Clinical trial NCT00605215: 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®)
Official title: A Multinational, Multicenter, Randomized, Parallel-Group Study Performed in Subjects With Relapsing-Remitting Multiple Sclerosis (RRMS) to Assess the Efficacy, Safety and Tolerability of Laquinimod Over Placebo in a Double-blind Design and of a Reference Arm of Interferon β-1a (Avonex®) in a Rater-blinded Design
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Sclerosis
Lead sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Sponsor class: INDUSTRY
First posted: 2008-01-30
Enrollment: 1331
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: 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®).


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 between screening (month -1) and baseline visits (month 0).
4. Subjects must have had experienced one of the following:
5. At least one documented relapse in the 12 months prior to screening
6. At least two documented relapses in the 24 months prior to screening
7. 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.
8. Subjects must be between 18 and 55 years of age, inclusive.
9. Subjects must have disease duration of at least 6 months (from first symptom) prior to screening.
10. Women of child-bearing potential must practice 2 acceptable methods of birth control \[acceptable methods of birth control in this study include: surgical sterilization, intrauterine devices, oral contraceptive, contraceptive patch, long-acting injectable contraceptive, partner's vasectomy or double-barrier method (condom or diaphragm with spermicide)\].
11. Subjects must be willing and able to comply with the protocol requirements for the duration of the study.

Exclusion Criteria:

1. 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).
2. Use of experimental or investigational drugs, and/or participation in drug clinical studies within the 6 months prior to screening.
3. Use of immunosuppressive (including Mitoxantrone (Novantrone®) or cytotoxic agents within 6 months prior to the screening visit.
4. Previous use of either of the following: natalizumab (Tysabri®), cladribine or laquinimod.
5. Previous treatment with glatiramer acetate (Copaxone®) or IVIG within 3 months prior to screening visit.
6. Previous treatment with Interferon beta-1a (Avonex® or Rebif®) or Interferon beta-1b (Betaseron®).
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 2 weeks prior to baseline visit.
12. Major trauma or surgery 2 weeks prior to baseline visit.
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) by history or 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 (see detailed list of drugs in protocol) (1 month for fluoxetine).
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, 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.
20. 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.
21. A known history of sensitivity to Gadolinium.
22. Inability to successfully undergo MRI scanning.
23. A known history of hypersensitivity to natural or recombinant interferon beta, human albumin, or any other component of the formulation of Avonex®.
24. Subjects who suffer from any form of progressive MS
25. Any condition which the investigator feels may interfere with participation in the study
26. Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation
27. Subjects who received any investigational medication, immunosuppressives or cytotoxic agents within 6 months prior to screening
28. Previous treatment with immunomodulators within two months prior to screening
29. Pregnancy or breastfeeding

Primary outcomes:
measure: Annualized Rate of Confirmed Relapses
timeFrame: Baseline up to Month 24
Secondary outcomes:
measure: Change From Baseline in Disability as Assessed by the Multiple Sclerosis Functional Composite (MSFC) Score
timeFrame: Baseline, Month 24
measure: Percent Change From Baseline in Brain Volume
timeFrame: Baseline, Month 24
measure: Accumulation of Physical Disability Measured by the Number of Participants With Confirmed Progression of EDSS
timeFrame: Baseline up to Month 24
Other outcomes:
measure: 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
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24
measure: 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
timeFrame: Baseline, Month 6, Month 12, Month 18, Month 24
measure: Cumulative Number of New or Enlarging Hypointense Lesions on Enhanced T1 Scans
timeFrame: Months 12 and 24
