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®)

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00605215
• Collaborator: (none)
• Enrollment: 1,331
• Locations: 170
• Arms: 3
• Actual Duration (Months): 37.5
• Patients Per Site: 7.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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®).

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: Laquinimod; Drug: Placebo; Drug: Avonex®	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1331 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Apr 24, 2008
• Actual Primary Completion Date: Jun 10, 2011
• Actual Study Completion Date: Jun 10, 2011

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants will receive 1 capsule of placebo matching to laquinimod orally once daily for 24 months.	Drug: Placebo; Placebo matching to laquinimod will be administered per schedule specified in the arm description.
Experimental: Laquinimod Participants will receive 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Drug: Laquinimod; Laquinimod will be administered per dose and schedule specified in the arm description.
Active Comparator: Avonex® Participants will receive an injection of Avonex® 30 micrograms (mcg) given intramuscularly (IM) once weekly for 24 months.	Drug: Avonex®; Avonex® will be administered per dose and schedule specified in the arm description.; Other Names: Interferon β-1a

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. 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.

Other Outcome Measures

1. 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]

   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.

2. 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]

   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.

3. Cumulative Number of New or Enlarging Hypointense Lesions on Enhanced T1 Scans [Months 12 and 24]

   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.

4. Cumulative Number of Enhancing Lesions on T1-Weighted Images [Months 12 and 24]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

1. 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.

2. A known history of sensitivity to Gadolinium.

3. Inability to successfully undergo MRI scanning.

4. A known history of hypersensitivity to natural or recombinant interferon beta, human albumin, or any other component of the formulation of Avonex®.

5. Subjects who suffer from any form of progressive MS

6. Any condition which the investigator feels may interfere with participation in the study

7. Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation

8. Subjects who received any investigational medication, immunosuppressives or cytotoxic agents within 6 months prior to screening

