Safety and Efficacy of Orally Administered Laquinimod Versus Placebo for Treatment of Relapsing Remitting Multiple Sclerosis (RRMS) (ALLEGRO)

A Multinational, Multicenter, Randomized, Double-blind, Parallel-group, Placebo-controlled Study, to Evaluate the Safety, Tolerability and Efficacy of Daily Oral Administration of Laquinimod 0.6 mg in Subjects With RRMS

Determination the efficacy of daily oral treatment with laquinimod 0.6 mg capsules as compared to placebo in subjects with Relapsing Remitting Multiple Sclerosis (RRMS).

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: Laquinimod; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 1106
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Klagenfurt, Austria, 9020
    • Teva Investigational Site 3300
  • Linz, Austria, A-4021
    • Teva Investigational Site 3303
  • Sankt Polten, Austria, 3100
    • Teva Investigational Site 3302
  • Villach, Austria, 9500
    • Teva Investigational Site 3301
• Bulgaria
  • Pleven, Bulgaria, 5800
    • Teva Investigational Site 5901
  • Sofia, Bulgaria, 1113
    • Teva Investigational Site 5904
  • Sofia, Bulgaria, 1309
    • Teva Investigational Site 5903
  • Sofia, Bulgaria, 1606
    • Teva Investigational Site 5900
  • Sofia, Bulgaria, 1606
    • Teva Investigational Site 5905
  • Varna, Bulgaria, 9010
    • Teva Investigational Site 5902
• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3M 0A6
      • Teva Investigational Site 1132
  • Ontario
    • London, Ontario, Canada, N6A 5A5
      • Teva Investigational Site 1126
    • Ottawa, Ontario, Canada, K2G 6E2
      • Teva Investigational Site 1128
    • Toronto, Ontario, Canada, M4N 3M5
      • Teva Investigational Site 1134
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2J2
      • Teva Investigational Site 1130
    • Montreal, Quebec, Canada, H1T 2M4
      • Teva Investigational Site 1129
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Teva Investigational Site 1131
• Czechia
  • Olomouc, Czechia, 779 00
    • Teva Investigational Site 5417
  • Ostrava - poruba, Czechia, 708 52
    • Teva Investigational Site 5416
• Estonia
  • Tallinn, Estonia, EE-10617
    • Teva Investigational Site 5504
  • Tartu, Estonia, EE-51014
    • Teva Investigational Site 5505
• France
  • Besancon, France, 25030
    • Teva Investigational Site 3525
  • Bron Cedex, France, 69677
    • Teva Investigational Site 3527
  • Clermont-Ferrand Cedex 1, France, 63003
    • Teva Investigational Site 3526
  • Lille Cedex, France, 59037
    • Teva Investigational Site 3524
  • Marseille Cedex 5, France, 13385
    • Teva Investigational Site 3528
  • Rennes Cedex 9, France, 35033
    • Teva Investigational Site 3529
• Georgia
  • Tbilisi, Georgia, 0112
    • Teva Investigational Site 8100
  • Tbilisi, Georgia, 0179
    • Teva Investigational Site 8101
• Germany
  • Bayreuth, Germany, 95445
    • Teva Investigational Site 3247
  • Berlin, Germany, 10713
    • Teva Investigational Site 3241
  • Berlin, Germany, 13347
    • Teva Investigational Site 3238
  • Bochum, Germany, 44791
    • Teva Investigational Site 3248
  • Dresden, Germany, 01307
    • Teva Investigational Site 3245
  • Emden, Germany, 26721
    • Teva Investigational Site 3237
  • Erbach, Germany, 64711
    • Teva Investigational Site 3242
  • Erfurt, Germany, 99089
    • Teva Investigational Site 3240
  • Freiburg, Germany, 79106
    • Teva Investigational Site 3249
  • Hamburg, Germany, 20246
    • Teva Investigational Site 3236
  • Hamburg, Germany, 22417
    • Teva Investigational Site 3246
  • Hannover, Germany, 30559
    • Teva Investigational Site 3239
  • Heidelberg, Germany, 69120
    • Teva Investigational Site 3243
  • Munster, Germany, 48149
    • Teva Investigational Site 3251
  • Trier, Germany, 54292
    • Teva Investigational Site 3250
