A Study to Compare the Safety and Efficacy of Dysport® and Botox® in Adults With Upper Limb Spasticity. (DIRECTION)

A Multicentre, Interventional, Post-marketing, Randomised, Double-blind, Crossover Study to Evaluate the Clinical Safety and Efficacy of AbobotulinumtoxinA (Dysport®) in Comparison With OnabotulinumtoxinA (Botox®) When Treating Adults With Upper Limb Spasticity

This study is aiming to demonstrate the non-inferiority of AbobotulinumtoxinA (aboBoNT-A) versus OnabotulinumtoxinA (onaBoNT-A) as the primary safety endpoint, and the superiority of aboBoNT-A over onaBoNT-A with respect to duration of response as the key secondary efficacy endpoint when used at optimal doses according to approved prescribing information of each product.

Study Overview

• Status: Recruiting
• Conditions: Upper Limb Spasticity
• Intervention / Treatment: Biological: AboBoNT-A; Biological: OnaBoNT-A

• Study Type: Interventional
• Enrollment (Estimated): 298
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ipsen Recruitment Enquiries; Phone Number: See email; Email: clinical.trials@ipsen.com

Study Locations

• Canada
  • Edmonton, Canada, T5G 0B7
    • Not yet recruiting
    • Glenrose Rehabilitation Hospital
  • Halifax, Canada
    • Withdrawn
    • CDHA
  • Moncton, Canada, E1C 6Z8
    • Recruiting
    • Moncton Hospital
  • Montréal, Canada, H3A 2B4
    • Not yet recruiting
    • McGill University Health Center
  • Montréal, Canada, H3A 2B4
    • Recruiting
    • Genge Partners
    • Contact: Genge Partners
  • New Westminster, Canada
    • Withdrawn
    • Royal Columbian Hospital
  • Saint Catharines, Canada
    • Not yet recruiting
    • Hotel Dieu Shaver Health And Rehabilitation Centre
  • Toronto, Canada
    • Withdrawn
    • West Park Healthcare Centre
  • Victoria, Canada, V9A 3P2
    • Recruiting
    • Victoria Medical Rehab Consultants
  • Ontario
    • London, Ontario, Canada, N6C 5J1
      • Recruiting
      • Lawson Health Research Institute
• France
  • Angers, France, 49100
    • Recruiting
    • Centre Les Capucins
  • Bordeaux, France, 33000
    • Recruiting
    • Hôpital Pellegrin CHU Bordeaux
  • Créteil, France, 94000
    • Withdrawn
    • Hopital Albert Chennevier (CHU Henri Mondor)
  • Echirolles, France, 38434
    • Not yet recruiting
    • Hopital Sud
  • Marseille, France, 13384
    • Not yet recruiting
    • Hôpital d'Instruction des Armées Laveran
  • Nantes, France, 44000
    • Recruiting
    • Hôpital Saint-Jacques (CHU Nantes)
  • Nice, France, 06202
    • Recruiting
    • Hopital Archet (CHU de Nice)
  • Paris, France, 75010
    • Recruiting
    • Hopital Fernand Widal
  • Paris, France
    • Recruiting
    • Hôpital Sainte-Marie Paris - Groupe VYV
  • Ploemeur, France
    • Not yet recruiting
    • Centre Mutualiste de Rééducation et de Réadaptation Fonction
  • Poitiers, France, 86000
    • Withdrawn
    • Hôpital Jean Bernard (CHU Poitiers)
  • Rennes, France, 35033
    • Recruiting
    • Hôpital Pontchaillou (CHU Rennes)
  • Rennes, France, 35043
    • Recruiting
    • Pole Saint Helier
  • Roscoff, France, 29680
    • Recruiting
    • Centre de Perharidy
  • Saint-Amand-Montrond, France, 18200
    • Recruiting
    • Centre Hospitalier de Saint Amand Montrond
  • Saint-Amand-les-Eaux, France, 59230
    • Recruiting
    • Centre Hospitalier de Saint-Amand-les-Eaux
  • Saint-Genis-Laval, France, 69230
    • Recruiting
    • Hopital Henry Gabrielle (HCL)
  • Strasbourg, France, 67091
    • Recruiting
    • Hopitaux Universitaires de Strasbourg
  • Toulouse, France, 31059
    • Recruiting
    • Hôpital de Rangueil
• Puerto Rico
  • Santurce, Puerto Rico, 00912
    • Recruiting
    • University of Puerto Rico
• United States
  • Alabama
    • Birmingham, Alabama, United States, 25233
      • Recruiting
      • University Of Alabama
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Recruiting
      • HonorHealth Scottsdale Osborn Medical Center
    • Scottsdale, Arizona, United States, 85258
      • Recruiting
      • Movement Disorders Center of Arizona
    • Tucson, Arizona, United States, 85724
      • Recruiting
      • The University of Arizona
  • California
    • Downey, California, United States, 90242
      • Withdrawn
      • Rancho Los Amigos National Rehabilitation Center (RLANRC) - Neurology
    • Fountain Valley, California, United States, 92708