9. Previous treatment with immunomodulators within two months prior to screening

10. Pregnancy or breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 1267	Birmingham	Alabama	United States	35209
2	Teva Investigational Site 1237	Phoenix	Arizona	United States	85013
3	Teva Investigational Site 1252	Phoenix	Arizona	United States	85018
4	Teva Investigational Site 1279	Phoenix	Arizona	United States	85018
5	Teva Investigational Site 1276	Tucson	Arizona	United States	85741-3537
6	Teva Investigational Site 1272	Pasadena	California	United States	91105
7	Teva Investigational Site 1238	Sacramento	California	United States	95817
8	Teva Investigational Site 1280	Aurora	Colorado	United States	80045
9	Teva Investigational Site 1255	Orlando	Florida	United States	32806
10	Teva Investigational Site 1282	Sarasota	Florida	United States	34233
11	Teva Investigational Site 1275	Atlanta	Georgia	United States	30309
12	Teva Investigational Site 1250	Peoria	Illinois	United States	61603
13	Teva Investigational Site 1260	Indianapolis	Indiana	United States	46202
14	Teva Investigational Site 1268	Lenexa	Kansas	United States	66214
15	Teva Investigational Site 1277	New Orleans	Louisiana	United States	70115
16	Teva Investigational Site 1263	Shreveport	Louisiana	United States	71103
17	Teva Investigational Site 1269	Baltimore	Maryland	United States	21201
18	Teva Investigational Site 1274	Grand Rapids	Michigan	United States	49525
19	Teva Investigational Site 1239	Lebanon	New Hampshire	United States	03766
20	Teva Investigational Site 1265	Teaneck	New Jersey	United States	07666
21	Teva Investigational Site 1273	Albany	New York	United States	12205
22	Teva Investigational Site 1264	Amherst	New York	United States	14226
23	Teva Investigational Site 1283	Cedarhurst	New York	United States	11516
24	Teva Investigational Site 1249	Raleigh	North Carolina	United States	27607
25	Teva Investigational Site 1262	Winston-Salem	North Carolina	United States	27103
26	Teva Investigational Site 1261	Akron	Ohio	United States	44320
27	Teva Investigational Site 1241	Canton	Ohio	United States	44718
28	Teva Investigational Site 1245	Cleveland	Ohio	United States	44195-5244
29	Teva Investigational Site 1247	Columbus	Ohio	United States	43221
30	Teva Investigational Site 1244	Portland	Oregon	United States	97225
31	Teva Investigational Site 1258	Philadelphia	Pennsylvania	United States	19107
32	Teva Investigational Site 1281	Nashville	Tennessee	United States	37205
33	Teva Investigational Site 1284	San Antonio	Texas	United States	78231
34	Teva Investigational Site 1248	Richmond	Virginia	United States	23298-0599
35	Teva Investigational Site 1270	Roanoke	Virginia	United States	24018
36	Teva Investigational Site 1253	Tacoma	Washington	United States	98405
37	Teva Investigational Site 5914	Pleven		Bulgaria	5800
38	Teva Investigational Site 5915	Pleven		Bulgaria	5800
39	Teva Investigational Site 5917	Plovdiv		Bulgaria	4000
40	Teva Investigational Site 4212	Ruse		Bulgaria	7000
41	Teva Investigational Site 5916	Shumen		Bulgaria	9700
42	Teva Investigational Site 5920	Sofia		Bulgaria	1000
43	Teva Investigational Site 5907	Sofia		Bulgaria	1113
44	Teva Investigational Site 5910	Sofia		Bulgaria	1113
45	Teva Investigational Site 5909	Sofia		Bulgaria	1309
46	Teva Investigational Site 5919	Sofia		Bulgaria	1407
47	Teva Investigational Site 5906	Sofia		Bulgaria	1606
48	Teva Investigational Site 5908	Sofia		Bulgaria	1606
49	Teva Investigational Site 5911	Sofia		Bulgaria	1606
50	Teva Investigational Site 5912	Sofia		Bulgaria	1606
51	Teva Investigational Site 5918	Stara Zagora		Bulgaria	6000
