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®)

Multiple Sclerosis Clinical Trial

— BRAVO  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00605215
• Other study ID #: MS-LAQ-302
• Secondary ID: 2007-005450-23
• Status: Completed
• Phase: Phase 3
• Start date: April 24, 2008
• Est. completion date: June 10, 2011

Study information

• Verified date: March 2022
• Source: Teva Branded Pharmaceutical Products R&D, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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®).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1331
• Est. completion date: June 10, 2011
• Est. primary completion date: June 10, 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

Intervention

Drug:
• Laquinimod
Laquinimod will be administered per dose and schedule specified in the arm description.
• Placebo
Placebo matching to laquinimod will be administered per schedule specified in the arm description.
• Avonex®
Avonex® will be administered per dose and schedule specified in the arm description.

Locations

Country	Name	City	State
Bulgaria	Teva Investigational Site 5914	Pleven
Bulgaria	Teva Investigational Site 5915	Pleven
Bulgaria	Teva Investigational Site 5917	Plovdiv
Bulgaria	Teva Investigational Site 4212	Ruse
Bulgaria	Teva Investigational Site 5916	Shumen
Bulgaria	Teva Investigational Site 5906	Sofia
Bulgaria	Teva Investigational Site 5907	Sofia
Bulgaria	Teva Investigational Site 5908	Sofia
Bulgaria	Teva Investigational Site 5909	Sofia
Bulgaria	Teva Investigational Site 5910	Sofia
Bulgaria	Teva Investigational Site 5911	Sofia
Bulgaria	Teva Investigational Site 5912	Sofia
Bulgaria	Teva Investigational Site 5919	Sofia
Bulgaria	Teva Investigational Site 5920	Sofia
Bulgaria	Teva Investigational Site 5918	Stara Zagora
Bulgaria	Teva Investigational Site 5913	Varna
Bulgaria	Teva Investigational Site 4211	Veliko Tarnovo
Croatia	Teva Investigational Site 6003	Osijek
Croatia	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 6006	Zagreb
Czechia	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 5421	Teplice
Estonia	Teva Investigational Site 5508	Kohtla-Jarve
Estonia	Teva Investigational Site 5507	Tallinn
Estonia	Teva Investigational Site 5509	Tartu
Georgia	Teva Investigational Site 8102	Tbilisi
Georgia	Teva Investigational Site 8103	Tbilisi
Georgia	Teva Investigational Site 8104	Tbilisi
Germany	Teva Investigational Site 6701	Bayreuth
Germany	Teva Investigational Site 6402	Berlin
Germany	Teva Investigational Site 6700	Berlin
Germany	Teva Investigational Site 6703	Berlin
Germany	Teva Investigational Site 6702	Dresden
Germany	Teva Investigational Site 6401	Hannover
Germany	Teva Investigational Site 6403	Munster
Germany	Teva Investigational Site 6400	Ulm
Israel	Teva Investigational Site 8043	Haifa
Israel	Teva Investigational Site 8041	Jerusalem
Israel	Teva Investigational Site 8040	Ramat Gan
Israel	Teva Investigational Site 8042	Ramat Gan
Italy	Teva Investigational Site 3056	Bologna
Italy	Teva Investigational Site 3062	Catania
Italy	Teva Investigational Site 3053	Cefalu
Italy	Teva Investigational Site 3054	Chieti
Italy	Teva Investigational Site 3061	Empoli
Italy	Teva Investigational Site 3049	Firenze
Italy	Teva Investigational Site 3055	Napoli
Italy	Teva Investigational Site 3048	Rome
Italy	Teva Investigational Site 3050	Rome
Italy	Teva Investigational Site 3052	Rome
Italy	Teva Investigational Site 3060	Rome
Italy	Teva Investigational Site 3051	Torino
Lithuania	Teva Investigational Site 5708	Kaunas
Lithuania	Teva Investigational Site 5707	Siauliai
North Macedonia	Teva Investigational Site 6502	Bitola
North Macedonia	Teva Investigational Site 6500	Skopje
North Macedonia	Teva Investigational Site 6501	Skopje
Poland	Teva Investigational Site 5337	Bialystok
Poland	Teva Investigational Site 5329	Gdansk
Poland	Teva Investigational Site 5338	Gdansk
Poland	Teva Investigational Site 6602	Gorzow Wielkopolski
Poland	Teva Investigational Site 5333	Grodzisk Mazowiecki
Poland	Teva Investigational Site 5334	Katowice
Poland	Teva Investigational Site 5339	Katowice
Poland	Teva Investigational Site 6603	Kielce
Poland	Teva Investigational Site 4213	Konskie
Poland	Teva Investigational Site 5332	Koscierzyna
Poland	Teva Investigational Site 5345	Krakow
Poland	Teva Investigational Site 5328	Lodz
Poland	Teva Investigational Site 5330	Olsztyn
Poland	Teva Investigational Site 5331	Szczecin
Poland	Teva Investigational Site 5336	Warsaw
Poland	Teva Investigational Site 5340	Warszawa
Poland	Teva Investigational Site 5341	Warszawa
Poland	Teva Investigational Site 5335	Wroclaw
Puerto Rico	Teva Investigational Site 1243	Guaynabo
Romania	Teva Investigational Site 5218	Bucharest
Romania	Teva Investigational Site 5213	Bucuresti
Romania	Teva Investigational Site 5214	Bucuresti
Romania	Teva Investigational Site 5215	Cluj-Napoca
