Clinical trial NCT00509145: Safety and Efficacy of Orally Administered Laquinimod Versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis (RRMS)
Official title: A Multinational, Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled Study, to Evaluate the Safety, Tolerability and Efficacy of Daily Oral Administration of Laquinimod 0.6 mg in Subjects With RRMS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Sclerosis
Keywords: Relapsing
Remitting
Lead sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Sponsor class: INDUSTRY
First posted: 2007-07-31
Enrollment: 1106
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Determination the efficacy of daily oral treatment with laquinimod 0.6 mg capsules as compared to placebo in subjects with Relapsing Remitting Multiple Sclerosis (RRMS).


Eligibility criteria: Inclusion Criteria:

1. Subjects must have a confirmed and documented MS diagnosis as defined by the Revised McDonald criteria \[Ann Neurol 2005: 58:840-846\], with a relapsing-remitting disease course.
2. Subjects must be ambulatory with converted Kurtzke EDSS score of 0-5.5.
3. Subjects must be in a stable neurological condition and free of corticosteroid treatment \[intravenous (iv), intramuscular (im) and/or per os (po)\] 30 days prior to screening (month -1).
4. Subjects must have had experienced one of the following:

   * At least one documented relapse in the 12 months prior to screening
   * At least two documented relapses in the 24 months prior to screening
   * One documented relapse between 12 and 24 months prior to screening with at least one documented T1-Gd enhancing lesion in an MRI performed within 12 months prior to screening.
5. Subjects must be between 18 and 55 years of age, inclusive.
6. Subjects must have disease duration of at least 6 months (from the first symptom) prior to screening.
7. Women of child-bearing potential must practice an acceptable method of birth control \[acceptable methods of birth control in this study include: surgical sterilization, intrauterine devices, oral contraceptive, contraceptive patch, long-acting injectable contraceptive, partner's vasectomy or double-barrier method (condom or diaphragm with spermicide).
8. Subjects must be able to sign and date a written informed consent prior to entering the study
9. Subjects must be willing and able to comply with the protocol requirements for the duration of the study.

Exclusion Criteria:

1. Subjects with progressive forms of MS
2. An onset of relapse, unstable neurological condition or any treatment with corticosteroids \[intravenous (iv), intramuscular (im) and/or per os (po)\] or ACTH between month -1 (screening) and 0 (baseline).
3. Use of experimental or investigational drugs, and/or participation in drug clinical studies within the 6 months prior to screening.
4. Use of immunosuppressive including Mitoxantrone (Novantrone®) or cytotoxic agents within 6 months prior to the screening visit.
5. Previous use of either of the following: natalizumab (Tysabri®), cladribine, laquinimod.
6. Previous treatment with glatiramer acetate (Copaxone®) Interferon-β (either 1a or 1b) or IVIG within 2 months prior to screening visit.
7. Systemic corticosteroid treatment of ≥30 consecutive days duration within 2 months prior to screening visit.
8. Previous total body irradiation or total lymphoid irradiation.
9. Previous stem cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation.
10. A known history of tuberculosis.
11. Acute infection two weeks prior to baseline visit.
12. Major trauma or surgery two weeks prior to baseline
13. A history of vascular thrombosis (excluding catheter-site superficial venous thrombophlebitis).
14. A carrier state of factor V Leiden mutation (either homo- or heterozygous) as disclosed at screening.
15. Positive screening test for Hepatitis B surface antigen, Hepatitis C antibody, or HIV antibody as disclosed at screening visit.
16. Use of potent inhibitors of CYP3A4 within 2 weeks prior to baseline visit (1 month for fluoxetine) see detailed list in Appendix 5
17. Use of amiodarone within 2 years prior to screening visit.
18. Pregnancy or breastfeeding.
19. Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation, as determined by medical history, physical examinations, ECG, laboratory tests or chest X-ray. Such conditions may include:

    * A cardiovascular or pulmonary disorder that cannot be well-controlled by standard treatment permitted by the study protocol.
    * A gastrointestinal disorder that may affect the absorption of study medication.
    * Renal or metabolic diseases.
    * Any form of chronic liver disease, including known non-alcoholic steatohepatitis.
    * A ≥2xULN serum elevation of either of the following at screening: ALT, AST or direct bilirubin
    * A QTC interval (obtained from either 2 ECG recordings at screening or from the mean value calculated from 3 measurements at baseline visit) which is \>450msec.
    * A family history of Long- QT syndrome.
    * A history of drug and/or alcohol abuse.
    * Major psychiatric disorder.
20. A known history of sensitivity to Gd.
21. Inability to successfully undergo MRI scanning.
22. Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to: mannitol, meglumine or sodium stearyl fumarate.