      • Recruiting
      • Parkinson's & Movement Disorders Institute
    • Fresno, California, United States, 93710
      • Recruiting
      • Neuro-Pain Medical Center
    • Loma Linda, California, United States, 92350
      • Recruiting
      • Loma Linda University Health Care
    • Long Beach, California, United States, 90808
      • Withdrawn
      • Southland Neurologic Institute
    • Los Angeles, California, United States, 90095
      • Not yet recruiting
      • University of California Los Angeles
  • Connecticut
    • New Haven, Connecticut, United States, 06511
      • Recruiting
      • Hasbani And Hasbani Medical Group
    • Stamford, Connecticut, United States, 06905
      • Recruiting
      • Ki Health Partners LLC D/B/A New England Institute for Clinical Research
  • Florida
    • Boca Raton, Florida, United States, 33428
      • Recruiting
      • First Choice Neurology
    • Port Charlotte, Florida, United States, 33980
      • Withdrawn
      • Parkinson's Disease Treatment Center of S.W. Florida
    • Saint Petersburg, Florida, United States, 33713
      • Withdrawn
      • Suncoast Neuroscience Associates, Inc
    • Tampa, Florida, United States, 33612
      • Recruiting
      • University of South Florida Health-Morsani Center for Advanced Healthcare
    • Tampa, Florida, United States, 33612
      • Recruiting
      • James A Haley Veterans Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory University of School of Medicine
  • Hawaii
    • Honolulu, Hawaii, United States, 96817
      • Recruiting
      • Hawaii Pacific Neuroscience
  • Illinois
    • Chicago, Illinois, United States, 60611-3167
      • Recruiting
      • Shirley Ryan Ability Lab
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • Recruiting
      • Fort Wayne Neurological Center
  • Iowa
    • Ames, Iowa, United States, 500101
      • Withdrawn
      • McFarland Clinic PC
  • Kansas
    • Overland Park, Kansas, United States, 66211-1358
      • Recruiting
      • Kansas City Bone and Joint Clinic, P.A. (KCBJ) - Overland Pa
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Recruiting
      • University of Louisville
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Not yet recruiting
      • University Medical Center New Orleans
    • New Orleans, Louisiana, United States, 70115
      • Withdrawn
      • Culicchia Neurological Clinic
    • New Orleans, Louisiana, United States, 70112
      • Recruiting
      • LSU Healthcare network
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • Not yet recruiting
      • UMass Memorial Medical Center - University Campus
  • Michigan
    • Bingham Farms, Michigan, United States, 48025
      • Withdrawn
      • Quest Research Institute
    • Dearborn, Michigan, United States, 48124
      • Recruiting
      • William Beaumont Hospital
    • Grand Blanc, Michigan, United States, 48439
      • Withdrawn
      • Ascension Genesys Hospital
    • Grand Blanc, Michigan, United States, 48439
      • Recruiting
      • Medical Rehabilitation Group, PC
    • Grand Rapids, Michigan, United States, 49503
      • Recruiting
      • Mary Free Bed Rehabilitation Hospital
    • Grosse Pointe, Michigan, United States, 48230
      • Not yet recruiting
      • Beaumont Hospital, Grosse Pointe
    • Grosse Pointe, Michigan, United States, 48334
      • Recruiting
      • Michigan Center of Medical Research
    • Plymouth, Michigan, United States, 48170
      • Withdrawn
      • Wayne Neurology PLC
  • Missouri
    • Columbia, Missouri, United States, 65203-3248
      • Recruiting
      • Rusk Rehabilitation Center
  • Nevada
    • Las Vegas, Nevada, United States, 89106
      • Recruiting
      • Wr-Crcn, Llc
  • New Jersey
    • Cherry Hill, New Jersey, United States, 08003
      • Recruiting
      • Cooper University Health Care
  • New York
    • Bronx, New York, United States, 10467
      • Recruiting
      • Montefiore Medical Center
    • New York, New York, United States, 10016
      • Recruiting
      • New York University
    • New York, New York, United States, 10029
      • Withdrawn
      • Mount Sinai Medical Center
    • New York, New York, United States, 10065
      • Recruiting
      • Weill Cornell Medicine Clinical and Translational Science Center
    • New York, New York, United States, 10003
      • Withdrawn
      • NY Neurology Institute
