Safety and Efficacy of Orally Administered Laquinimod Versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis (RRMS)

Phase 3

Completed

Conditions: Multiple Sclerosis

Interventions: Other: Placebo
Drug: Laquinimod

Registration Number: NCT00509145

Lead Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 1106

Inclusion Criteria

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.
Subjects must be ambulatory with converted Kurtzke EDSS score of 0-5.5.
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).
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.
Subjects must be between 18 and 55 years of age, inclusive.
Subjects must have disease duration of at least 6 months (from the first symptom) prior to screening.
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).
Subjects must be able to sign and date a written informed consent prior to entering the study
Subjects must be willing and able to comply with the protocol requirements for the duration of the study.

Exclusion Criteria

Subjects with progressive forms of MS
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).
Use of experimental or investigational drugs, and/or participation in drug clinical studies within the 6 months prior to screening.
Use of immunosuppressive including Mitoxantrone (Novantrone®) or cytotoxic agents within 6 months prior to the screening visit.
Previous use of either of the following: natalizumab (Tysabri®), cladribine, laquinimod.
Previous treatment with glatiramer acetate (Copaxone®) Interferon-β (either 1a or 1b) or IVIG within 2 months prior to screening visit.
Systemic corticosteroid treatment of ≥30 consecutive days duration within 2 months prior to screening visit.
Previous total body irradiation or total lymphoid irradiation.
Previous stem cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation.
A known history of tuberculosis.
Acute infection two weeks prior to baseline visit.
Major trauma or surgery two weeks prior to baseline
A history of vascular thrombosis (excluding catheter-site superficial venous thrombophlebitis).
A carrier state of factor V Leiden mutation (either homo- or heterozygous) as disclosed at screening.
Positive screening test for Hepatitis B surface antigen, Hepatitis C antibody, or HIV antibody as disclosed at screening visit.
Use of potent inhibitors of CYP3A4 within 2 weeks prior to baseline visit (1 month for fluoxetine) see detailed list in Appendix 5
Use of amiodarone within 2 years prior to screening visit.
Pregnancy or breastfeeding.
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.
A known history of sensitivity to Gd.
Inability to successfully undergo MRI scanning.
Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to: mannitol, meglumine or sodium stearyl fumarate.

Exclusion Criteria:

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Matching placebo
Laquinimod	Laquinimod	Laquinimod 0.6 mg, oral

Primary Outcome Measures

Name	Time	Method
Relapse Rate: Number of Confirmed Relapses During the Double Blind Study Period	Up to Month 24	A relapse was defined as the appearance of at least one new neurological abnormality or the reappearance of at least one previously observed neurological abnormalities lasting greater than or equal to 48 hours and immediately preceded by an improving neurological state of greater than or equal to 30 days from onset of previous relapse. An event was counted as a relapse only when the participant's symptoms were accompanied by observed objective neurological changes, consistent with one or more of the following: An increase of greater than or equal to 0.5 in the Expanded Disability Status Scale (EDSS) score as compared to previous evaluation, an increase of one grade in the actual score of greater than or equal to 2 of the 7 functional systems (FS), as compared to previous evaluation, or an increase of 2 grades in the actual score of one FS as compared to the previous evaluation.

