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®)

NCT00605215 | Completed Phase 3 Results DMC

• 2 other identifiers: MS-LAQ-3022007-005450-23
• Study Type: interventional
• Target: 1,331
• Locations: 18 countries
• Sites: 163

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®).

Conditions

Multiple Sclerosis

Outcome Measures

Primary Outcomes (1)

• Annualized Rate of Confirmed Relapses

  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.

  Baseline up to Month 24

Secondary Outcomes (3)

• Change From Baseline in Disability as Assessed by the Multiple Sclerosis Functional Composite (MSFC) Score

  Baseline, Month 24

• Percent Change From Baseline in Brain Volume

  Baseline, Month 24

• Accumulation of Physical Disability Measured by the Number of Participants With Confirmed Progression of EDSS

  Baseline up to Month 24

Other Outcomes (4)

• Change From Baseline in General Health Status as Assessed by the Short-Form General Health Survey (SF-36) Patient-Reported Questionnaire For Physical Component Summary (PCS) Scores

  Baseline, Month 6, Month 12, Month 18, Month 24

• Change From Baseline in General Health Status as Assessed by the Short-Form General Health Survey (SF-36) Patient-Reported Questionnaire For Mental Component Summary (MCS) Scores

  Baseline, Month 6, Month 12, Month 18, Month 24

• Cumulative Number of New or Enlarging Hypointense Lesions on Enhanced T1 Scans

  Months 12 and 24

Study Arms (3)

Placebo

PLACEBO COMPARATOR

Participants will receive 1 capsule of placebo matching to laquinimod orally once daily for 24 months.

Drug: Placebo

Laquinimod

EXPERIMENTAL

Participants will receive 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.

Drug: Laquinimod

Avonex®

ACTIVE COMPARATOR

Participants will receive an injection of Avonex® 30 micrograms (mcg) given intramuscularly (IM) once weekly for 24 months.

Drug: Avonex®

Interventions

Laquinimod DRUG

Laquinimod will be administered per dose and schedule specified in the arm description.

Laquinimod

Placebo DRUG

Placebo matching to laquinimod will be administered per schedule specified in the arm description.

Placebo

Avonex® DRUG

Avonex® will be administered per dose and schedule specified in the arm description.

Also known as: Interferon β-1a

Avonex®

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.: lead

Study Sites (170)

Teva Investigational Site 1267

Birmingham, Alabama, 35209, United States

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Teva Investigational Site 1237

Phoenix, Arizona, 85013, United States

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Teva Investigational Site 1252

Phoenix, Arizona, 85018, United States

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Teva Investigational Site 1279

Phoenix, Arizona, 85018, United States

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Teva Investigational Site 1276

Tucson, Arizona, 85741-3537, United States

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Teva Investigational Site 1272

Pasadena, California, 91105, United States

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Teva Investigational Site 1238

Sacramento, California, 95817, United States

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Teva Investigational Site 1280

Aurora, Colorado, 80045, United States

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Teva Investigational Site 1255

Orlando, Florida, 32806, United States

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Teva Investigational Site 1282

Sarasota, Florida, 34233, United States

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Teva Investigational Site 1275

Atlanta, Georgia, 30309, United States

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Teva Investigational Site 1250

Peoria, Illinois, 61603, United States

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Teva Investigational Site 1260

Indianapolis, Indiana, 46202, United States

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Teva Investigational Site 1268

Lenexa, Kansas, 66214, United States

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Teva Investigational Site 1277

New Orleans, Louisiana, 70115, United States

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Teva Investigational Site 1263

Shreveport, Louisiana, 71103, United States

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Teva Investigational Site 1269

Baltimore, Maryland, 21201, United States

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Teva Investigational Site 1274

Grand Rapids, Michigan, 49525, United States

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Teva Investigational Site 1239

Lebanon, New Hampshire, 03766, United States

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Teva Investigational Site 1265

Teaneck, New Jersey, 07666, United States

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Teva Investigational Site 1273

Albany, New York, 12205, United States

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Teva Investigational Site 1264

Amherst, New York, 14226, United States

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Teva Investigational Site 1283