Romania	Teva Investigational Site 5217	Constanta
Romania	Teva Investigational Site 8209	Craiova
Romania	Teva Investigational Site 5216	Iasi
Romania	Teva Investigational Site 5219	Sibiu
Russian Federation	Teva Investigational Site 5043	Barnaul
Russian Federation	Teva Investigational Site 5032	Moscow
Russian Federation	Teva Investigational Site 5033	Moscow
Russian Federation	Teva Investigational Site 5041	Moscow
Russian Federation	Teva Investigational Site 5038	Novosibirsk
Russian Federation	Teva Investigational Site 5042	Novosibirsk
Russian Federation	Teva Investigational Site 5035	Saint Petersburg
Russian Federation	Teva Investigational Site 5037	Samara
Russian Federation	Teva Investigational Site 5034	St. Petersburg
Russian Federation	Teva Investigational Site 5036	St. Petersburg
Russian Federation	Teva Investigational Site 5044	Ufa
Slovakia	Teva Investigational Site 6200	Bratislava
Slovakia	Teva Investigational Site 6201	Bratislava
Slovakia	Teva Investigational Site 6202	Nitra
Slovakia	Teva Investigational Site 6203	Zilina
South Africa	Teva Investigational Site 9007	Bloemfontein
South Africa	Teva Investigational Site 9001	Cape Town
South Africa	Teva Investigational Site 9003	Johannesburg
South Africa	Teva Investigational Site 9004	Johannesburg
South Africa	Teva Investigational Site 9008	Pietermaritzburg
South Africa	Teva Investigational Site 9005	Pretoria
South Africa	Teva Investigational Site 9006	Rosebank
Spain	Teva Investigational Site 3147	Barcelona
Spain	Teva Investigational Site 3154	Figueres-Girona
Spain	Teva Investigational Site 3149	L'Hospitalet de Llobregat
Spain	Teva Investigational Site 3152	Madrid
Spain	Teva Investigational Site 3151	Malaga
Spain	Teva Investigational Site 3148	Sevilla
Spain	Teva Investigational Site 3153	Tortosa-Tarragona
Ukraine	Teva Investigational Site 6503	Chernihiv
Ukraine	Teva Investigational Site 5823	Chernivtsi
Ukraine	Teva Investigational Site 5811	Dnipropetrovsk
Ukraine	Teva Investigational Site 5812	Donetsk
Ukraine	Teva Investigational Site 5814	Ivano-Frankivsk
Ukraine	Teva Investigational Site 5815	Kharkiv
Ukraine	Teva Investigational Site 5817	Kharkiv
Ukraine	Teva Investigational Site 5818	Kharkiv
Ukraine	Teva Investigational Site 5822	Kyiv
Ukraine	Teva Investigational Site 5809	Lviv
Ukraine	Teva Investigational Site 5820	Odessa
Ukraine	Teva Investigational Site 5821	Poltava
Ukraine	Teva Investigational Site 5810	Vinnytsya
Ukraine	Teva Investigational Site 5816	Zaporizhzhya
Ukraine	Teva Investigational Site 5819	Zaporizhzhya
United States	Teva Investigational Site 1261	Akron	Ohio
United States	Teva Investigational Site 1273	Albany	New York
United States	Teva Investigational Site 1264	Amherst	New York
United States	Teva Investigational Site 1275	Atlanta	Georgia
United States	Teva Investigational Site 1280	Aurora	Colorado
United States	Teva Investigational Site 1269	Baltimore	Maryland
United States	Teva Investigational Site 1267	Birmingham	Alabama
United States	Teva Investigational Site 1241	Canton	Ohio
United States	Teva Investigational Site 1283	Cedarhurst	New York
United States	Teva Investigational Site 1245	Cleveland	Ohio
United States	Teva Investigational Site 1247	Columbus	Ohio
United States	Teva Investigational Site 1274	Grand Rapids	Michigan
United States	Teva Investigational Site 1260	Indianapolis	Indiana
United States	Teva Investigational Site 1239	Lebanon	New Hampshire
United States	Teva Investigational Site 1268	Lenexa	Kansas
United States	Teva Investigational Site 1281	Nashville	Tennessee
United States	Teva Investigational Site 1277	New Orleans	Louisiana
United States	Teva Investigational Site 1255	Orlando	Florida
United States	Teva Investigational Site 1272	Pasadena	California
United States	Teva Investigational Site 1250	Peoria	Illinois
United States	Teva Investigational Site 1258	Philadelphia	Pennsylvania
United States	Teva Investigational Site 1237	Phoenix	Arizona
United States	Teva Investigational Site 1252	Phoenix	Arizona
United States	Teva Investigational Site 1279	Phoenix	Arizona
United States	Teva Investigational Site 1244	Portland	Oregon
United States	Teva Investigational Site 1249	Raleigh	North Carolina
United States	Teva Investigational Site 1248	Richmond	Virginia
United States	Teva Investigational Site 1270	Roanoke	Virginia
United States	Teva Investigational Site 1238	Sacramento	California
United States	Teva Investigational Site 1284	San Antonio	Texas
United States	Teva Investigational Site 1282	Sarasota	Florida
United States	Teva Investigational Site 1263	Shreveport	Louisiana
United States	Teva Investigational Site 1253	Tacoma	Washington
United States	Teva Investigational Site 1265	Teaneck	New Jersey
United States	Teva Investigational Site 1276	Tucson	Arizona
United States	Teva Investigational Site 1262	Winston-Salem	North Carolina