    • Port Jefferson, New York, United States, 11725
      • Recruiting
      • North Suffolk Neurology
    • Rochester, New York, United States, 55905
      • Recruiting
      • Mayo Clinic
    • Schenectady, New York, United States, 12308
      • Recruiting
      • Sunnyview Rehabilitation Hospital
    • Stony Brook, New York, United States, 11794
      • Recruiting
      • Stony Brook University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Not yet recruiting
      • Cleveland Clinic - Neurological Institute
  • Pennsylvania
    • Elkins Park, Pennsylvania, United States, 20010
      • Recruiting
      • MossRehab - Einstein Medical Center
    • Hershey, Pennsylvania, United States, 17033
      • Not yet recruiting
      • Penn State Health Physical Medicine and Rehabilitation - Neurology
    • Paoli, Pennsylvania, United States, 19301
      • Withdrawn
      • Rehabilitation Associates of the Main Line
    • Philadelphia, Pennsylvania, United States, 19140
      • Withdrawn
      • Temple University Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • Not yet recruiting
      • University of Pittsburgh Medical Center (Upmc)
    • Plains, Pennsylvania, United States, 18705
      • Withdrawn
      • Albert D. Janerich M.D. and Associates
    • Wayne, Pennsylvania, United States, 19087
      • Recruiting
      • Aether Medicine
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • Recruiting
      • Siskin Hospital for Rehabilitation - Neurology
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • The Vanderbilt Clinic
  • Texas
    • Dallas, Texas, United States, 75390
      • Recruiting
      • University of Texas Southwestern
    • Frisco, Texas, United States, 75034
      • Withdrawn
      • North Texas Institute of Neurology & Headache
    • Houston, Texas, United States, 77030
      • Not yet recruiting
      • TIRR Memorial Hermann Research Center
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • UT Health San Antonio
    • Sherman, Texas, United States, 75093
      • Recruiting
      • Texas Institute for Neurological Disorders
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Recruiting
      • University of Utah School of Medicine
  • Virginia
    • Roanoke, Virginia, United States, 24016
      • Not yet recruiting
      • Virginia Tech - Carilion School of Medicine
    • Roanoke, Virginia, United States, 24016
      • Recruiting
      • Carilion Clinic Institute of Orthopaedics and Neurosciences
  • Washington
    • Columbia, Washington, United States, 20010
      • Recruiting
      • MedStar National Rehabilitation Network
    • Seattle, Washington, United States, 98122
      • Not yet recruiting
      • Swedish Neuroscience Institute
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Medical College of Wisconsin - Froedtert Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participant must be 18 to 80 years of age inclusive, at the time of signing the informed consent
• 2a. [US/France] Participants with stable Upper Limb Spasticity (ULS) for at least 3 months, in whom treatment of only one upper limb is necessary for the duration of the study;
• 2b. [Canada] Participants with stable post-stroke ULS for at least 3 months, in whom treatment of only one upper limb is necessary for the duration of the study
• Participants who are either naïve to Botulinum toxin type A (BoNT-A) for ULS or who have been previously treated with BoNT-A for ULS;
• Participants with MAS score of at least 2 at two muscle groups (one of these two muscles groups should be the PTMG) and at least 1 in the remaining muscle group.
• Participants with DAS score of at least 2 on the Principal Target of Treatment (PTT) (one of four functional domains: dressing, hygiene, limb position and pain);
• Participants who require BoNT-A injection in all of the following muscles: flexor carpi radialis, flexor carpi ulnaris, flexor digitorum profundus, flexor digitorum superficialis and biceps brachii;
• Participants for whom injection of a total dose of 900 Units aboBoNT-A or 360 Units onaBoNT-A is considered by the investigator to be clinically appropriate;
• Participants who have been stable for at least 3 months prior to study entry in terms of oral antispasticity, anticoagulant and/or anticholinergic medication if treated are considered by the investigator likely to remain stable for the duration of the study;