Secondary Outcome Measures

Name	Time	Method
Composite Endpoint: Sum of the Number of T1 Gadolinium (Gd)-Enhanced Lesions on T1-Weighted MRI Images	Month 12, Month 24	Composite score was calculated as the sum of the number of gadolinium (Gd)-enhanced lesions at Month 12 and the number of gadolinium (Gd)-enhanced lesions at Month 24 on T1-Weighted MRI scans.
Accumulation of Physical Disability Measured by the Time to Confirmed Progression of Expanded Disability Status Scale (EDSS)	Baseline to Month 24	EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis \[MS\]). A confirmed progression of EDSS is defined as at least 1 point increase from baseline if baseline EDSS was between 0 and 5.0, or at least 0.5 point increase if baseline EDSS was 5.5 or higher, confirmed 3 months later. Participants were assessed between baseline and month 24 visit. Participants that met these criteria for any 3 consecutive months were counted in the progression category. Progression could not be confirmed during an MS relapse. Data is presented as a distribution of confirmed disease progression (CDP) events (number of participants with CDP).
Change From Baseline in Disability as Assessed by the Multiple Sclerosis Functional Composite (MSFC) Score	Baseline, Month 24	The Multiple Sclerosis Functional Composite is an instrument assessing disability that consists of 3 clinical assessments. The 3 are Timed 25-Foot Walk, 9-Hole Peg Test which measures upper extremity (arm and hand) function, and PASAT (Paced Auditory Serial Addition Test) which is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. A Z-score is used to define a common metric from the 3 assessments that constitute the MSFC score. The study's population at baseline was used as reference population for the Z-score calculation. A Z-score of 0 represents the population mean at baseline. Higher Z-scores correspond to an improved outcome.
Composite Endpoint: Sum of the Number of New/Enlarging T2 Lesions	Month 12, Month 24	Composite score calculated as the sum of T2 lesions at Months 12 and 24 that are new or enlarged.