Exclusion Criteria:

1. Subjects who suffer from any form of progressive MS.
2. Any condition which the investigator feels may interfere with participation in the study.
3. Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation,
4. Subjects who received any investigational medication, immunosuppressives or cytotoxic agents within 6 months prior to screening
5. Previous treatment with immunomodulators within two months prior to screening
6. Pregnancy or breastfeeding.

Primary outcomes:
measure: Relapse Rate: Number of Confirmed Relapses During the Double Blind Study Period
timeFrame: Up to Month 24
Secondary outcomes:
measure: Composite Endpoint: Sum of the Number of T1 Gadolinium (Gd)-Enhanced Lesions on T1-Weighted MRI Images
timeFrame: Month 12, Month 24
measure: Composite Endpoint: Sum of the Number of New/Enlarging T2 Lesions
timeFrame: Month 12, Month 24
measure: Accumulation of Physical Disability Measured by the Time to Confirmed Progression of Expanded Disability Status Scale (EDSS)
timeFrame: Baseline to Month 24
measure: Change From Baseline in Disability as Assessed by the Multiple Sclerosis Functional Composite (MSFC) Score
timeFrame: Baseline, Month 24
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Teva Investigational Site 1076
state: Arizona
city: Centennial
country: United States
facility: Teva Investigational Site 1090
state: Colorado
city: Fort Collins
country: United States
facility: Teva Investigational Site 1088
state: Colorado
city: New Haven
country: United States
facility: Teva Investigational Site 1094
state: Connecticut
city: Northbrook
country: United States
facility: Teva Investigational Site 1102
state: Illinois
city: Fort Wayne
country: United States
facility: Teva Investigational Site 1081
state: Indiana
city: Des Moines
country: United States
facility: Teva Investigational Site 1083
state: Iowa
city: Kansas City
country: United States
facility: Teva Investigational Site 1086
state: Kansas
city: Lexington
country: United States
facility: Teva Investigational Site 1101
state: Kentucky
city: Farmington Hills
country: United States
facility: Teva Investigational Site 1096
state: Michigan
city: Minneapolis
country: United States
facility: Teva Investigational Site 1093
state: Minnesota
city: Saint Louis
country: United States
facility: Teva Investigational Site 1098
state: Missouri
city: New York
country: United States
facility: Teva Investigational Site 1082
state: New York
city: Rochester
country: United States
facility: Teva Investigational Site 1079
state: New York
city: Winston-Salem
country: United States
facility: Teva Investigational Site 1073
state: North Carolina
city: Fargo
country: United States
facility: Teva Investigational Site 1097
state: North Dakota
city: Dayton
country: United States
facility: Teva Investigational Site 1084
state: Ohio
city: Oklahoma City
country: United States
facility: Teva Investigational Site 1092
state: Oklahoma
city: Hershey
country: United States
facility: Teva Investigational Site 1100
state: Pennsylvania
city: Philadelphia
country: United States
facility: Teva Investigational Site 1087
state: Pennsylvania
city: Lubbock
country: United States
facility: Teva Investigational Site 1075
state: Texas
city: San Antonio
country: United States
facility: Teva Investigational Site 1078
state: Texas
city: Milwaukee
country: United States
facility: Teva Investigational Site 1085
state: Wisconsin
city: Klagenfurt
country: Austria
facility: Teva Investigational Site 3300
city: Linz
country: Austria
facility: Teva Investigational Site 3303
city: Sankt Polten
country: Austria
facility: Teva Investigational Site 3302
city: Villach
country: Austria
facility: Teva Investigational Site 3301
city: Pleven
country: Bulgaria
facility: Teva Investigational Site 5901
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5904
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5903
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5900
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5905
city: Varna
country: Bulgaria
facility: Teva Investigational Site 5902
city: Halifax
country: Canada
facility: Teva Investigational Site 1132
state: Nova Scotia
city: London
country: Canada
facility: Teva Investigational Site 1126
state: Ontario
city: Ottawa
country: Canada
facility: Teva Investigational Site 1128
state: Ontario
city: Toronto
country: Canada
facility: Teva Investigational Site 1134
state: Ontario
