Clinical trial NCT02936037: Effect of MD1003 in Progressive Multiple Sclerosis (SPI2)
Official title: Effect of MD1003 in Progressive Multiple Sclerosis: a Randomized Double Blind Placebo Controlled Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Multiple Sclerosis
Keywords: progressive multiple sclerosis
MS
EDSS
TW25
multiple sclerosis
Lead sponsor: MedDay Pharmaceuticals SA
Sponsor class: INDUSTRY
First posted: 2016-10-18
Enrollment: 642
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: PART 1:

Total duration of Part 1 is 27 months. The randomized double-blind placebo-controlled period ranges from 15 to 27 months depending upon the randomization date of an individual patient.

Once the last month 15 evaluation of the study has been completed, patients will switch to the active drug at the next planned visit. Participants and study personnel will remain blinded as to the original treatment assignment.

Maximum duration of double-blind period per patient will be no longer than 27 months.

PART 2:

At the last evaluation of Part 1 (Visit 11/Month 27) all participants will be offered active treatment in an open label extension for 39 additional months (From V11/M27 to V18/M66).

The purpose of the active drug extension is to further define the safety of MD1003.
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to demonstrate the superiority of MD1003 over placebo in the disability of patients suffering from progressive multiple sclerosis and especially those with gait impairment.


Eligibility criteria: Inclusion Criteria:

* Patient aged 18-65 years old
* Signed and dated written informed consent form in accordance with local regulations: having freely given their written informed consent to participate in the study
* Diagnosis of primary or secondary progressive MS fulfilling revised McDonald criteria (2010) and Lublin criteria (2014)
* Documented evidence of clinical disability progression within the 2 years prior to inclusion, i.e. a) progression of EDSS during the past two years of at least 1 point sustained for at least 6 months if inclusion EDSS is from 3.5 to 5.5 or at least 0.5 point increase sustained for at least 6 months if inclusion EDSS is from 6 to 6.5 or b) increase of TW25 by at least 20% in the last two years sustained for at least 6 months or c) other well-documented objective worsening validated by the Adjudication Committee
* EDSS at inclusion from 3.5 to 6.5
* TW25 \< 40 seconds at inclusion visit
* Kurtzke pyramidal functional subscore ≥2 defined as "minimal disability: patient complains of motor-fatigability or reduced performance in strenuous motor tasks (motor performance grade 1) and/or BMRC grade 4 in one or two muscle groups"

Exclusion Criteria:

* Clinical evidence of a relapse in 24 months prior to inclusion
* Treatment with any product containing biotin as single ingredient within six months prior to inclusion (multivitamin supplementation authorized if biotin \< 1mg per day)
* Concomitant treatment with fampridine at inclusion or in the 30 days prior to inclusion
* New immunosuppressive/immunomodulatory drug initiated less than 90 days prior to inclusion
* Treatment with botulinum toxin (except for cosmetic purpose) initiated within 6 months prior to inclusion
* In-patient rehabilitation program within the 3 months prior to inclusion
* Pregnancy, breastfeeding or women with childbearing potential without acceptable form of contraception
* Men unwilling to use an acceptable form of contraception
* Any general chronic handicapping/incapacitating disease other than MS
* Any serious disease necessitating biological follow-up with biological tests using biotinylated antibodies or substrates
* Past history of rhabdomyolysis/metabolic myopathy
* Known fatty acids beta oxidation defect
* Known hypersensitivity or intolerance to biotin, analogues or excipients, patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
* Patients with hypersensitivity or any contra-indication to Gadolinium
* Patients with uncontrolled hepatic disorder, renal or cardiovascular disease, or cancer
* Laboratory tests out of normal ranges considered by the investigator as clinically significant with regards to the study continuation
* Patients with history or presence of alcohol abuse or drug addiction
* Untreated or uncontrolled psychiatric disorders, especially suicidal risk assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)
* Participation in another research study involving an investigational product (IP) in the 90 days prior to inclusion, or planned use during the study duration
* Patients likely to be non-compliant to the study procedures or for whom a long-term follow-up seems to be difficult to achieve
* Relapse that occurs between inclusion and randomization visit