52	Teva Investigational Site 5913	Varna		Bulgaria	9010
53	Teva Investigational Site 4211	Veliko Tarnovo		Bulgaria	5000
54	Teva Investigational Site 6003	Osijek		Croatia	31 000
55	Teva Investigational Site 6004	Split		Croatia	21000
56	Teva Investigational Site 6005	Varazdin		Croatia	42000
57	Teva Investigational Site 6001	Zagreb		Croatia	10000
58	Teva Investigational Site 6002	Zagreb		Croatia	10000
59	Teva Investigational Site 6006	Zagreb		Croatia	10000
60	Teva Investigational Site 5422	Brno		Czechia	602 00
61	Teva Investigational Site 5419	Olomouc		Czechia	779 00
62	Teva Investigational Site 5418	Praha 2		Czechia	128 08
63	Teva Investigational Site 5420	Praha 5- Motol		Czechia	150 06
64	Teva Investigational Site 5421	Teplice		Czechia	415 29
65	Teva Investigational Site 5508	Kohtla-Jarve		Estonia	31025
66	Teva Investigational Site 5507	Tallinn		Estonia	EE-10617
67	Teva Investigational Site 5509	Tartu		Estonia	EE-51014
68	Teva Investigational Site 8102	Tbilisi		Georgia	0112
69	Teva Investigational Site 8104	Tbilisi		Georgia	0112
70	Teva Investigational Site 8103	Tbilisi		Georgia	0179
71	Teva Investigational Site 6701	Bayreuth		Germany	95445
72	Teva Investigational Site 6703	Berlin		Germany	10117
73	Teva Investigational Site 6402	Berlin		Germany	12203
74	Teva Investigational Site 6700	Berlin		Germany	13088
75	Teva Investigational Site 6702	Dresden		Germany	01307
76	Teva Investigational Site 6401	Hannover		Germany	30559
77	Teva Investigational Site 6403	Munster		Germany	48149
78	Teva Investigational Site 6400	Ulm		Germany	89081
79	Teva Investigational Site 8043	Haifa		Israel	3436212
80	Teva Investigational Site 8041	Jerusalem		Israel	9112001
81	Teva Investigational Site 8040	Ramat Gan		Israel	5262160
82	Teva Investigational Site 8042	Ramat Gan		Israel	5262160
83	Teva Investigational Site 3056	Bologna		Italy	40139
84	Teva Investigational Site 3062	Catania		Italy	95122
85	Teva Investigational Site 3053	Cefalu		Italy	90015
86	Teva Investigational Site 3054	Chieti		Italy	66100
87	Teva Investigational Site 3061	Empoli		Italy	50053
88	Teva Investigational Site 3049	Firenze		Italy	50139
89	Teva Investigational Site 3055	Napoli		Italy	80131
90	Teva Investigational Site 3048	Rome		Italy	00133
91	Teva Investigational Site 3052	Rome		Italy	00149
92	Teva Investigational Site 3050	Rome		Italy	00168
93	Teva Investigational Site 3060	Rome		Italy	163
94	Teva Investigational Site 3051	Torino		Italy	10126
95	Teva Investigational Site 5708	Kaunas		Lithuania	50009
96	Teva Investigational Site 5707	Siauliai		Lithuania	76231
97	Teva Investigational Site 6502	Bitola		North Macedonia	7000
98	Teva Investigational Site 6500	Skopje		North Macedonia	1000
99	Teva Investigational Site 6501	Skopje		North Macedonia	1000
100	Teva Investigational Site 5337	Bialystok		Poland	15-402
101	Teva Investigational Site 5329	Gdansk		Poland	80-803
102	Teva Investigational Site 5338	Gdansk		Poland	80-952
103	Teva Investigational Site 6602	Gorzow Wielkopolski		Poland	66-400
104	Teva Investigational Site 5333	Grodzisk Mazowiecki		Poland	05-825
105	Teva Investigational Site 5339	Katowice		Poland	40-635
106	Teva Investigational Site 5334	Katowice		Poland	40-752
107	Teva Investigational Site 6603	Kielce		Poland	25-736
108	Teva Investigational Site 4213	Konskie		Poland	26-200
109	Teva Investigational Site 5332	Koscierzyna		Poland	83-400
110	Teva Investigational Site 5345	Krakow		Poland	31-826
111	Teva Investigational Site 5328	Lodz		Poland	90-153
112	Teva Investigational Site 5330	Olsztyn		Poland	10-560
113	Teva Investigational Site 5331	Szczecin		Poland	70-215