city: Greenfield Park
country: Canada
facility: Teva Investigational Site 1130
state: Quebec
city: Montreal
country: Canada
facility: Teva Investigational Site 1129
state: Quebec
city: Sherbrooke
country: Canada
facility: Teva Investigational Site 1131
state: Quebec
city: Olomouc
country: Czechia
facility: Teva Investigational Site 5417
city: Ostrava - poruba
country: Czechia
facility: Teva Investigational Site 5416
city: Tallinn
country: Estonia
facility: Teva Investigational Site 5504
city: Tartu
country: Estonia
facility: Teva Investigational Site 5505
city: Besancon
country: France
facility: Teva Investigational Site 3525
city: Bron Cedex
country: France
facility: Teva Investigational Site 3527
city: Clermont-Ferrand Cedex 1
country: France
facility: Teva Investigational Site 3526
city: Lille Cedex
country: France
facility: Teva Investigational Site 3524
city: Marseille Cedex 5
country: France
facility: Teva Investigational Site 3528
city: Rennes Cedex 9
country: France
facility: Teva Investigational Site 3529
city: Tbilisi
country: Georgia
facility: Teva Investigational Site 8100
city: Tbilisi
country: Georgia
facility: Teva Investigational Site 8101
city: Bayreuth
country: Germany
facility: Teva Investigational Site 3247
city: Berlin
country: Germany
facility: Teva Investigational Site 3241
city: Berlin
country: Germany
facility: Teva Investigational Site 3238
city: Bochum
country: Germany
facility: Teva Investigational Site 3248
city: Dresden
country: Germany
facility: Teva Investigational Site 3245
city: Emden
country: Germany
facility: Teva Investigational Site 3237
city: Erbach
country: Germany
facility: Teva Investigational Site 3242
city: Erfurt
country: Germany
facility: Teva Investigational Site 3240
city: Freiburg
country: Germany
facility: Teva Investigational Site 3249
city: Hamburg
country: Germany
facility: Teva Investigational Site 3236
city: Hamburg
country: Germany
facility: Teva Investigational Site 3246
city: Hannover
country: Germany
facility: Teva Investigational Site 3239
city: Heidelberg
country: Germany
facility: Teva Investigational Site 3243
city: Munster
country: Germany
facility: Teva Investigational Site 3251
city: Trier
country: Germany
facility: Teva Investigational Site 3250
city: Ulm
country: Germany
facility: Teva Investigational Site 3244
city: Budapest
country: Hungary
facility: Teva Investigational Site 5115
city: Debrecen
country: Hungary
facility: Teva Investigational Site 5114
city: Miskolc
country: Hungary
facility: Teva Investigational Site 5116
city: Veszprem
country: Hungary
facility: Teva Investigational Site 5117
city: Haifa
country: Israel
facility: Teva Investigational Site 8034
city: Haifa
country: Israel
facility: Teva Investigational Site 8031
city: Jerusalem
country: Israel
facility: Teva Investigational Site 8030
city: Ramat Gan
country: Israel
facility: Teva Investigational Site 8033
city: Tel Aviv
country: Israel
facility: Teva Investigational Site 8032
city: Catania
country: Italy
facility: Teva Investigational Site 3044
city: Fidenza
country: Italy
facility: Teva Investigational Site 3045
city: Gallarate
country: Italy
facility: Teva Investigational Site 3042
city: Grosseto
country: Italy
facility: Teva Investigational Site 3046
city: Milano
country: Italy
facility: Teva Investigational Site 3047
city: Milano
country: Italy
facility: Teva Investigational Site 3038
city: Milano
country: Italy
facility: Teva Investigational Site 555
city: Milano
country: Italy
facility: Teva Investigational Site 3039
city: Palermo
country: Italy
facility: Teva Investigational Site 3041
city: Rome
country: Italy
facility: Teva Investigational Site 3040
city: Riga
country: Latvia
facility: Teva Investigational Site 5604
city: Kaunas
country: Lithuania
facility: Teva Investigational Site 5704
city: Siauliai
country: Lithuania
facility: Teva Investigational Site 5705
city: Groesbeek
country: Netherlands
facility: Teva Investigational Site 3809
city: Nieuwegein
country: Netherlands
facility: Teva Investigational Site 3810
city: Tilburg
country: Netherlands
facility: Teva Investigational Site 3811
city: Czestochowa
country: Poland
facility: Teva Investigational Site 5322
city: Gorzow Wielkopolski
country: Poland
facility: Teva Investigational Site 5320
city: Katowice
country: Poland
facility: Teva Investigational Site 5316
city: Kielce
country: Poland
facility: Teva Investigational Site 5318
city: Konskie