measure: Cumulative Number of Enhancing Lesions on T1-Weighted Images
timeFrame: Months 12 and 24
Locations:
city: Birmingham
country: United States
facility: Teva Investigational Site 1267
state: Alabama
city: Phoenix
country: United States
facility: Teva Investigational Site 1237
state: Arizona
city: Phoenix
country: United States
facility: Teva Investigational Site 1252
state: Arizona
city: Phoenix
country: United States
facility: Teva Investigational Site 1279
state: Arizona
city: Tucson
country: United States
facility: Teva Investigational Site 1276
state: Arizona
city: Pasadena
country: United States
facility: Teva Investigational Site 1272
state: California
city: Sacramento
country: United States
facility: Teva Investigational Site 1238
state: California
city: Aurora
country: United States
facility: Teva Investigational Site 1280
state: Colorado
city: Orlando
country: United States
facility: Teva Investigational Site 1255
state: Florida
city: Sarasota
country: United States
facility: Teva Investigational Site 1282
state: Florida
city: Atlanta
country: United States
facility: Teva Investigational Site 1275
state: Georgia
city: Peoria
country: United States
facility: Teva Investigational Site 1250
state: Illinois
city: Indianapolis
country: United States
facility: Teva Investigational Site 1260
state: Indiana
city: Lenexa
country: United States
facility: Teva Investigational Site 1268
state: Kansas
city: New Orleans
country: United States
facility: Teva Investigational Site 1277
state: Louisiana
city: Shreveport
country: United States
facility: Teva Investigational Site 1263
state: Louisiana
city: Baltimore
country: United States
facility: Teva Investigational Site 1269
state: Maryland
city: Grand Rapids
country: United States
facility: Teva Investigational Site 1274
state: Michigan
city: Lebanon
country: United States
facility: Teva Investigational Site 1239
state: New Hampshire
city: Teaneck
country: United States
facility: Teva Investigational Site 1265
state: New Jersey
city: Albany
country: United States
facility: Teva Investigational Site 1273
state: New York
city: Amherst
country: United States
facility: Teva Investigational Site 1264
state: New York
city: Cedarhurst
country: United States
facility: Teva Investigational Site 1283
state: New York
city: Raleigh
country: United States
facility: Teva Investigational Site 1249
state: North Carolina
city: Winston-Salem
country: United States
facility: Teva Investigational Site 1262
state: North Carolina
city: Akron
country: United States
facility: Teva Investigational Site 1261
state: Ohio
city: Canton
country: United States
facility: Teva Investigational Site 1241
state: Ohio
city: Cleveland
country: United States
facility: Teva Investigational Site 1245
state: Ohio
city: Columbus
country: United States
facility: Teva Investigational Site 1247
state: Ohio
city: Portland
country: United States
facility: Teva Investigational Site 1244
state: Oregon
city: Philadelphia
country: United States
facility: Teva Investigational Site 1258
state: Pennsylvania
city: Nashville
country: United States
facility: Teva Investigational Site 1281
state: Tennessee
city: San Antonio
country: United States
facility: Teva Investigational Site 1284
state: Texas
city: Richmond
country: United States
facility: Teva Investigational Site 1248
state: Virginia
city: Roanoke
country: United States
facility: Teva Investigational Site 1270
state: Virginia
city: Tacoma
country: United States
facility: Teva Investigational Site 1253
state: Washington
city: Pleven
country: Bulgaria
facility: Teva Investigational Site 5914
city: Pleven
country: Bulgaria
facility: Teva Investigational Site 5915
city: Plovdiv
country: Bulgaria
facility: Teva Investigational Site 5917
city: Ruse
country: Bulgaria
facility: Teva Investigational Site 4212
city: Shumen
country: Bulgaria
facility: Teva Investigational Site 5916
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5920
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5907
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5910
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5909
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5919
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5906
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5908
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5911
city: Sofia
country: Bulgaria
facility: Teva Investigational Site 5912
city: Stara Zagora
country: Bulgaria
facility: Teva Investigational Site 5918
city: Varna
