 5	A treatment responder was defined as a patient with >30% improvement in TWSTRS Total score compared to baseline. TWSTRS measures the degree of CD and is comprised of three different components, namely Severity, Disability and Pain subscales. There is an ordinal scale score and range for each component. Severity scores range from 0 (absence of severity) to 35 (maximum severity), Disability scores range from 0 (no disability) to 30 (maximum disability) and Pain scores range from 0 (no pain) to 20 (maximum pain). TWSTRS Total score is the sum of the 3 component scores ranging from 0 to a maximum of 85, with higher scores denoting worse outcome. If the change from baseline is negative, this represents an improvement in symptoms.	Treatment cycle Baseline and Week 4

Collaborators and Investigators

• Sponsor: Ipsen

Publications and helpful links

General Publications

• Poewe W, Burbaud P, Castelnovo G, Jost WH, Ceballos-Baumann AO, Banach M, Potulska-Chromik A, Ferreira JJ, Bihari K, Ehler E, Bares M, Dzyak LA, Belova AN, Pham E, Liu WJ, Picaut P. Efficacy and safety of abobotulinumtoxinA liquid formulation in cervical dystonia: A randomized-controlled trial. Mov Disord. 2016 Nov;31(11):1649-1657. doi: 10.1002/mds.26760. Epub 2016 Sep 21.

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Actual): May 1, 2012
• Study Completion (Actual): June 1, 2013

Study Registration Dates

• First Submitted: December 15, 2010
• First Submitted That Met QC Criteria: December 15, 2010
• First Posted (Estimate): December 16, 2010

Study Record Updates

• Last Update Posted (Actual): September 28, 2022
• Last Update Submitted That Met QC Criteria: September 15, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Movement Disorders; Dyskinesias; Dystonia; Dystonic Disorders; Torticollis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Cholinergic Agents; Membrane Transport Modulators; Acetylcholine Release Inhibitors; Neuromuscular Agents; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
• Other Study ID Numbers: Y-52-52120-134; 2010-019907-43 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, annotated case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized, and study documents will be redacted to protect the privacy of study participants.

Any requests should be submitted to www.vivli.org for assessment by an independent scientific review board.

• IPD Sharing Time Frame: Where applicable, data from eligible studies are available 6 months after the studied medicine and indication have been approved in the US and EU or after the primary manuscript describing the results has been accepted for publication, whichever is later.
• IPD Sharing Access Criteria: Further details on Ipsen's sharing criteria, eligible studies and process for sharing are available here (https://vivli.org/members/ourmembers/).