BRAVO Study: Laquinimod Double-blind Placebo-controlled Study in Participants With Relapsing-Remitting Multiple Sclerosis (RRMS) With a Rater Blinded Reference Arm of Interferon β-1a (Avonex®)
- Registration Number
- NCT00605215
- Lead Sponsor
- Teva Branded Pharmaceutical Products R&D, Inc.
- Brief Summary
The study aims to compare the effect of daily oral treatment of laquinimod capsules 0.6 milligrams (mg) with the effect of placebo capsules (capsules that contain no active medication) as well as with the effect of an existing Multiple Sclerosis (MS) injectable drug: Interferon β-1a (Avonex®).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 1331
- 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 between screening (month -1) and baseline visits (month 0).
- 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 first symptom) prior to screening.
- Women of child-bearing potential must practice 2 acceptable methods 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 willing and able to comply with the protocol requirements for the duration of the study.
-
An onset of relapse 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 or laquinimod.
-
Previous treatment with glatiramer acetate (Copaxone®) or IVIG within 3 months prior to screening visit.
-
Previous treatment with Interferon beta-1a (Avonex® or Rebif®) or Interferon beta-1b (Betaseron®).
-
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.
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Acute infection 2 weeks prior to baseline visit.
-
Major trauma or surgery 2 weeks prior to baseline visit.
-
A history of vascular thrombosis (excluding catheter-site superficial venous thrombophlebitis).
-
A carrier state of factor V Leiden mutation (either homo- or heterozygous) by history or 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 (see detailed list of drugs in protocol) (1 month for fluoxetine).
-
Use of amiodarone within 2 years prior to screening visit.
-
Pregnancy or breastfeeding.
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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, metabolic, endocrinological or hematological 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 two ECG recordings at screening or from the mean value calculated from three 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 history of a convulsive disorder.
- Known hypersensitivity to either of the following: mannitol, meglumine or sodium stearyl fumarate.
- Known hypersensitivity that would preclude administration of laquinimod.
-
The subject's inability to give informed consent, or to complete the study, or if the subject is considered by the investigator to be, for any reason, an unsuitable candidate for this study.
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A known history of sensitivity to Gadolinium.
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Inability to successfully undergo MRI scanning.
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A known history of hypersensitivity to natural or recombinant interferon beta, human albumin, or any other component of the formulation of Avonex®.
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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 Participants will receive 1 capsule of placebo matching to laquinimod orally once daily for 24 months. Avonex® Avonex® Participants will receive an injection of Avonex® 30 micrograms (mcg) given intramuscularly (IM) once weekly for 24 months. Laquinimod Laquinimod Participants will receive 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.
- Primary Outcome Measures
Name Time Method Annualized Rate of Confirmed Relapses Baseline up to Month 24 A relapse was defined as the appearance of new neurological abnormalities or the reappearance of previously observed neurological abnormalities; lasting at least 48 hours and immediately preceded by an improved neurological state of ≥30 days from onset of previous relapse, accompanied by observed objective neurological changes (an increase of ≥0.5 in Expanded Disability Status Scale \[EDSS\] score, or an increase of 1 grade in the score of 2 or more of the 7 Functional Systems \[FS\], or an increase of 2 grades in the score of 1 FS as compared to the previous evaluation). Total number of confirmed relapses during the treatment period was divided by the sum of number of days on study in the treatment period and then multiplied by the number of days in the year to calculate the annualized relapse rate. Annualized relapse rate was derived from a baseline-adjusted negative binomial regression.
- Secondary Outcome Measures
Name Time Method 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.
Accumulation of Physical Disability Measured by the Number of Participants With Confirmed Progression of EDSS Baseline up to Month 24 A confirmed progression of EDSS was defined as a 1 point increase from baseline on EDSS score if baseline EDSS was between 0 and 5.0, or a 0.5 point increase if baseline EDSS was 5.5, confirmed 3 months later. EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis \[MS\]). Data is presented as distribution of confirmed progression (number of participants with confirmed progression of EDSS) sustained for 3 months. Progression could not be confirmed during a relapse.
Percent Change From Baseline in Brain Volume Baseline, Month 24 Change in brain volume was derived from MRI scans obtained at baseline and at Month 24.