114	Teva Investigational Site 5336	Warsaw		Poland	02-957
115	Teva Investigational Site 5340	Warszawa		Poland	00-909
116	Teva Investigational Site 5341	Warszawa		Poland	02-097
117	Teva Investigational Site 5335	Wroclaw		Poland	50-556
118	Teva Investigational Site 1243	Guaynabo		Puerto Rico	00969
119	Teva Investigational Site 5218	Bucharest		Romania	010825
120	Teva Investigational Site 5214	Bucuresti		Romania	022328
121	Teva Investigational Site 5213	Bucuresti		Romania	050098
122	Teva Investigational Site 5215	Cluj-Napoca		Romania	400012
123	Teva Investigational Site 5217	Constanta		Romania	900591
124	Teva Investigational Site 8209	Craiova		Romania	200515
125	Teva Investigational Site 5216	Iasi		Romania	700661
126	Teva Investigational Site 5219	Sibiu		Romania	550245
127	Teva Investigational Site 5043	Barnaul		Russian Federation	656024
128	Teva Investigational Site 5033	Moscow		Russian Federation	117152
129	Teva Investigational Site 5032	Moscow		Russian Federation	117997
130	Teva Investigational Site 5041	Moscow		Russian Federation	125367
131	Teva Investigational Site 5038	Novosibirsk		Russian Federation	630087
132	Teva Investigational Site 5042	Novosibirsk		Russian Federation	630117
133	Teva Investigational Site 5035	Saint Petersburg		Russian Federation	197022
134	Teva Investigational Site 5037	Samara		Russian Federation	443095
135	Teva Investigational Site 5036	St. Petersburg		Russian Federation	194291
136	Teva Investigational Site 5034	St. Petersburg		Russian Federation	197376
137	Teva Investigational Site 5044	Ufa		Russian Federation	450007
138	Teva Investigational Site 6200	Bratislava		Slovakia	813 69
139	Teva Investigational Site 6201	Bratislava		Slovakia	826 06
140	Teva Investigational Site 6202	Nitra		Slovakia	949 01
141	Teva Investigational Site 6203	Zilina		Slovakia	010 01
142	Teva Investigational Site 9007	Bloemfontein		South Africa	9301
143	Teva Investigational Site 9001	Cape Town		South Africa	7925
144	Teva Investigational Site 9004	Johannesburg		South Africa	2157
145	Teva Investigational Site 9003	Johannesburg		South Africa	2193
146	Teva Investigational Site 9008	Pietermaritzburg		South Africa	3201
147	Teva Investigational Site 9005	Pretoria		South Africa	0041
148	Teva Investigational Site 9006	Rosebank		South Africa	2196
149	Teva Investigational Site 3147	Barcelona		Spain	08035
150	Teva Investigational Site 3154	Figueres-Girona		Spain	17600
151	Teva Investigational Site 3149	L'Hospitalet de Llobregat		Spain	08907
152	Teva Investigational Site 3152	Madrid		Spain	28041
153	Teva Investigational Site 3151	Malaga		Spain	29010
154	Teva Investigational Site 3148	Sevilla		Spain	41009
155	Teva Investigational Site 3153	Tortosa-Tarragona		Spain	43500
156	Teva Investigational Site 6503	Chernihiv		Ukraine	14029
157	Teva Investigational Site 5823	Chernivtsi		Ukraine	58018
158	Teva Investigational Site 5811	Dnipropetrovsk		Ukraine	49027
159	Teva Investigational Site 5812	Donetsk		Ukraine	83003
160	Teva Investigational Site 5814	Ivano-Frankivsk		Ukraine	76008
161	Teva Investigational Site 5817	Kharkiv		Ukraine	61018
162	Teva Investigational Site 5818	Kharkiv		Ukraine	61068
163	Teva Investigational Site 5815	Kharkiv		Ukraine	61103
164	Teva Investigational Site 5822	Kyiv		Ukraine	03110
165	Teva Investigational Site 5809	Lviv		Ukraine	79010
166	Teva Investigational Site 5820	Odessa		Ukraine	65025
167	Teva Investigational Site 5821	Poltava		Ukraine	36024
168	Teva Investigational Site 5810	Vinnytsya		Ukraine	21005
169	Teva Investigational Site 5819	Zaporizhzhya		Ukraine	69035
170	Teva Investigational Site 5816	Zaporizhzhya		Ukraine	69600