Cedarhurst, New York, 11516, United States

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Teva Investigational Site 1249

Raleigh, North Carolina, 27607, United States

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Teva Investigational Site 1262

Winston-Salem, North Carolina, 27103, United States

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Teva Investigational Site 1261

Akron, Ohio, 44320, United States

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Teva Investigational Site 1241

Canton, Ohio, 44718, United States

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Teva Investigational Site 1245

Cleveland, Ohio, 44195-5244, United States

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Teva Investigational Site 1247

Columbus, Ohio, 43221, United States

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Teva Investigational Site 1244

Portland, Oregon, 97225, United States

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Teva Investigational Site 1258

Philadelphia, Pennsylvania, 19107, United States

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Teva Investigational Site 1281

Nashville, Tennessee, 37205, United States

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Teva Investigational Site 1284

San Antonio, Texas, 78231, United States

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Teva Investigational Site 1248

Richmond, Virginia, 23298-0599, United States

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Teva Investigational Site 1270

Roanoke, Virginia, 24018, United States

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Teva Investigational Site 1253

Tacoma, Washington, 98405, United States

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Teva Investigational Site 5914

Pleven, 5800, Bulgaria

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Teva Investigational Site 5915

Pleven, 5800, Bulgaria

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Teva Investigational Site 5917

Plovdiv, 4000, Bulgaria

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Teva Investigational Site 4212

Rousse, 7000, Bulgaria

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Teva Investigational Site 5916

Shumen, 9700, Bulgaria

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Teva Investigational Site 5920

Sofia, 1000, Bulgaria

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Teva Investigational Site 5907

Sofia, 1113, Bulgaria

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Teva Investigational Site 5910

Sofia, 1113, Bulgaria

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Teva Investigational Site 5909

Sofia, 1309, Bulgaria

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Teva Investigational Site 5919

Sofia, 1407, Bulgaria

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Teva Investigational Site 5906

Sofia, 1606, Bulgaria

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Teva Investigational Site 5908

Sofia, 1606, Bulgaria

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Teva Investigational Site 5911

Sofia, 1606, Bulgaria

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Teva Investigational Site 5912

Sofia, 1606, Bulgaria

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Teva Investigational Site 5918

Stara Zagora, 6000, Bulgaria

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Teva Investigational Site 5913

Varna, 9010, Bulgaria

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Teva Investigational Site 4211

Veliko Tarnovo, 5000, Bulgaria

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Teva Investigational Site 6003

Osijek, 31 000, Croatia

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Teva Investigational Site 6004

Split, 21000, Croatia

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Teva Investigational Site 6005

Varaždin, 42000, Croatia

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Teva Investigational Site 6001

Zagreb, 10000, Croatia

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Teva Investigational Site 6002

Zagreb, 10000, Croatia

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Teva Investigational Site 6006

Zagreb, 10000, Croatia

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Teva Investigational Site 5422

Brno, 602 00, Czechia

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Teva Investigational Site 5419

Olomouc, 779 00, Czechia

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Teva Investigational Site 5418

Prague, 128 08, Czechia

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Teva Investigational Site 5420

Praha 5- Motol, 150 06, Czechia

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Teva Investigational Site 5421

Teplice, 415 29, Czechia

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Teva Investigational Site 5508

Kohtla-Järve, 31025, Estonia

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Teva Investigational Site 5507

Tallinn, EE-10617, Estonia

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Teva Investigational Site 5509

Tartu, EE-51014, Estonia

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Teva Investigational Site 8102

Tbilisi, 0112, Georgia

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Teva Investigational Site 8104

Tbilisi, 0112, Georgia

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Teva Investigational Site 8103

Tbilisi, 0179, Georgia

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Teva Investigational Site 6701

Bayreuth, 95445, Germany

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Teva Investigational Site 6703

Berlin, 10117, Germany

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Teva Investigational Site 6402

Berlin, 12203, Germany

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Teva Investigational Site 6700

Berlin, 13088, Germany

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Teva Investigational Site 6702

Dresden, 01307, Germany

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Teva Investigational Site 6401

Hanover, 30559, Germany

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Teva Investigational Site 6403

Münster, 48149, Germany

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Teva Investigational Site 6400