Trial Locations
- Locations (170)
Teva Investigational Site 1263
🇺🇸Shreveport, Louisiana, United States
Teva Investigational Site 5219
🇷🇴Sibiu, Romania
Teva Investigational Site 6402
🇩🇪Berlin, Germany
Teva Investigational Site 6403
🇩🇪Munster, Germany
Teva Investigational Site 6401
🇩🇪Hannover, Germany
Teva Investigational Site 6703
🇩🇪Berlin, Germany
Teva Investigational Site 6500
🇲🇰Skopje, North Macedonia
Teva Investigational Site 6702
🇩🇪Dresden, Germany
Teva Investigational Site 6400
🇩🇪Ulm, Germany
Teva Investigational Site 6602
🇵🇱Gorzow Wielkopolski, Poland
Teva Investigational Site 8103
🇬🇪Tbilisi, Georgia
Teva Investigational Site 6701
🇩🇪Bayreuth, Germany
Teva Investigational Site 5329
🇵🇱Gdansk, Poland
Teva Investigational Site 3149
🇪🇸L'Hospitalet de Llobregat, Spain
Teva Investigational Site 9001
🇿🇦Cape Town, South Africa
Teva Investigational Site 3148
🇪🇸Sevilla, Spain
Teva Investigational Site 9003
🇿🇦Johannesburg, South Africa
Teva Investigational Site 3147
🇪🇸Barcelona, Spain
Teva Investigational Site 9008
🇿🇦Pietermaritzburg, South Africa
Teva Investigational Site 3153
🇪🇸Tortosa-Tarragona, Spain
Teva Investigational Site 9007
🇿🇦Bloemfontein, South Africa
Teva Investigational Site 1260
🇺🇸Indianapolis, Indiana, United States
Teva Investigational Site 1275
🇺🇸Atlanta, Georgia, United States
Teva Investigational Site 1250
🇺🇸Peoria, Illinois, United States
Teva Investigational Site 1276
🇺🇸Tucson, Arizona, United States
Teva Investigational Site 1272
🇺🇸Pasadena, California, United States
Teva Investigational Site 1238
🇺🇸Sacramento, California, United States
Teva Investigational Site 1280
🇺🇸Aurora, Colorado, United States
Teva Investigational Site 1255
🇺🇸Orlando, Florida, United States
Teva Investigational Site 1282
🇺🇸Sarasota, Florida, United States
Teva Investigational Site 1269
🇺🇸Baltimore, Maryland, United States
Teva Investigational Site 1274
🇺🇸Grand Rapids, Michigan, United States
Teva Investigational Site 1273
🇺🇸Albany, New York, United States
Teva Investigational Site 1264
🇺🇸Amherst, New York, United States
Teva Investigational Site 1283
🇺🇸Cedarhurst, New York, United States
Teva Investigational Site 1249
🇺🇸Raleigh, North Carolina, United States
Teva Investigational Site 1262
🇺🇸Winston-Salem, North Carolina, United States
Teva Investigational Site 1261
🇺🇸Akron, Ohio, United States
Teva Investigational Site 1245
🇺🇸Cleveland, Ohio, United States
Teva Investigational Site 1241
🇺🇸Canton, Ohio, United States
Teva Investigational Site 1247
🇺🇸Columbus, Ohio, United States
Teva Investigational Site 1258
🇺🇸Philadelphia, Pennsylvania, United States
Teva Investigational Site 1248
🇺🇸Richmond, Virginia, United States
Teva Investigational Site 1284
🇺🇸San Antonio, Texas, United States
Teva Investigational Site 1270
🇺🇸Roanoke, Virginia, United States
Teva Investigational Site 1253
🇺🇸Tacoma, Washington, United States
Teva Investigational Site 5914
🇧🇬Pleven, Bulgaria
Teva Investigational Site 5916
🇧🇬Shumen, Bulgaria
Teva Investigational Site 5920
🇧🇬Sofia, Bulgaria
Teva Investigational Site 5907
🇧🇬Sofia, Bulgaria
Teva Investigational Site 5910
🇧🇬Sofia, Bulgaria
Teva Investigational Site 5911