Primary outcomes:
measure: Proportion of Patients Improved on Either Expanded Disability Status Scale (EDSS) or Time to Walk 25 Feet (TW25)
timeFrame: 15 months
Secondary outcomes:
measure: Time to 12-Weeks Confirmed EDSS Progression
timeFrame: 3 to 27 months
measure: CGI-I Score (Clinical Global Impression of Change - Improvement), Evaluated Both by the Patient (SGI) and by the Evaluating Physician (CGI)
timeFrame: 15 months
measure: Mean Change in TW25 Between M0 and M15
timeFrame: 15 months
Other outcomes:
measure: Brain MRI Changes Between M0 and M15
timeFrame: 15 months
measure: Remote Monitoring of Ambulation
timeFrame: 27 months
measure: (MSQOL54) & (CAREQOL-MS) Subscores and Composite Scores
timeFrame: 15 months
measure: Subscores of the Kurtzke Functional Score
timeFrame: 15 months
measure: Symbol Digit Modalities Test (SDMT)
timeFrame: 15 months
Locations:
city: Phoenix
country: United States
facility: Barrow Neurology Clinics (BNC)
state: Arizona
city: Scottsdale
country: United States
facility: Mayo Clinic Scottsdale
state: Arizona
city: Berkeley
country: United States
facility: Jordan Research And Education Institute Of Alta Bates Summit
state: California
city: Fresno
country: United States
facility: Neuro-Pain Medical Center
state: California
city: Los Angeles
country: United States
facility: University of Southern California Keck School of Medicine
state: California
city: Newport Beach
country: United States
facility: MS Center of California
state: California
city: Sacramento
country: United States
facility: UC Davis Health System
state: California
city: San Francisco
country: United States
facility: UCSF Multiple Sclerosis Center
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: North Haven
country: United States
facility: Yale New Haven Hospital
state: Connecticut
city: Bradenton
country: United States
facility: Nova Clinical Research, LLC
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine
state: Florida
city: Tampa
country: United States
facility: University of South Florida - Neurology
state: Florida
city: Chicago
country: United States
facility: Northwestern University - Feinberg School of Medicine
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Medical Center-Duchossois Center for Advanced Medicine (DCAM)
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Lenexa
country: United States
facility: Rowe Neurology Institute
state: Kansas
city: New Orleans
country: United States
facility: Ochsner Health System
state: Louisiana
city: Baltimore
country: United States
facility: The Johns Hopkins Outpatient Center
state: Maryland
city: Boston
country: United States
facility: Harvard Medical School - Brigham and Women's Hospital - Center for Neurologic Diseases
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University - Comp Clinic and MS Center
state: Michigan
city: Golden Valley
country: United States
facility: Minneapolis Clinic of Neurology, LTD
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Teaneck
country: United States
facility: Holy Name Hospital
state: New Jersey
city: Albuquerque
country: United States
facility: The University of New Mexico - Multiple Sclerosis Specialty Clinic
state: New Mexico
city: Buffalo
country: United States
facility: UBMD Neurology
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine - Corinne Goldsmith Dickinson Center for MS
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Stony Brook
country: United States
facility: State University of New York (SUNY)
state: New York
city: Raleigh
country: United States
facility: Raleigh Neurology Associates, P.A.
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic Mellen Center for MS
state: Ohio
city: Portland
country: United States
facility: Providence Multiple Sclerosis Center
state: Oregon
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Knoxville
country: United States
facility: New Orleans Center for Clinical Research
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Comprehensive Multiple Sclerosis Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Round Rock
country: United States
facility: Central Texas Neurology Consultants
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
city: Seattle
country: United States
facility: Virginia Mason Medical Center
state: Washington
city: Sydney
country: Australia
facility: Brain and Mind Centre/University of Sydney
state: New South Wales
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Parkville
country: Australia
facility: The Royal Melbourne Hospital
state: Victoria