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Director: Teva Medical Expert, M.D., Teva Branded Pharmaceutical Products R&D, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT00605215
• Other Study ID Numbers: MS-LAQ-302; 2007-005450-23
• First Posted: Jan 30, 2008
• Last Update Posted: Apr 21, 2022
• Last Verified: Mar 1, 2022

• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Interferons; Interferon beta-1a; Interferon-beta

Study Results

Participant Flow

Arm/Group Title	Placebo	Laquinimod	Avonex®
Arm/Group Description	Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Participants received 1 capsule of laquinimod 0.6 millograms (mg) orally once daily for 24 months.	Participants received an injection of Avonex® 30 micrograms (mcg) given intramuscularly (IM) once weekly for 24 months.
Period Title: Overall Study
STARTED	450	434	447
Received at Least 1 Dose of Study Drug	449	433	442
COMPLETED	359	353	378
NOT COMPLETED	91	81	69

Baseline Characteristics

Arm/Group Title	Placebo	Laquinimod	Avonex®	Total
Arm/Group Description	Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.	Total of all reporting groups
Overall Participants	450	434	447	1331
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.5 (9.5)	37.0 (9.3)	38.2 (9.5)	37.6 (9.5)
Sex: Female, Male (Count of Participants)
Female	321 71.3%	282 65%	307 68.7%	910 68.4%
Male	129 28.7%	152 35%	140 31.3%	421 31.6%
Race/Ethnicity, Customized (Count of Participants)
Asian	0 0%	1 0.2%	1 0.2%	2 0.2%
Black of African Heritage	1 0.2%	1 0.2%	0 0%	2 0.2%
Black/African American	2 0.4%	1 0.2%	4 0.9%	7 0.5%
White	443 98.4%	426 98.2%	440 98.4%	1309 98.3%
Hispanic	3 0.7%	3 0.7%	1 0.2%	7 0.5%
Other	1 0.2%	2 0.5%	1 0.2%	4 0.3%

Outcome Measures

1. Primary Outcome

Title	Annualized Rate of Confirmed Relapses
Description	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.
Time Frame	Baseline up to Month 24

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants.

Arm/Group Title	Placebo	Laquinimod	Avonex®
Arm/Group Description	Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
Measure Participants	450	434	447
Mean (95% Confidence Interval) [relapse per year]	0.344	0.283	0.255

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Laquinimod
	Comments	Analysis was performed using baseline-adjusted negative binomial regression, where a participant's number of relapses during the double-blind, placebo-controlled phase served as the response variable and an offset based on the log of participant's exposure in years was employed to adjust for variability of treatment exposure. The model included baseline EDSS score, log of (prior 2-year number of relapses+1) and CGR as covariates.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0746
	Comments	Threshold for significance at 0.05 level.
	Method	Negative Binomial Regression
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.823
	Confidence Interval	(2-Sided) 95%; 0.664 to 1.020
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.090
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Avonex®
	Comments	Analysis was performed using baseline-adjusted negative binomial regression, where a participant's number of relapses during the double-blind, placebo-controlled phase served as the response variable and an offset based on the log of participant's exposure in years was employed to adjust for variability of treatment exposure. The model included baseline EDSS score, log of (prior 2-year number of relapses+1) and CGR as covariates.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0067
	Comments
	Method	Negative Binomial Regression
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.741
	Confidence Interval	(2-Sided) 95%; 0.596 to 0.920
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.082
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Disability as Assessed by the Multiple Sclerosis Functional Composite (MSFC) Score
Description	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.
Time Frame	Baseline, Month 24

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Laquinimod	Avonex®
Arm/Group Description	Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
Measure Participants	358	351	377
Mean (Standard Deviation) [Z score]	-0.5 (0.85)	-0.00 (0.85)	-0.01 (0.75)

3. Secondary Outcome

Title	Percent Change From Baseline in Brain Volume
Description	Change in brain volume was derived from MRI scans obtained at baseline and at Month 24.
Time Frame	Baseline, Month 24

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Laquinimod	Avonex®
Arm/Group Description	Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
Measure Participants	341	332	361
Mean (Standard Deviation) [Percent Change]	-0.53 (0.65)	-0.51 (0.65)	-0.53 (0.65)

4. Secondary Outcome

Title	Accumulation of Physical Disability Measured by the Number of Participants With Confirmed Progression of EDSS
Description	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.
Time Frame	Baseline up to Month 24

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants.

Arm/Group Title	Placebo	Laquinimod	Avonex®
Arm/Group Description	Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
Measure Participants	450	434	447
Count of Participants [Participants]	60 13.3%	42 9.7%	47 10.5%

5. Other Pre-specified Outcome

Title	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
Description	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.
Time Frame	Baseline, Month 6, Month 12, Month 18, Month 24

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Laquinimod	Avonex®
Arm/Group Description	Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
Measure Participants	450	434	447
Month 6	-0.2 (6.3)	0.1 (6.3)	-0.1 (6.3)
Month 12	-0.3 (6.9)	-0.1 (6.9)	0.0 (6.7)
Month 18	-0.5 (7.0)	-0.3 (7.0)	0.2 (6.9)
Month 24	-0.6 (7.6)	0.1 (6.9)	0.2 (7.0)

6. Other Pre-specified Outcome

Title	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
Description	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.
Time Frame	Baseline, Month 6, Month 12, Month 18, Month 24