Trial Locations

Locations (144): Teva Investigational Site 5320
🇵🇱
Gorzow Wielkopolski, Poland
Teva Investigational Site 5026
🇷🇺
Saint-Petersburg, Russian Federation
Teva Investigational Site 5023
🇷🇺
St. Petersburg, Russian Federation
Teva Investigational Site 6100
🇷🇸
Belgrade, Serbia
Teva Investigational Site 6102
🇷🇸
Nis, Serbia
Teva Investigational Site 5316
🇵🇱
Katowice, Poland
Teva Investigational Site 5315
🇵🇱
Lodz, Poland
Teva Investigational Site 5325
🇵🇱
Warszawa, Poland
Teva Investigational Site 5211
🇷🇴
Targu-Mures, Romania
Teva Investigational Site 5031
🇷🇺
Kemerovo, Russian Federation
Teva Investigational Site 5210
🇷🇴
Cluj-Napoca, Romania
Teva Investigational Site 5025
🇷🇺
St. Petersburg, Russian Federation
Teva Investigational Site 5027
🇷🇺
Novosibirsk, Russian Federation
Teva Investigational Site 5802
🇺🇦
Kyiv, Ukraine
Teva Investigational Site 5804
🇺🇦
Kyiv, Ukraine
Teva Investigational Site 5800
🇺🇦
Lviv, Ukraine
Teva Investigational Site 5901
🇧🇬
Pleven, Bulgaria
Teva Investigational Site 5319
🇵🇱
Konskie, Poland
Teva Investigational Site 5208
🇷🇴
Bucharest, Romania
Teva Investigational Site 5212
🇷🇴
Constanta, Romania
Teva Investigational Site 3143
🇪🇸
Valencia, Spain
Teva Investigational Site 5021
🇷🇺
Moscow, Russian Federation
Teva Investigational Site 3139
🇪🇸
Santiago de Compostela, Spain
Teva Investigational Site 5322
🇵🇱
Czestochowa, Poland
Teva Investigational Site 5028
🇷🇺
Nizhny Novgorod, Russian Federation
Teva Investigational Site 5022
🇷🇺
Saint Petersburg, Russian Federation
Teva Investigational Site 3425
🇬🇧
Liverpool, United Kingdom
Teva Investigational Site 8201
🇹🇷
Izmir, Turkey
Teva Investigational Site 3146
🇪🇸
Madrid, Spain
Teva Investigational Site 3134
🇪🇸
Barcelona, Spain
Teva Investigational Site 3137
🇪🇸
Murcia, Spain
Teva Investigational Site 5318
🇵🇱
Kielce, Poland
Teva Investigational Site 3144
🇪🇸
Barcelona, Spain
Teva Investigational Site 5029
🇷🇺
Ekaterinburg, Russian Federation
Teva Investigational Site 5030
🇷🇺
Perm, Russian Federation
Teva Investigational Site 4206
🇸🇪
Stockholm, Sweden
Teva Investigational Site 3422
🇬🇧
Sheffield, United Kingdom
Teva Investigational Site 5317
🇵🇱
Krakow, Poland
Teva Investigational Site 5209
🇷🇴
Timisoara, Romania
Teva Investigational Site 3424
🇬🇧
London, United Kingdom
Teva Investigational Site 3133
🇪🇸
Madrid, Spain
Teva Investigational Site 3132
🇪🇸
Barcelona, Spain
Teva Investigational Site 3136
🇪🇸
Girona, Spain
Teva Investigational Site 5024
🇷🇺
St. Petersburg, Russian Federation
Teva Investigational Site 3142
🇪🇸
Getafe, Spain
Teva Investigational Site 4205
🇸🇪
Stockholm, Sweden
Teva Investigational Site 3140
🇪🇸
Beade-Vigo, Spain
Teva Investigational Site 3135
🇪🇸
Lleida, Spain
Teva Investigational Site 3138
🇪🇸
Pontevedra, Spain
Teva Investigational Site 5803
🇺🇦
Dnipropetrovsk, Ukraine
Teva Investigational Site 5801
🇺🇦
Vinnytsya, Ukraine
Teva Investigational Site 4204
🇸🇪
Stockholm, Sweden
Teva Investigational Site 3238
🇩🇪
Berlin, Germany
Teva Investigational Site 8101
🇬🇪
Tbilisi, Georgia
Teva Investigational Site 3245
🇩🇪
Dresden, Germany
Teva Investigational Site 3237
🇩🇪
Emden, Germany
Teva Investigational Site 3240
🇩🇪
Erfurt, Germany
Teva Investigational Site 3250
🇩🇪
Trier, Germany
Teva Investigational Site 1090
🇺🇸
Centennial, Colorado, United States
Teva Investigational Site 1088
🇺🇸
Fort Collins, Colorado, United States
Teva Investigational Site 1094
🇺🇸
New Haven, Connecticut, United States
Teva Investigational Site 1102
🇺🇸
Northbrook, Illinois, United States
Teva Investigational Site 1083
🇺🇸
Des Moines, Iowa, United States
Teva Investigational Site 1081
🇺🇸
Fort Wayne, Indiana, United States
Teva Investigational Site 1086
🇺🇸
Kansas City, Kansas, United States
Teva Investigational Site 1096
🇺🇸
Farmington Hills, Michigan, United States
Teva Investigational Site 1098
🇺🇸
Saint Louis, Missouri, United States
Teva Investigational Site 1082
🇺🇸
New York, New York, United States
Teva Investigational Site 1079
🇺🇸
Rochester, New York, United States
Teva Investigational Site 1084
🇺🇸
Dayton, Ohio, United States
Teva Investigational Site 1073