  • Ulm, Germany, 89081
    • Teva Investigational Site 3244
• Hungary
  • Budapest, Hungary, H-1145
    • Teva Investigational Site 5115
  • Debrecen, Hungary, 4043
    • Teva Investigational Site 5114
  • Miskolc, Hungary, 3526
    • Teva Investigational Site 5116
  • Veszprem, Hungary, H-8200
    • Teva Investigational Site 5117
• Israel
  • Haifa, Israel, 3436212
    • Teva Investigational Site 8031
  • Haifa, Israel, 31048
    • Teva Investigational Site 8034
  • Jerusalem, Israel, 9112001
    • Teva Investigational Site 8030
  • Ramat Gan, Israel, 5262160
    • Teva Investigational Site 8033
  • Tel Aviv, Israel, 78278
    • Teva Investigational Site 8032
• Italy
  • Catania, Italy, 95122
    • Teva Investigational Site 3044
  • Fidenza, Italy, 43036
    • Teva Investigational Site 3045
  • Gallarate, Italy, 21013
    • Teva Investigational Site 3042
  • Grosseto, Italy, 58100
    • Teva Investigational Site 3046
  • Milano, Italy, 20132
    • Teva Investigational Site 3038
  • Milano, Italy, 20132
    • Teva Investigational Site 555
  • Milano, Italy, 20148
    • Teva Investigational Site 3039
  • Milano, Italy, 20122
    • Teva Investigational Site 3047
  • Palermo, Italy, 90146
    • Teva Investigational Site 3041
  • Rome, Italy, 00133
    • Teva Investigational Site 3040
• Latvia
  • Riga, Latvia, 1015
    • Teva Investigational Site 5604
• Lithuania
  • Kaunas, Lithuania, 50009
    • Teva Investigational Site 5704
  • Siauliai, Lithuania, 76231
    • Teva Investigational Site 5705
• Netherlands
  • Groesbeek, Netherlands, 6561 KE
    • Teva Investigational Site 3809
  • Nieuwegein, Netherlands, 3430 EM
    • Teva Investigational Site 3810
  • Tilburg, Netherlands, 5022 GC
    • Teva Investigational Site 3811
• Poland
  • Czestochowa, Poland, 42-200
    • Teva Investigational Site 5322
  • Gorzow Wielkopolski, Poland, 66-400
    • Teva Investigational Site 5320
  • Katowice, Poland, 40-752
    • Teva Investigational Site 5316
  • Kielce, Poland, 25-736
    • Teva Investigational Site 5318
  • Konskie, Poland, 26-200
    • Teva Investigational Site 5319
  • Krakow, Poland, 31-826
    • Teva Investigational Site 5317
  • Lodz, Poland, 90-153
    • Teva Investigational Site 5315
  • Warszawa, Poland, 04-749
    • Teva Investigational Site 5325
• Romania
  • Bucharest, Romania, 011461
    • Teva Investigational Site 5208
  • Cluj-Napoca, Romania, 400437
    • Teva Investigational Site 5210
  • Constanta, Romania, 900123
    • Teva Investigational Site 5212
  • Targu-Mures, Romania, 540136
    • Teva Investigational Site 5211
  • Timisoara, Romania, 300736
    • Teva Investigational Site 5209
• Russian Federation
  • Ekaterinburg, Russian Federation, 620102
    • Teva Investigational Site 5029
  • Kemerovo, Russian Federation, 650066
    • Teva Investigational Site 5031
  • Moscow, Russian Federation, 127018
    • Teva Investigational Site 5021
  • Nizhny Novgorod, Russian Federation, 603126
    • Teva Investigational Site 5028
  • Novosibirsk, Russian Federation, 630087
    • Teva Investigational Site 5027
  • Perm, Russian Federation, 614990
    • Teva Investigational Site 5030
  • Saint Petersburg, Russian Federation, 197022
    • Teva Investigational Site 5022
  • Saint-Petersburg, Russian Federation, 191025
    • Teva Investigational Site 5026
  • St. Petersburg, Russian Federation, 194044
    • Teva Investigational Site 5025
  • St. Petersburg, Russian Federation, 194354
    • Teva Investigational Site 5024
  • St. Petersburg, Russian Federation, 197376
    • Teva Investigational Site 5023
• Serbia
  • Belgrade, Serbia, 11000
    • Teva Investigational Site 6100
  • Nis, Serbia, 18 000
    • Teva Investigational Site 6102
• Spain
  • Barcelona, Spain, 08035
    • Teva Investigational Site 3132
  • Barcelona, Spain, 08036