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Laquinimod	Avonex®
Arm/Group Description	Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
Measure Participants	450	434	447
Month 6	-0.4 (8.5)	-0.6 (8.2)	-0.4 (8.9)
Month 12	-0.7 (9.2)	-0.1 (9.8)	-0.5 (9.0)
Month 18	-0.9 (9.3)	-1.4 (10.4)	-0.7 (9.2)
Month 24	-0.5 (9.2)	-0.9 (9.6)	-0.3 (9.3)

7. Other Pre-specified Outcome

Title	Cumulative Number of New or Enlarging Hypointense Lesions on Enhanced T1 Scans
Description	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.
Time Frame	Months 12 and 24

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Laquinimod	Avonex®
Arm/Group Description	Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
Measure Participants	393	381	403
Mean (Standard Deviation) [lesions]	7.10 (10.25)	7.33 (10.87)	5.91 (8.58)

8. Other Pre-specified Outcome

Title	Cumulative Number of Enhancing Lesions on T1-Weighted Images
Description	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.
Time Frame	Months 12 and 24

Outcome Measure Data

Analysis Population Description

ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure.

Arm/Group Title	Placebo	Laquinimod	Avonex®
Arm/Group Description	Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.	Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.	Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
Measure Participants	393	381	404
Mean (Standard Deviation) [lesions]	2.70 (8.00)	2.58 (7.40)	1.23 (3.32)