🇧🇬Sofia, Bulgaria
Teva Investigational Site 5918
🇧🇬Stara Zagora, Bulgaria
Teva Investigational Site 6004
🇭🇷Split, Croatia
Teva Investigational Site 6005
🇭🇷Varazdin, Croatia
Teva Investigational Site 6001
🇭🇷Zagreb, Croatia
Teva Investigational Site 6002
🇭🇷Zagreb, Croatia
Teva Investigational Site 5422
🇨🇿Brno, Czechia
Teva Investigational Site 5419
🇨🇿Olomouc, Czechia
Teva Investigational Site 5418
🇨🇿Praha 2, Czechia
Teva Investigational Site 5420
🇨🇿Praha 5- Motol, Czechia
Teva Investigational Site 5508
🇪🇪Kohtla-Jarve, Estonia
Teva Investigational Site 5421
🇨🇿Teplice, Czechia
Teva Investigational Site 8104
🇬🇪Tbilisi, Georgia
Teva Investigational Site 6700
🇩🇪Berlin, Germany
Teva Investigational Site 8043
🇮🇱Haifa, Israel
Teva Investigational Site 8040
🇮🇱Ramat Gan, Israel
Teva Investigational Site 5708
🇱🇹Kaunas, Lithuania
Teva Investigational Site 5707
🇱🇹Siauliai, Lithuania
Teva Investigational Site 6502
🇲🇰Bitola, North Macedonia
Teva Investigational Site 9005
🇿🇦Pretoria, South Africa
Teva Investigational Site 1268
🇺🇸Lenexa, Kansas, United States
Teva Investigational Site 3056
🇮🇹Bologna, Italy
Teva Investigational Site 3053
🇮🇹Cefalu, Italy
Teva Investigational Site 3062
🇮🇹Catania, Italy
Teva Investigational Site 3061
🇮🇹Empoli, Italy
Teva Investigational Site 3049
🇮🇹Firenze, Italy
Teva Investigational Site 3054
🇮🇹Chieti, Italy
Teva Investigational Site 3055
🇮🇹Napoli, Italy
Teva Investigational Site 3048
🇮🇹Rome, Italy
Teva Investigational Site 3052
🇮🇹Rome, Italy
Teva Investigational Site 3050
🇮🇹Rome, Italy
Teva Investigational Site 3060
🇮🇹Rome, Italy
Teva Investigational Site 3051
🇮🇹Torino, Italy
Teva Investigational Site 1267
🇺🇸Birmingham, Alabama, United States
Teva Investigational Site 1237
🇺🇸Phoenix, Arizona, United States
Teva Investigational Site 1279
🇺🇸Phoenix, Arizona, United States
Teva Investigational Site 1281
🇺🇸Nashville, Tennessee, United States
Teva Investigational Site 1244
🇺🇸Portland, Oregon, United States
Teva Investigational Site 1265
🇺🇸Teaneck, New Jersey, United States
Teva Investigational Site 1252
🇺🇸Phoenix, Arizona, United States
Teva Investigational Site 5908
🇧🇬Sofia, Bulgaria
Teva Investigational Site 5337
🇵🇱Bialystok, Poland
Teva Investigational Site 5331
🇵🇱Szczecin, Poland
Teva Investigational Site 5340
🇵🇱Warszawa, Poland
Teva Investigational Site 5218
🇷🇴Bucharest, Romania
Teva Investigational Site 5038
🇷🇺Novosibirsk, Russian Federation
Teva Investigational Site 5036
🇷🇺St. Petersburg, Russian Federation
Teva Investigational Site 6503
🇺🇦Chernihiv, Ukraine
Teva Investigational Site 5906
🇧🇬Sofia, Bulgaria
Teva Investigational Site 6003
🇭🇷Osijek, Croatia
Teva Investigational Site 6603
🇵🇱Kielce, Poland
Teva Investigational Site 4213
🇵🇱Konskie, Poland
Teva Investigational Site 5214
🇷🇴Bucuresti, Romania
Teva Investigational Site 5915
🇧🇬Pleven, Bulgaria
Teva Investigational Site 5919
🇧🇬Sofia, Bulgaria
Teva Investigational Site 1239
🇺🇸Lebanon, New Hampshire, United States
Teva Investigational Site 5917
🇧🇬Plovdiv, Bulgaria
Teva Investigational Site 5909
🇧🇬Sofia, Bulgaria
Teva Investigational Site 4212
🇧🇬Ruse, Bulgaria
Teva Investigational Site 4211
🇧🇬Veliko Tarnovo, Bulgaria