    • Teva Investigational Site 3134
  • Barcelona, Spain, 08041
    • Teva Investigational Site 3144
  • Beade-Vigo, Spain, 36312
    • Teva Investigational Site 3140
  • Getafe, Spain, 28905
    • Teva Investigational Site 3142
  • Girona, Spain, 17007
    • Teva Investigational Site 3136
  • Lleida, Spain, 25198
    • Teva Investigational Site 3135
  • Madrid, Spain, 28040
    • Teva Investigational Site 3133
  • Madrid, Spain, 28046
    • Teva Investigational Site 3146
  • Murcia, Spain, 30120
    • Teva Investigational Site 3137
  • Pontevedra, Spain, 36001
    • Teva Investigational Site 3138
  • Santiago de Compostela, Spain, 15706
    • Teva Investigational Site 3139
  • Valencia, Spain, 46010
    • Teva Investigational Site 3143
• Sweden
  • Stockholm, Sweden, 14186
    • Teva Investigational Site 4204
  • Stockholm, Sweden, 17176
    • Teva Investigational Site 4205
  • Stockholm, Sweden, 18288
    • Teva Investigational Site 4206
• Turkey
  • Izmir, Turkey, 35340
    • Teva Investigational Site 8201
• Ukraine
  • Dnipropetrovsk, Ukraine, 49027
    • Teva Investigational Site 5803
  • Kyiv, Ukraine, 03110
    • Teva Investigational Site 5802
  • Kyiv, Ukraine, 03115
    • Teva Investigational Site 5804
  • Lviv, Ukraine, 79010
    • Teva Investigational Site 5800
  • Vinnytsya, Ukraine, 21005
    • Teva Investigational Site 5801
• United Kingdom
  • Liverpool, United Kingdom, L9 7LJ
    • Teva Investigational Site 3425
  • London, United Kingdom, E1 2AT
    • Teva Investigational Site 3424
  • Sheffield, United Kingdom, S10 2JF
    • Teva Investigational Site 3422
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85004
      • Teva Investigational Site 1076
  • Colorado
    • Centennial, Colorado, United States, 80112
      • Teva Investigational Site 1090
    • Fort Collins, Colorado, United States, 80528
      • Teva Investigational Site 1088
  • Connecticut
    • New Haven, Connecticut, United States, 06520-8018
      • Teva Investigational Site 1094
  • Illinois
    • Northbrook, Illinois, United States, 60062
      • Teva Investigational Site 1102
  • Indiana
    • Fort Wayne, Indiana, United States, 46805
      • Teva Investigational Site 1081
  • Iowa
    • Des Moines, Iowa, United States, 50314
      • Teva Investigational Site 1083
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Teva Investigational Site 1086
  • Kentucky
    • Lexington, Kentucky, United States, 40513
      • Teva Investigational Site 1101
  • Michigan
    • Farmington Hills, Michigan, United States, 48334
      • Teva Investigational Site 1096
  • Minnesota
    • Minneapolis, Minnesota, United States, 55414
      • Teva Investigational Site 1093
  • Missouri
    • Saint Louis, Missouri, United States, 63104
      • Teva Investigational Site 1098
  • New York
    • New York, New York, United States, 10003
      • Teva Investigational Site 1082
    • Rochester, New York, United States, 14642
      • Teva Investigational Site 1079
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Teva Investigational Site 1073
  • North Dakota
    • Fargo, North Dakota, United States, 58103
      • Teva Investigational Site 1097
  • Ohio
    • Dayton, Ohio, United States, 45417
      • Teva Investigational Site 1084
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73120
      • Teva Investigational Site 1092
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Teva Investigational Site 1100
    • Philadelphia, Pennsylvania, United States, 19104
      • Teva Investigational Site 1087
  • Texas
    • Lubbock, Texas, United States, 79410
      • Teva Investigational Site 1075
    • San Antonio, Texas, United States, 78231
      • Teva Investigational Site 1078
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Teva Investigational Site 1085