country: Poland
facility: Teva Investigational Site 5319
city: Krakow
country: Poland
facility: Teva Investigational Site 5317
city: Lodz
country: Poland
facility: Teva Investigational Site 5315
city: Warszawa
country: Poland
facility: Teva Investigational Site 5325
city: Bucharest
country: Romania
facility: Teva Investigational Site 5208
city: Cluj-Napoca
country: Romania
facility: Teva Investigational Site 5210
city: Constanta
country: Romania
facility: Teva Investigational Site 5212
city: Targu-Mures
country: Romania
facility: Teva Investigational Site 5211
city: Timisoara
country: Romania
facility: Teva Investigational Site 5209
city: Ekaterinburg
country: Russian Federation
facility: Teva Investigational Site 5029
city: Kemerovo
country: Russian Federation
facility: Teva Investigational Site 5031
city: Moscow
country: Russian Federation
facility: Teva Investigational Site 5021
city: Nizhny Novgorod
country: Russian Federation
facility: Teva Investigational Site 5028
city: Novosibirsk
country: Russian Federation
facility: Teva Investigational Site 5027
city: Perm
country: Russian Federation
facility: Teva Investigational Site 5030
city: Saint Petersburg
country: Russian Federation
facility: Teva Investigational Site 5022
city: Saint-Petersburg
country: Russian Federation
facility: Teva Investigational Site 5026
city: St. Petersburg
country: Russian Federation
facility: Teva Investigational Site 5025
city: St. Petersburg
country: Russian Federation
facility: Teva Investigational Site 5024
city: St. Petersburg
country: Russian Federation
facility: Teva Investigational Site 5023
city: Belgrade
country: Serbia
facility: Teva Investigational Site 6100
city: Nis
country: Serbia
facility: Teva Investigational Site 6102
city: Barcelona
country: Spain
facility: Teva Investigational Site 3132
city: Barcelona
country: Spain
facility: Teva Investigational Site 3134
city: Barcelona
country: Spain
facility: Teva Investigational Site 3144
city: Beade-Vigo
country: Spain
facility: Teva Investigational Site 3140
city: Getafe
country: Spain
facility: Teva Investigational Site 3142
city: Girona
country: Spain
facility: Teva Investigational Site 3136
city: Lleida
country: Spain
facility: Teva Investigational Site 3135
city: Madrid
country: Spain
facility: Teva Investigational Site 3133
city: Madrid
country: Spain
facility: Teva Investigational Site 3146
city: Murcia
country: Spain
facility: Teva Investigational Site 3137
city: Pontevedra
country: Spain
facility: Teva Investigational Site 3138
city: Santiago de Compostela
country: Spain
facility: Teva Investigational Site 3139
city: Valencia
country: Spain
facility: Teva Investigational Site 3143
city: Stockholm
country: Sweden
facility: Teva Investigational Site 4204
city: Stockholm
country: Sweden
facility: Teva Investigational Site 4205
city: Stockholm
country: Sweden
facility: Teva Investigational Site 4206
city: Izmir
country: Turkey
facility: Teva Investigational Site 8201
city: Dnipropetrovsk
country: Ukraine
facility: Teva Investigational Site 5803
city: Kyiv
country: Ukraine
facility: Teva Investigational Site 5802
city: Kyiv
country: Ukraine
facility: Teva Investigational Site 5804
city: Lviv
country: Ukraine
facility: Teva Investigational Site 5800
city: Vinnytsya
country: Ukraine
facility: Teva Investigational Site 5801
city: Liverpool
country: United Kingdom
facility: Teva Investigational Site 3425
city: London
country: United Kingdom
facility: Teva Investigational Site 3424
city: Sheffield
country: United Kingdom
facility: Teva Investigational Site 3422
Study officials:
affiliation: U.O.Neurology-Neurorehabilitation and Clinical Neurophysiology
name: Giancarlo Comi
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kolb-Sobieraj C, Gupta S, Weinstock-Guttman B. Laquinimod therapy in multiple sclerosis: a comprehensive review. Neurol Ther. 2014 May 6;3(1):29-39. doi: 10.1007/s40120-014-0017-6. eCollection 2014 Jun.
citation: Filippi M, Rocca MA, Pagani E, De Stefano N, Jeffery D, Kappos L, Montalban X, Boyko AN, Comi G; ALLEGRO Study Group. Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage. J Neurol Neurosurg Psychiatry. 2014 Aug;85(8):851-8. doi: 10.1136/jnnp-2013-306132. Epub 2013 Sep 12.
citation: Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, Rocca MA, Filippi M; ALLEGRO Study Group. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012 Mar 15;366(11):1000-9. doi: 10.1056/NEJMoa1104318.