Teva Investigational Site 6006
🇭🇷Zagreb, Croatia
Teva Investigational Site 5334
🇵🇱Katowice, Poland
Teva Investigational Site 5336
🇵🇱Warsaw, Poland
Teva Investigational Site 5213
🇷🇴Bucuresti, Romania
Teva Investigational Site 5217
🇷🇴Constanta, Romania
Teva Investigational Site 5913
🇧🇬Varna, Bulgaria
Teva Investigational Site 5912
🇧🇬Sofia, Bulgaria
Teva Investigational Site 5507
🇪🇪Tallinn, Estonia
Teva Investigational Site 8041
🇮🇱Jerusalem, Israel
Teva Investigational Site 8042
🇮🇱Ramat Gan, Israel
Teva Investigational Site 6501
🇲🇰Skopje, North Macedonia
Teva Investigational Site 5338
🇵🇱Gdansk, Poland
Teva Investigational Site 5333
🇵🇱Grodzisk Mazowiecki, Poland
Teva Investigational Site 5339
🇵🇱Katowice, Poland
Teva Investigational Site 5332
🇵🇱Koscierzyna, Poland
Teva Investigational Site 5345
🇵🇱Krakow, Poland
Teva Investigational Site 5328
🇵🇱Lodz, Poland
Teva Investigational Site 5341
🇵🇱Warszawa, Poland
Teva Investigational Site 5335
🇵🇱Wroclaw, Poland
Teva Investigational Site 1243
🇵🇷Guaynabo, Puerto Rico
Teva Investigational Site 5215
🇷🇴Cluj-Napoca, Romania
Teva Investigational Site 5043
🇷🇺Barnaul, Russian Federation
Teva Investigational Site 5509
🇪🇪Tartu, Estonia
Teva Investigational Site 8102
🇬🇪Tbilisi, Georgia
Teva Investigational Site 5330
🇵🇱Olsztyn, Poland
Teva Investigational Site 5033
🇷🇺Moscow, Russian Federation
Teva Investigational Site 5032
🇷🇺Moscow, Russian Federation
Teva Investigational Site 8209
🇷🇴Craiova, Romania
Teva Investigational Site 5216
🇷🇴Iasi, Romania
Teva Investigational Site 5042
🇷🇺Novosibirsk, Russian Federation
Teva Investigational Site 6200
🇸🇰Bratislava, Slovakia
Teva Investigational Site 6202
🇸🇰Nitra, Slovakia
Teva Investigational Site 5034
🇷🇺St. Petersburg, Russian Federation
Teva Investigational Site 5044
🇷🇺Ufa, Russian Federation
Teva Investigational Site 6201
🇸🇰Bratislava, Slovakia
Teva Investigational Site 6203
🇸🇰Zilina, Slovakia
Teva Investigational Site 5041
🇷🇺Moscow, Russian Federation
Teva Investigational Site 5035
🇷🇺Saint Petersburg, Russian Federation
Teva Investigational Site 5037
🇷🇺Samara, Russian Federation
Teva Investigational Site 5823
🇺🇦Chernivtsi, Ukraine
Teva Investigational Site 5809
🇺🇦Lviv, Ukraine
Teva Investigational Site 5811
🇺🇦Dnipropetrovsk, Ukraine
Teva Investigational Site 5814
🇺🇦Ivano-Frankivsk, Ukraine
Teva Investigational Site 5821
🇺🇦Poltava, Ukraine
Teva Investigational Site 5812
🇺🇦Donetsk, Ukraine
Teva Investigational Site 5817
🇺🇦Kharkiv, Ukraine
Teva Investigational Site 5818
🇺🇦Kharkiv, Ukraine
Teva Investigational Site 5820
🇺🇦Odessa, Ukraine
Teva Investigational Site 5810
🇺🇦Vinnytsya, Ukraine
Teva Investigational Site 5815
🇺🇦Kharkiv, Ukraine
Teva Investigational Site 5822
🇺🇦Kyiv, Ukraine
Teva Investigational Site 5819
🇺🇦Zaporizhzhya, Ukraine
Teva Investigational Site 5816
🇺🇦Zaporizhzhya, Ukraine
Teva Investigational Site 9004
🇿🇦Johannesburg, South Africa
Teva Investigational Site 9006
🇿🇦Rosebank, South Africa
Teva Investigational Site 3154
🇪🇸Figueres-Girona, Spain
Teva Investigational Site 3151
🇪🇸Malaga, Spain
Teva Investigational Site 3152
🇪🇸Madrid, Spain
Teva Investigational Site 1277
🇺🇸New Orleans, Louisiana, United States