country: Bulgaria
facility: Teva Investigational Site 5913
city: Veliko Tarnovo
country: Bulgaria
facility: Teva Investigational Site 4211
city: Osijek
country: Croatia
facility: Teva Investigational Site 6003
city: Split
country: Croatia
facility: Teva Investigational Site 6004
city: Varazdin
country: Croatia
facility: Teva Investigational Site 6005
city: Zagreb
country: Croatia
facility: Teva Investigational Site 6001
city: Zagreb
country: Croatia
facility: Teva Investigational Site 6002
city: Zagreb
country: Croatia
facility: Teva Investigational Site 6006
city: Brno
country: Czechia
facility: Teva Investigational Site 5422
city: Olomouc
country: Czechia
facility: Teva Investigational Site 5419
city: Praha 2
country: Czechia
facility: Teva Investigational Site 5418
city: Praha 5- Motol
country: Czechia
facility: Teva Investigational Site 5420
city: Teplice
country: Czechia
facility: Teva Investigational Site 5421
city: Kohtla-Jarve
country: Estonia
facility: Teva Investigational Site 5508
city: Tallinn
country: Estonia
facility: Teva Investigational Site 5507
city: Tartu
country: Estonia
facility: Teva Investigational Site 5509
city: Tbilisi
country: Georgia
facility: Teva Investigational Site 8102
city: Tbilisi
country: Georgia
facility: Teva Investigational Site 8104
city: Tbilisi
country: Georgia
facility: Teva Investigational Site 8103
city: Bayreuth
country: Germany
facility: Teva Investigational Site 6701
city: Berlin
country: Germany
facility: Teva Investigational Site 6703
city: Berlin
country: Germany
facility: Teva Investigational Site 6402
city: Berlin
country: Germany
facility: Teva Investigational Site 6700
city: Dresden
country: Germany
facility: Teva Investigational Site 6702
city: Hannover
country: Germany
facility: Teva Investigational Site 6401
city: Munster
country: Germany
facility: Teva Investigational Site 6403
city: Ulm
country: Germany
facility: Teva Investigational Site 6400
city: Haifa
country: Israel
facility: Teva Investigational Site 8043
city: Jerusalem
country: Israel
facility: Teva Investigational Site 8041
city: Ramat Gan
country: Israel
facility: Teva Investigational Site 8040
city: Ramat Gan
country: Israel
facility: Teva Investigational Site 8042
city: Bologna
country: Italy
facility: Teva Investigational Site 3056
city: Catania
country: Italy
facility: Teva Investigational Site 3062
city: Cefalu
country: Italy
facility: Teva Investigational Site 3053
city: Chieti
country: Italy
facility: Teva Investigational Site 3054
city: Empoli
country: Italy
facility: Teva Investigational Site 3061
city: Firenze
country: Italy
facility: Teva Investigational Site 3049
city: Napoli
country: Italy
facility: Teva Investigational Site 3055
city: Rome
country: Italy
facility: Teva Investigational Site 3048
city: Rome
country: Italy
facility: Teva Investigational Site 3052
city: Rome
country: Italy
facility: Teva Investigational Site 3050
city: Rome
country: Italy
facility: Teva Investigational Site 3060
city: Torino
country: Italy
facility: Teva Investigational Site 3051
city: Kaunas
country: Lithuania
facility: Teva Investigational Site 5708
city: Siauliai
country: Lithuania
facility: Teva Investigational Site 5707
city: Bitola
country: North Macedonia
facility: Teva Investigational Site 6502
city: Skopje
country: North Macedonia
facility: Teva Investigational Site 6500
city: Skopje
country: North Macedonia
facility: Teva Investigational Site 6501
city: Bialystok
country: Poland
facility: Teva Investigational Site 5337
city: Gdansk
country: Poland
facility: Teva Investigational Site 5329
city: Gdansk
country: Poland
facility: Teva Investigational Site 5338
city: Gorzow Wielkopolski
country: Poland
facility: Teva Investigational Site 6602
city: Grodzisk Mazowiecki
country: Poland
facility: Teva Investigational Site 5333
city: Katowice
country: Poland
facility: Teva Investigational Site 5339
city: Katowice
country: Poland
facility: Teva Investigational Site 5334
city: Kielce
country: Poland
facility: Teva Investigational Site 6603
city: Konskie
country: Poland
facility: Teva Investigational Site 4213
city: Koscierzyna
country: Poland
facility: Teva Investigational Site 5332
city: Krakow
country: Poland
facility: Teva Investigational Site 5345
city: Lodz
country: Poland
facility: Teva Investigational Site 5328
city: Olsztyn
country: Poland
facility: Teva Investigational Site 5330
city: Szczecin
country: Poland
facility: Teva Investigational Site 5331
city: Warsaw
country: Poland
facility: Teva Investigational Site 5336