🇺🇸
Winston-Salem, North Carolina, United States
Teva Investigational Site 1097
🇺🇸
Fargo, North Dakota, United States
Teva Investigational Site 1100
🇺🇸
Hershey, Pennsylvania, United States
Teva Investigational Site 1075
🇺🇸
Lubbock, Texas, United States
Teva Investigational Site 3300
🇦🇹
Klagenfurt, Austria
Teva Investigational Site 3303
🇦🇹
Linz, Austria
Teva Investigational Site 3302
🇦🇹
Sankt Polten, Austria
Teva Investigational Site 3301
🇦🇹
Villach, Austria
Teva Investigational Site 5904
🇧🇬
Sofia, Bulgaria
Teva Investigational Site 5903
🇧🇬
Sofia, Bulgaria
Teva Investigational Site 5902
🇧🇬
Varna, Bulgaria
Teva Investigational Site 5900
🇧🇬
Sofia, Bulgaria
Teva Investigational Site 5905
🇧🇬
Sofia, Bulgaria
Teva Investigational Site 5115
🇭🇺
Budapest, Hungary
Teva Investigational Site 1129
🇨🇦
Montreal, Quebec, Canada
Teva Investigational Site 1130
🇨🇦
Greenfield Park, Quebec, Canada
Teva Investigational Site 1131
🇨🇦
Sherbrooke, Quebec, Canada
Teva Investigational Site 5416
🇨🇿
Ostrava - poruba, Czechia
Teva Investigational Site 5417
🇨🇿
Olomouc, Czechia
Teva Investigational Site 5505
🇪🇪
Tartu, Estonia
Teva Investigational Site 5504
🇪🇪
Tallinn, Estonia
Teva Investigational Site 3525
🇫🇷
Besancon, France
Teva Investigational Site 3526
🇫🇷
Clermont-Ferrand Cedex 1, France
Teva Investigational Site 3527
🇫🇷
Bron Cedex, France
Teva Investigational Site 3524
🇫🇷
Lille Cedex, France
Teva Investigational Site 3528
🇫🇷
Marseille Cedex 5, France
Teva Investigational Site 3529
🇫🇷
Rennes Cedex 9, France
Teva Investigational Site 8100
🇬🇪
Tbilisi, Georgia
Teva Investigational Site 3247
🇩🇪
Bayreuth, Germany
Teva Investigational Site 3249
🇩🇪
Freiburg, Germany
Teva Investigational Site 3236
🇩🇪
Hamburg, Germany
Teva Investigational Site 3246
🇩🇪
Hamburg, Germany
Teva Investigational Site 3239
🇩🇪
Hannover, Germany
Teva Investigational Site 3244
🇩🇪
Ulm, Germany
Teva Investigational Site 5114
🇭🇺
Debrecen, Hungary
Teva Investigational Site 5116
🇭🇺
Miskolc, Hungary
Teva Investigational Site 5117
🇭🇺
Veszprem, Hungary
Teva Investigational Site 8034
🇮🇱
Haifa, Israel
Teva Investigational Site 8030
🇮🇱
Jerusalem, Israel
Teva Investigational Site 8031
🇮🇱
Haifa, Israel
Teva Investigational Site 8033
🇮🇱
Ramat Gan, Israel
Teva Investigational Site 3045
🇮🇹
Fidenza, Italy
Teva Investigational Site 8032
🇮🇱
Tel Aviv, Israel
Teva Investigational Site 3044
🇮🇹
Catania, Italy
Teva Investigational Site 3046
🇮🇹
Grosseto, Italy
Teva Investigational Site 3042
🇮🇹
Gallarate, Italy
Teva Investigational Site 3047
🇮🇹
Milano, Italy
Teva Investigational Site 3038
🇮🇹
Milano, Italy
Teva Investigational Site 555
🇮🇹
Milano, Italy
Teva Investigational Site 3041
🇮🇹
Palermo, Italy
Teva Investigational Site 3039
🇮🇹
Milano, Italy
Teva Investigational Site 3040
🇮🇹
Rome, Italy
Teva Investigational Site 5604
🇱🇻
Riga, Latvia
Teva Investigational Site 5704
🇱🇹
Kaunas, Lithuania
Teva Investigational Site 5705
🇱🇹
Siauliai, Lithuania
Teva Investigational Site 3809
🇳🇱
Groesbeek, Netherlands
Teva Investigational Site 3810
🇳🇱
Nieuwegein, Netherlands
Teva Investigational Site 3811
🇳🇱
Tilburg, Netherlands
Teva Investigational Site 1126
🇨🇦
London, Ontario, Canada
Teva Investigational Site 1128
🇨🇦
Ottawa, Ontario, Canada
Teva Investigational Site 1078
🇺🇸
San Antonio, Texas, United States
Teva Investigational Site 1076
🇺🇸
Phoenix, Arizona, United States
Teva Investigational Site 1093
🇺🇸
Minneapolis, Minnesota, United States
Teva Investigational Site 1085
🇺🇸
Milwaukee, Wisconsin, United States
Teva Investigational Site 1092
🇺🇸
Oklahoma City, Oklahoma, United States
Teva Investigational Site 1087
🇺🇸
Philadelphia, Pennsylvania, United States
Teva Investigational Site 1134
🇨🇦
Toronto, Ontario, Canada
Teva Investigational Site 3241
🇩🇪
Berlin, Germany
Teva Investigational Site 3248
🇩🇪
Bochum, Germany
Teva Investigational Site 3242
🇩🇪
Erbach, Germany
Teva Investigational Site 3243
🇩🇪
Heidelberg, Germany
Teva Investigational Site 3251
🇩🇪
Munster, Germany
Teva Investigational Site 1132
🇨🇦
Halifax, Nova Scotia, Canada
Teva Investigational Site 1101
🇺🇸
Lexington, Kentucky, United States