Exclusion Criteria:

• Major limitations in the passive range of motion in the paretic upper limb;
• Major neurological impairment (other than limb paresis) that could negatively affect functional performance;
• Participants clinically requiring injection into any upper limb muscles other than the five muscles of one arm listed in Section 5.1, or requiring injection into both arms or any lower limb within the timeframe of the study;
• Hypersensitivity to any BoNT product or excipients;
• Hypersensitivity to cow's milk protein (casein);
• Infection at the proposed injection site(s);
• Known peripheral motor neuropathic diseases, amyotrophic lateral sclerosis or neuromuscular junction disorders (e.g. myasthenia gravis or Lambert-Eaton syndrome);
• Any medical condition (including dysphagia or breathing difficulties/compromised respiratory function) that in the opinion of the investigator, might jeopardize the participant's safety;
• Women who are pregnant or lactating
• Participants treated with BoNT of any type for any indication (e.g. bladder injection, headache or cosmetic) within the previous 12 weeks or planned/likely to be treated during the course of the study;
• Prior history of non-responsiveness to BoNT treatment;
• Previous surgery, or administration of alcohol or phenol in the study limb 6 months or earlier from study enrolment or planned/likely to be treated during the course of the study;
• Participants treated with intrathecal baclofen (except if treatment has reached a stable dose for >4 weeks and is likely to remain stable throughout the study), aminoglycosides or other agents interfering with neuromuscular transmission (e.g. curare-like agents) within the 4 weeks prior to study enrolment or planned/likely to be treated during the course of the study
• BoNT naïve participants with a history of facial neurogenic disorder (facial paralysis, polyradiculoneuropathy) (only for France).
• Participants receiving concomitant medication treatment with the following PT/OT interventions on the study limb: new splinting/orthotics/casting, serial casting, shockwave therapy, dry needling and needle tenotomies. However, PT/OT interventions not intended to reduce study limb spasticity (e.g. functional training exercises) or with a transient (<1 day) reduction of study limb spasticity (e.g. stretching, weight bearing) are allowed.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Sequence 1; Participants will receive one cycle of aboBoNT-A followed by one cycle of onaBoNT-A in the selected overactive upper limb muscles	Biological: AboBoNT-A; AbobotulinumtoxinA for injection: 500 Unit vial. Dose: 900 Units (3.6 mL); Other Names: Dysport®; Biological: OnaBoNT-A; OnabotulinumtoxinA for injection: 200 Unit vial. Dose: 360 Units (3.6 mL); Other Names: Botox®
Other: Sequence 2; Participants will receive one cycle of onaBoNT-A followed by one cycle of aboBoNT-A in the selected overactive upper limb muscles	Biological: AboBoNT-A; AbobotulinumtoxinA for injection: 500 Unit vial. Dose: 900 Units (3.6 mL); Other Names: Dysport®; Biological: OnaBoNT-A; OnabotulinumtoxinA for injection: 200 Unit vial. Dose: 360 Units (3.6 mL); Other Names: Botox®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Rate of Treatment-emergent Adverse Events (TEAEs)	from baseline (injection) to 12 weeks (injection cycle 1 and 2, each cycle is a maximum 24 weeks))