Adverse Events

Time Frame	Baseline up to Month 24
Adverse Event Reporting Description	Safety analysis set included all randomized participants who received at least 1 dose of laquinimod.
Arm/Group Title	Placebo		Laquinimod		Avonex®
Arm/Group Description	Participants received 1 capsule of placebo matched to laquinimod orally once daily for 24 months.		Participants received 1 capsule of laquinimod 0.6 mg orally once daily for 24 months.		Participants received an injection of Avonex® 30 mcg given IM once weekly for 24 months.
All Cause Mortality
	Placebo		Laquinimod		Avonex®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/449 (0%)		1/433 (0.2%)		1/442 (0.2%)
Serious Adverse Events
	Placebo		Laquinimod		Avonex®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/449 (8%)		31/433 (7.2%)		25/442 (5.7%)
Blood and lymphatic system disorders
Anaemia	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Iron deficiency anaemia	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Lymphadenitis	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Cardiac disorders
Acute myocardial infarction	0/449 (0%)	0	0/433 (0%)	0	2/442 (0.5%)	2
Cardiopulmonary failure	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Myocardial ischaemia	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Palpitations	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Supraventricular tachycardia	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Ear and labyrinth disorders
Vertigo positional	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/449 (0.2%)	1	0/433 (0%)	0	1/442 (0.2%)	1
Abdominal pain upper	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Gastric perforation	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Gastritis	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
General disorders
Chest pain	0/449 (0%)	0	2/433 (0.5%)	2	1/442 (0.2%)	1
Hepatobiliary disorders
Cholelithiasis	1/449 (0.2%)	1	1/433 (0.2%)	1	1/442 (0.2%)	1
Infections and infestations
Acute tonsillitis	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Appendicitis	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Bronchopneumonia	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Cellulitis	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Diverticulitis	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Influenza	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Injection site abscess	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Measles	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Pharyngitis	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Pneumonia	1/449 (0.2%)	1	1/433 (0.2%)	1	1/442 (0.2%)	1
Pneumonia bacterial	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Pneumonia measles	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Pulmonary tuberculosis	0/449 (0%)	0	1/433 (0.2%)	1	1/442 (0.2%)	1
Pyelonephritis acute	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Respiratory tract infection	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Secondary syphilis	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Sepsis	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Upper respiratory tract infection	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Urinary tract infection	1/449 (0.2%)	1	1/433 (0.2%)	1	0/442 (0%)	0
Viral infection	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Injury, poisoning and procedural complications
Ankle fracture	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Clavicle fracture	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Femur fracture	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Jaw fracture	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Limb injury	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Road traffic accident	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Investigations
Blood creatine phosphokinase increased	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Hepatic enzyme increased	2/449 (0.4%)	2	0/433 (0%)	0	0/442 (0%)	0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	2/449 (0.4%)	2	0/433 (0%)	0	0/442 (0%)	0
Muscular weakness	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Osteoarthritis	0/449 (0%)	0	2/433 (0.5%)	2	0/442 (0%)	0
Osteochondrosis	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Angiomyolipoma	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Fibroadenoma of breast	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Thyroid cancer	0/449 (0%)	0	1/433 (0.2%)	1	1/442 (0.2%)	1
Uterine leiomyoma	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Nervous system disorders
Cerebrovascular accident	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Cervicobrachial syndrome	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Headache	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Ischaemic stroke	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Migraine	2/449 (0.4%)	2	0/433 (0%)	0	0/442 (0%)	0
Multiple sclerosis relapse	2/449 (0.4%)	2	3/433 (0.7%)	3	0/442 (0%)	0
Myelitis	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Neurological decompensation	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Paraesthesia	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Radiculopathy	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Reversible ischaemic neurological deficit	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Sciatica	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Trigeminal neuralgia	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/449 (0.2%)	1	1/433 (0.2%)	1	1/442 (0.2%)	1
Abortion threatened	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Psychiatric disorders
Depression	0/449 (0%)	0	1/433 (0.2%)	1	1/442 (0.2%)	1
Depression suicidal	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Mania	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Renal and urinary disorders
Nephrolithiasis	2/449 (0.4%)	2	0/433 (0%)	0	0/442 (0%)	0
Renal colic	2/449 (0.4%)	2	0/433 (0%)	0	0/442 (0%)	0
Reproductive system and breast disorders
Cervical dysplasia	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Dysmenorrhoea	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Endometrial hyperplasia	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Ovarian cyst	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Sperm granuloma	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Uterine haemorrhage	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Respiratory, thoracic and mediastinal disorders
Paranasal cyst	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Pleural effusion	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Pneumomediastinum	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Pneumothorax	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Skin and subcutaneous tissue disorders
Angioedema	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Dermal cyst	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Erythema nodosum	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Surgical and medical procedures
Acoustic neuroma removal	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Colectomy	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Hysterectomy	2/449 (0.4%)	2	1/433 (0.2%)	1	0/442 (0%)	0
Internal fixation of spine	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Intervertebral disc operation	1/449 (0.2%)	1	1/433 (0.2%)	1	0/442 (0%)	0
Lymphadenectomy	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Meniscus removal	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Nasal septal operation	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Orchidectomy	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Radical hysterectomy	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Spinal cord operation	0/449 (0%)	0	1/433 (0.2%)	1	0/442 (0%)	0
Thyroidectomy	0/449 (0%)	0	0/433 (0%)	0	1/442 (0.2%)	1
Tonsillectomy	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Vascular disorders
Deep vein thrombosis	1/449 (0.2%)	1	0/433 (0%)	0	2/442 (0.5%)	3
Hypotension	1/449 (0.2%)	1	0/433 (0%)	0	0/442 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Laquinimod		Avonex®
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	146/449 (32.5%)		158/433 (36.5%)		286/442 (64.7%)
General disorders
Influenza like illness	7/449 (1.6%)	7	5/433 (1.2%)	5	206/442 (46.6%)	385
Pyrexia	7/449 (1.6%)	10	6/433 (1.4%)	7	52/442 (11.8%)	77
Infections and infestations
Influenza	28/449 (6.2%)	32	27/433 (6.2%)	30	20/442 (4.5%)	30
Nasopharyngitis	35/449 (7.8%)	45	40/433 (9.2%)	63	29/442 (6.6%)	37
Upper respiratory tract infection	36/449 (8%)	43	34/433 (7.9%)	41	22/442 (5%)	27
Musculoskeletal and connective tissue disorders
Arthralgia	18/449 (4%)	26	24/433 (5.5%)	27	18/442 (4.1%)	21
Back pain	32/449 (7.1%)	50	44/433 (10.2%)	61	15/442 (3.4%)	30
Nervous system disorders
Headache	53/449 (11.8%)	105	54/433 (12.5%)	100	60/442 (13.6%)	99

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.