Ulm, 89081, Germany

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Teva Investigational Site 8043

Haifa, 3436212, Israel

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Teva Investigational Site 8041

Jerusalem, 9112001, Israel

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Teva Investigational Site 8040

Ramat Gan, 5262160, Israel

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Teva Investigational Site 8042

Ramat Gan, 5262160, Israel

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Teva Investigational Site 3056

Bologna, 40139, Italy

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Teva Investigational Site 3062

Catania, 95122, Italy

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Teva Investigational Site 3053

Cefalù, 90015, Italy

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Teva Investigational Site 3054

Chieti, 66100, Italy

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Teva Investigational Site 3061

Empoli, 50053, Italy

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Teva Investigational Site 3049

Florence, 50139, Italy

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Teva Investigational Site 3055

Napoli, 80131, Italy

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Teva Investigational Site 3048

Rome, 00133, Italy

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Teva Investigational Site 3052

Rome, 00149, Italy

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Teva Investigational Site 3050

Rome, 00168, Italy

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Teva Investigational Site 3060

Rome, 163, Italy

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Teva Investigational Site 3051

Torino, 10126, Italy

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Teva Investigational Site 5708

Kaunas, 50009, Lithuania

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Teva Investigational Site 5707

Šiauliai, 76231, Lithuania

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Teva Investigational Site 6502

Bitola, 7000, North Macedonia

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Teva Investigational Site 6500

Skopje, 1000, North Macedonia

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Teva Investigational Site 6501

Skopje, 1000, North Macedonia

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Teva Investigational Site 5337

Bialystok, 15-402, Poland

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Teva Investigational Site 5329

Gdansk, 80-803, Poland

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Teva Investigational Site 5338

Gdansk, 80-952, Poland

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Teva Investigational Site 4213

Gmina Końskie, 26-200, Poland

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Teva Investigational Site 6602

Gorzów Wielkopolski, 66-400, Poland

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Teva Investigational Site 5333

Grodzisk Mazowiecki, 05-825, Poland

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Teva Investigational Site 5339

Katowice, 40-635, Poland

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Teva Investigational Site 5334

Katowice, 40-752, Poland

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Teva Investigational Site 6603

Kielce, 25-736, Poland

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Teva Investigational Site 5332

Kościerzyna, 83-400, Poland

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Teva Investigational Site 5345

Krakow, 31-826, Poland

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Teva Investigational Site 5328

Lodz, 90-153, Poland

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Teva Investigational Site 5330

Olsztyn, 10-560, Poland

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Teva Investigational Site 5331

Szczecin, 70-215, Poland

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Teva Investigational Site 5340

Warsaw, 00-909, Poland

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Teva Investigational Site 5341

Warsaw, 02-097, Poland

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Teva Investigational Site 5336

Warsaw, 02-957, Poland

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Teva Investigational Site 5335

Wroclaw, 50-556, Poland

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Teva Investigational Site 1243

Guaynabo, 00969, Puerto Rico

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Teva Investigational Site 5218

Bucharest, 010825, Romania

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Teva Investigational Site 5214

Bucharest, 022328, Romania

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Teva Investigational Site 5213

Bucharest, 050098, Romania

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Teva Investigational Site 5215

Cluj-Napoca, 400012, Romania

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Teva Investigational Site 5217

Constanța, 900591, Romania

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Teva Investigational Site 8209

Craiova, 200515, Romania

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Teva Investigational Site 5216

Iași, 700661, Romania

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Teva Investigational Site 5219

Sibiu, 550245, Romania

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Teva Investigational Site 5043

Barnaul, 656024, Russia

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Teva Investigational Site 5033

Moscow, 117152, Russia

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Teva Investigational Site 5032

Moscow, 117997, Russia

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Teva Investigational Site 5041

Moscow, 125367, Russia

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Teva Investigational Site 5038

Novosibirsk, 630087, Russia

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Teva Investigational Site 5042

Novosibirsk, 630117, Russia

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Teva Investigational Site 5036

Saint Petersburg, 194291, Russia

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Teva Investigational Site 5035

Saint Petersburg, 197022, Russia

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Teva Investigational Site 5034