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Adverse Drug Reactions (ADRs), Serious Adverse Events (SAEs), Adverse Events of Special Interest (AESIs)		from baseline (injection) to 12 weeks (injection cycle 1 and 2, each cycle is a maximum 24 weeks))
Duration of response		baseline (injection) to retreatment criteria met, from week 10 up to week 24 (for each cycle, 1&2) or baseline to withdrawal or end of study if retreatment criteria not met, up to 24 weeks (for each cycle,1&2, each cycle is a maximum 24 weeks)
Muscle tone assessed by Modified Ashworth scale (MAS) total score	MAS is a scale which represents improvement in spasticity. This tool assesses muscle tone using a six-point scale from 0 = no change to 4 = considerable increase of affected/rigid region.	at baseline (injection), 1 week, 4 weeks, 10 weeks, 12 weeks and additional visits at 16 weeks, 20 weeks, 24 weeks (injection cycle 1 and 2; each cycle is a maximum 24 weeks)
Perceived function and pain assessed by the Disability Assessment Scale (DAS) total score	DAS scale to determine the extent of functional impairment in four domains: hygiene, dressing, limb position and pain. Impairment will be assessed on a four-point scale (range 0 to 3, where 0 indicates no disability and 3 indicates severe disability). The four domain ratings will be added to give an overall score between 0 and 12.	at baseline (injection), 1 week, 4 weeks, 10 weeks, 12 weeks and additional visits at 16 weeks, 20 weeks, 24 weeks (injection cycle 1 and 2; each cycle is a maximum 24 weeks)
Physician global assessment (PGA) of treatment response	PGA answers will be made on a nine-point rating scale (from -4 = markedly worse, to +4 = markedly improved).	at baseline (injection), 1 week, 4 weeks, 10 weeks, 12 weeks and additional visits at 16 weeks, 20 weeks, 24 weeks (injection cycle 1 and 2; each cycle is a maximum 24 weeks)
Change in Quality of Life (QoL) using the SF-12 perceived health score	12-Item Short-form Health Survey (SF-12) is a health survey that will assess general health and wellbeing. The SF-12 summary score is between 0 and 100, with higher scores indicating better self-reported health.	at baseline (injection), 4 weeks, 12 weeks and at end of each cycle (injection cycle 1 and 2; each cycle is a maximum 24 weeks)
Change in Quality of Life (QoL) using SQoL-6D	Spasticity-related Quality of Life Tool (SQoL-6D) is a brief questionnaire in six domains (pain/discomfort, involuntary movements or spasms, restricted range of movement, caring for the affected limb, using the affected limb and mobility/balance) using a five-level scale ranging from 0 to 4, with higher scores meaning worse condition.	at baseline (injection), 4 weeks, 12 weeks and at end of each cycle (injection cycle 1 and 2; each cycle is a maximum 24 weeks)

Collaborators and Investigators

• Sponsor: Ipsen
• Investigators: Study Director: Ipsen Medical Director, Ipsen

Publications and helpful links

General Publications

• Esquenazi A, Ayyoub Z, Verduzco-Gutierrez M, Maisonobe P, Otto J, Patel AT. AbobotulinumtoxinA Versus OnabotulinumtoxinA in Adults with Upper Limb Spasticity: A Randomized, Double-Blind, Crossover Study Protocol. Adv Ther. 2021 Nov;38(11):5623-5633. doi: 10.1007/s12325-021-01896-3. Epub 2021 Sep 25.

Study record dates

Study Major Dates

• Study Start (Actual): June 23, 2021
• Primary Completion (Estimated): June 28, 2025
• Study Completion (Estimated): June 28, 2025

Study Registration Dates

• First Submitted: June 9, 2021
• First Submitted That Met QC Criteria: June 22, 2021
• First Posted (Actual): June 23, 2021

Study Record Updates

• Last Update Posted (Actual): April 1, 2024
• Last Update Submitted That Met QC Criteria: March 29, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Manifestations; Muscle Hypertonia; Muscle Spasticity; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Membrane Transport Modulators; Acetylcholine Release Inhibitors; abobotulinumtoxinA
• Other Study ID Numbers: CLIN-52120-452; 2021-000161-32 (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/).

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No