Sponsors (1)

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

Countries where clinical trial is conducted

United States,  Bulgaria,  Croatia,  Czechia,  Estonia,  Georgia,  Germany,  Israel,  Italy,  Lithuania,  North Macedonia,  Poland,  Puerto Rico,  Romania,  Russian Federation,  Slovakia,  South Africa,  Spain,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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	The SF-36 questionnaire has 36 questions composing the scale that represent 8 domains: 1) physical functioning, role physical, 2) bodily pain, 3) general health, 4) vitality, 5) social functioning, 6) role, 7) emotional, and 8) mental health. The scores for the 8 domains were combined into two summary scores: the physical component summary (PCS) score and the mental component summary (MCS) score. Items 1 to 4 primarily contribute to the PCS score of the SF-36. Items 5-8 primarily contribute to the MCS score of the SF-36. Scores on each item were summed and averaged (range: 0=worst to 100=best). Higher scores represent better health status and functional ability.	Baseline, Month 6, Month 12, Month 18, Month 24
Other	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	The SF-36 questionnaire has 36 questions composing the scale that represent 8 domains: 1) physical functioning, role physical, 2) bodily pain, 3) general health, 4) vitality, 5) social functioning, 6) role, 7) emotional, and 8) mental health. The scores for the 8 domains were combined into two summary scores: the physical component summary (PCS) score and the mental component summary (MCS) score. Items 1 to 4 primarily contribute to the PCS score of the SF-36. Items 5-8 primarily contribute to the MCS score of the SF-36. Scores on each item were summed and averaged (range: 0=worst to 100=best). Higher scores represent better health status and functional ability.	Baseline, Month 6, Month 12, Month 18, Month 24
Other	Cumulative Number of New or Enlarging Hypointense Lesions on Enhanced T1 Scans	The cumulative number of new or enlarging hypointense lesions was calculated as the sum of the numbers of new or enlarging hypointense lesions observed on scans taken at Months 12 and 24.	Months 12 and 24
Other	Cumulative Number of Enhancing Lesions on T1-Weighted Images	The cumulative number of T1 Gadolinium (Gd)-enhancing lesions was calculated as the sum of the numbers of Gd-enhancing lesions observed on scans taken at Months 12 and 24.	Months 12 and 24
Primary	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	Change From Baseline in Disability as Assessed by the Multiple Sclerosis Functional Composite (MSFC) Score	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.	Baseline, Month 24
Secondary	Percent Change From Baseline in Brain Volume	Change in brain volume was derived from MRI scans obtained at baseline and at Month 24.	Baseline, Month 24
Secondary	Accumulation of Physical Disability Measured by the Number of Participants With Confirmed Progression of EDSS	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.	Baseline up to Month 24