city: Warszawa
country: Poland
facility: Teva Investigational Site 5340
city: Warszawa
country: Poland
facility: Teva Investigational Site 5341
city: Wroclaw
country: Poland
facility: Teva Investigational Site 5335
city: Guaynabo
country: Puerto Rico
facility: Teva Investigational Site 1243
city: Bucharest
country: Romania
facility: Teva Investigational Site 5218
city: Bucuresti
country: Romania
facility: Teva Investigational Site 5214
city: Bucuresti
country: Romania
facility: Teva Investigational Site 5213
city: Cluj-Napoca
country: Romania
facility: Teva Investigational Site 5215
city: Constanta
country: Romania
facility: Teva Investigational Site 5217
city: Craiova
country: Romania
facility: Teva Investigational Site 8209
city: Iasi
country: Romania
facility: Teva Investigational Site 5216
city: Sibiu
country: Romania
facility: Teva Investigational Site 5219
city: Barnaul
country: Russian Federation
facility: Teva Investigational Site 5043
city: Moscow
country: Russian Federation
facility: Teva Investigational Site 5033
city: Moscow
country: Russian Federation
facility: Teva Investigational Site 5032
city: Moscow
country: Russian Federation
facility: Teva Investigational Site 5041
city: Novosibirsk
country: Russian Federation
facility: Teva Investigational Site 5038
city: Novosibirsk
country: Russian Federation
facility: Teva Investigational Site 5042
city: Saint Petersburg
country: Russian Federation
facility: Teva Investigational Site 5035
city: Samara
country: Russian Federation
facility: Teva Investigational Site 5037
city: St. Petersburg
country: Russian Federation
facility: Teva Investigational Site 5036
city: St. Petersburg
country: Russian Federation
facility: Teva Investigational Site 5034
city: Ufa
country: Russian Federation
facility: Teva Investigational Site 5044
city: Bratislava
country: Slovakia
facility: Teva Investigational Site 6200
city: Bratislava
country: Slovakia
facility: Teva Investigational Site 6201
city: Nitra
country: Slovakia
facility: Teva Investigational Site 6202
city: Zilina
country: Slovakia
facility: Teva Investigational Site 6203
city: Bloemfontein
country: South Africa
facility: Teva Investigational Site 9007
city: Cape Town
country: South Africa
facility: Teva Investigational Site 9001
city: Johannesburg
country: South Africa
facility: Teva Investigational Site 9004
city: Johannesburg
country: South Africa
facility: Teva Investigational Site 9003
city: Pietermaritzburg
country: South Africa
facility: Teva Investigational Site 9008
city: Pretoria
country: South Africa
facility: Teva Investigational Site 9005
city: Rosebank
country: South Africa
facility: Teva Investigational Site 9006
city: Barcelona
country: Spain
facility: Teva Investigational Site 3147
city: Figueres-Girona
country: Spain
facility: Teva Investigational Site 3154
city: L'Hospitalet de Llobregat
country: Spain
facility: Teva Investigational Site 3149
city: Madrid
country: Spain
facility: Teva Investigational Site 3152
city: Malaga
country: Spain
facility: Teva Investigational Site 3151
city: Sevilla
country: Spain
facility: Teva Investigational Site 3148
city: Tortosa-Tarragona
country: Spain
facility: Teva Investigational Site 3153
city: Chernihiv
country: Ukraine
facility: Teva Investigational Site 6503
city: Chernivtsi
country: Ukraine
facility: Teva Investigational Site 5823
city: Dnipropetrovsk
country: Ukraine
facility: Teva Investigational Site 5811
city: Donetsk
country: Ukraine
facility: Teva Investigational Site 5812
city: Ivano-Frankivsk
country: Ukraine
facility: Teva Investigational Site 5814
city: Kharkiv
country: Ukraine
facility: Teva Investigational Site 5817
city: Kharkiv
country: Ukraine
facility: Teva Investigational Site 5818
city: Kharkiv
country: Ukraine
facility: Teva Investigational Site 5815
city: Kyiv
country: Ukraine
facility: Teva Investigational Site 5822
city: Lviv
country: Ukraine
facility: Teva Investigational Site 5809
city: Odessa
country: Ukraine
facility: Teva Investigational Site 5820
city: Poltava
country: Ukraine
facility: Teva Investigational Site 5821
city: Vinnytsya
country: Ukraine
facility: Teva Investigational Site 5810
city: Zaporizhzhya
country: Ukraine
facility: Teva Investigational Site 5819
city: Zaporizhzhya
country: Ukraine
facility: Teva Investigational Site 5816
Study officials:
affiliation: Teva Branded Pharmaceutical Products R&D, Inc.
name: Teva Medical Expert, M.D.
role: STUDY_DIRECTOR
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.