Saint Petersburg, 197376, Russia

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Teva Investigational Site 5037

Samara, 443095, Russia

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Teva Investigational Site 5044

Ufa, 450007, Russia

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Teva Investigational Site 6200

Bratislava, 813 69, Slovakia

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Teva Investigational Site 6201

Bratislava, 826 06, Slovakia

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Teva Investigational Site 6202

Nitra, 949 01, Slovakia

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Teva Investigational Site 6203

Žilina, 010 01, Slovakia

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Teva Investigational Site 9007

Bloemfontein, 9301, South Africa

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Teva Investigational Site 9001

Cape Town, 7925, South Africa

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Teva Investigational Site 9004

Johannesburg, 2157, South Africa

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Teva Investigational Site 9003

Johannesburg, 2193, South Africa

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Teva Investigational Site 9008

Pietermaritzburg, 3201, South Africa

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Teva Investigational Site 9005

Pretoria, 0041, South Africa

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Teva Investigational Site 9006

Rosebank, 2196, South Africa

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Teva Investigational Site 3147

Barcelona, 08035, Spain

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Teva Investigational Site 3154

Figueres-Girona, 17600, Spain

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Teva Investigational Site 3149

L'Hospitalet de Llobregat, 08907, Spain

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Teva Investigational Site 3152

Madrid, 28041, Spain

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Teva Investigational Site 3151

Málaga, 29010, Spain

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Teva Investigational Site 3148

Seville, 41009, Spain

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Teva Investigational Site 3153

Tortosa-Tarragona, 43500, Spain

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Teva Investigational Site 6503

Chernihiv, 14029, Ukraine

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Teva Investigational Site 5823

Chernivtsi, 58018, Ukraine

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Teva Investigational Site 5811

Dnipropetrovsk, 49027, Ukraine

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Teva Investigational Site 5812

Donetsk, 83003, Ukraine

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Teva Investigational Site 5814

Ivano-Frankivsk, 76008, Ukraine

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Teva Investigational Site 5817

Kharkiv, 61018, Ukraine

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Teva Investigational Site 5818

Kharkiv, 61068, Ukraine

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Teva Investigational Site 5815

Kharkiv, 61103, Ukraine

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Teva Investigational Site 5822

Kyiv, 03110, Ukraine

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Teva Investigational Site 5809

Lviv, 79010, Ukraine

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Teva Investigational Site 5820

Odesa, 65025, Ukraine

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Teva Investigational Site 5821

Poltava, 36024, Ukraine

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Teva Investigational Site 5810

Vinnytsia, 21005, Ukraine

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Teva Investigational Site 5819

Zaporizhzhya, 69035, Ukraine

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Teva Investigational Site 5816

Zaporizhzhya, 69600, Ukraine

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Related Publications (2)

• Falet JR, Durso-Finley J, Nichyporuk B, Schroeter J, Bovis F, Sormani MP, Precup D, Arbel T, Arnold DL. Estimating individual treatment effect on disability progression in multiple sclerosis using deep learning. Nat Commun. 2022 Sep 26;13(1):5645. doi: 10.1038/s41467-022-33269-x.

  PMID: 36163349 DERIVED

• 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.

  PMID: 26000222 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis

Interventions

laquinimod; Interferon beta-1a

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Interferon-beta; Interferon Type I; Interferons; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Director, Clinical Research
• Organization: Teva Branded Pharmaceutical Products R&D, Inc.

USMedInfo@tevapharm.com

1-888-483-8279

Study Officials

• Teva Medical Expert, M.D.

  Teva Branded Pharmaceutical Products R&D, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 8, 2008
• First Posted: January 30, 2008
• Study Start: April 24, 2008
• Primary Completion: June 10, 2011
• Study Completion: June 10, 2011
• Last Updated: April 21, 2022
• Results First Posted: April 21, 2022

Record last verified: 2022-03

Locations

ES (3); SL (4); IL (4); NO (3); CR (6); PL (18); IT (12); CZ (5); UA (15); US (36); ZA (7); RU (11); GE (3); DE (8); BU (17); LI (2); RO (8); PR (1)