city: Edegem
country: Belgium
facility: UZ Antwerpen
state: Antwerpen
city: Hasselt
country: Belgium
facility: Jessa Ziekenhuis - Campus Virga Jesse
state: Limburg
city: Halle
country: Belgium
facility: UZ Gent
state: Oost-Vlaanderen
city: Burnaby
country: Canada
facility: Burnaby Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver Hospital and Health Sciences Centre
state: British Columbia
city: Moncton
country: Canada
facility: Hôpital universitaire Dr George L-Dumont university Hospital
state: New Brunswick
city: Halifax
country: Canada
facility: Nova Scotia Rehabilitation Center
state: Nova Scotia
city: Ottawa
country: Canada
facility: Ottawa Hospital General Campus
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Montreal
country: Canada
facility: Montreal Neurologic Institute
state: Quebec
city: Montréal
country: Canada
facility: Hopital de Notre Dame
state: Quebec
city: Hradec Králové
country: Czechia
facility: doc. MUDr. Radomir Talab, CSc., neurologie
city: Jihlava
country: Czechia
facility: Nemocnice Jihlava
city: Praha
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Praha
country: Czechia
facility: Fakultni nemocnice v Motole
city: Teplice
country: Czechia
facility: Nemocnice Teplice
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig A.ö.R. - Klinik und Poliklinik
state: Sachsen
city: Wermsdorf
country: Germany
facility: Fachkrankenhaus Hubertusburg
state: Sachsen
city: Bad Mergentheim
country: Germany
facility: Caritas Krankenhaus
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin / NeuroCure Clinical Research Center
city: Dusseldorf
country: Germany
facility: Heinrich-Heine-Universität Düsseldorf
city: Erbach
country: Germany
facility: Neuro Centrum Science GmbH
city: Hamburg
country: Germany
facility: MultipEL Studies Institut für klinische Studien GbR
city: München
country: Germany
facility: Ludwig-Maximilians Universität München
city: Ulm
country: Germany
facility: Neuropoint GmbH
city: Ulm
country: Germany
facility: Poliklinik für Neurologie Universitätsklinikum Ulm
city: Esztergom
country: Hungary
facility: Valeomed Kft
city: Milano
country: Italy
facility: Ospedale San Raffaele, IRCCS
city: Roma
country: Italy
facility: AO S.Andrea, Università degli Studi di Roma La Sapienza
city: Bydgoszcz
country: Poland
facility: Nasz Lekarz Ośrodek Badań Klinicznych
city: Gdansk
country: Poland
facility: COPERNICUS PL sp z o.o.,Szpital im. M.Kopernika Oddział Neurologiczny
city: Nowa Sol
country: Poland
facility: Twoja Przychodnia Centrum Medyczne Nowa Sol
city: Warszawa
country: Poland
facility: Centrum Medyczne Pratia Warszawa
city: Salt
country: Spain
facility: Hospital Santa Caterina
state: Girona
city: Pozuelo de Alarcón
country: Spain
facility: Hostipal Universitario Quirónsalud Madrid
state: Madrid
city: Castilleja de la Cuesta
country: Spain
facility: Servicio de Neurología Hospital Vithas Nisa Aljarafe
state: Sevilla
city: Barcelona
country: Spain
facility: Hospital del Mar Servicio de Neurología
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Málaga
city: Göteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhus - MS Center forskningsenheten
city: Stockholm
country: Sweden
facility: Karolinska University Hospital - Neurologmottagningen
city: Samsun
country: Turkey
facility: Ondokuz Mayis University Medical Faculty
city: Edinburgh
country: United Kingdom
facility: The University of Edinburgh
city: Glasgow
country: United Kingdom
facility: Institute of Neurological Sciences
city: London
country: United Kingdom
facility: Barts And The London School Of Medicine And Dentistry Institute
city: London
country: United Kingdom
facility: University College London Institute of Neurology / National Hospital for Neurology & Neurosurgery
city: Newcastle upon Tyne
country: United Kingdom
facility: Tyne Hospitals NHS Foundation
city: Salford
country: United Kingdom
facility: Salford Royal Hospital
Study officials:
affiliation: University of California, San Francisco
name: Bruce Cree, MD, PHD
role: PRINCIPAL_INVESTIGATOR
affiliation: Medday Pharmaceuticals
name: Frederic Sedel, MD, PHD
role: STUDY_DIRECTOR
References:
citation: Cree BAC, Cutter G, Wolinsky JS, Freedman MS, Comi G, Giovannoni G, Hartung HP, Arnold D, Kuhle J, Block V, Munschauer FE, Sedel F, Lublin FD; SPI2 investigative teams. Safety and efficacy of MD1003 (high-dose biotin) in patients with progressive multiple sclerosis (SPI2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2020 Dec;19(12):988-997. doi: 10.1016/S1474-4422(20)30347-1. Epub 2020 Oct 23.