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 and free of corticosteroid treatment [intravenous (iv), intramuscular (im) and/or per os (po)] 30 days prior to screening (month -1).

4. 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.
5. Subjects must be between 18 and 55 years of age, inclusive.
6. Subjects must have disease duration of at least 6 months (from the first symptom) prior to screening.
7. Women of child-bearing potential must practice an acceptable method 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).
8. Subjects must be able to sign and date a written informed consent prior to entering the study
9. Subjects must be willing and able to comply with the protocol requirements for the duration of the study.

Exclusion Criteria:

1. Subjects with progressive forms of MS
2. An onset of relapse, unstable neurological condition or any treatment with corticosteroids [intravenous (iv), intramuscular (im) and/or per os (po)] or ACTH between month -1 (screening) and 0 (baseline).
3. Use of experimental or investigational drugs, and/or participation in drug clinical studies within the 6 months prior to screening.
4. Use of immunosuppressive including Mitoxantrone (Novantrone®) or cytotoxic agents within 6 months prior to the screening visit.
5. Previous use of either of the following: natalizumab (Tysabri®), cladribine, laquinimod.
6. Previous treatment with glatiramer acetate (Copaxone®) Interferon-β (either 1a or 1b) or IVIG within 2 months prior to screening visit.
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 two weeks prior to baseline visit.
12. Major trauma or surgery two weeks prior to baseline
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) 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 (1 month for fluoxetine) see detailed list in Appendix 5
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 or metabolic 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 2 ECG recordings at screening or from the mean value calculated from 3 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.
20. A known history of sensitivity to Gd.
21. Inability to successfully undergo MRI scanning.
22. Known drug hypersensitivity that would preclude administration of laquinimod, such as hypersensitivity to: mannitol, meglumine or sodium stearyl fumarate.

Exclusion Criteria:

1. Subjects who suffer from any form of progressive MS.
2. Any condition which the investigator feels may interfere with participation in the study.
3. Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation,
4. Subjects who received any investigational medication, immunosuppressives or cytotoxic agents within 6 months prior to screening
5. Previous treatment with immunomodulators within two months prior to screening
6. Pregnancy or breastfeeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Laquinimod; Laquinimod 0.6 mg, oral	Drug: Laquinimod; Laquinimod 0.6 mg capsule, oral, once daily; Other Names: TV-5600
PLACEBO_COMPARATOR: Placebo; Matching placebo	Other: Placebo; oral, once daily, capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse Rate: Number of Confirmed Relapses During the Double Blind Study Period	A relapse was defined as the appearance of at least one new neurological abnormality or the reappearance of at least one previously observed neurological abnormalities lasting greater than or equal to 48 hours and immediately preceded by an improving neurological state of greater than or equal to 30 days from onset of previous relapse. An event was counted as a relapse only when the participant's symptoms were accompanied by observed objective neurological changes, consistent with one or more of the following: An increase of greater than or equal to 0.5 in the Expanded Disability Status Scale (EDSS) score as compared to previous evaluation, an increase of one grade in the actual score of greater than or equal to 2 of the 7 functional systems (FS), as compared to previous evaluation, or an increase of 2 grades in the actual score of one FS as compared to the previous evaluation.	Up to Month 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite Endpoint: Sum of the Number of T1 Gadolinium (Gd)-Enhanced Lesions on T1-Weighted MRI Images	Composite score was calculated as the sum of the number of gadolinium (Gd)-enhanced lesions at Month 12 and the number of gadolinium (Gd)-enhanced lesions at Month 24 on T1-Weighted MRI scans.	Month 12, Month 24
Composite Endpoint: Sum of the Number of New/Enlarging T2 Lesions	Composite score calculated as the sum of T2 lesions at Months 12 and 24 that are new or enlarged.	Month 12, Month 24
Accumulation of Physical Disability Measured by the Time to Confirmed Progression of Expanded Disability Status Scale (EDSS)	EDSS assesses disability in 8 functional systems with an overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis [MS]). A confirmed progression of EDSS is defined as at least 1 point increase from baseline if baseline EDSS was between 0 and 5.0, or at least 0.5 point increase if baseline EDSS was 5.5 or higher, confirmed 3 months later. Participants were assessed between baseline and month 24 visit. Participants that met these criteria for any 3 consecutive months were counted in the progression category. Progression could not be confirmed during an MS relapse. Data is presented as a distribution of confirmed disease progression (CDP) events (number of participants with CDP).	Baseline to Month 24
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

Collaborators and Investigators

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
• Investigators: Principal Investigator: Giancarlo Comi, U.O.Neurology-Neurorehabilitation and Clinical Neurophysiology

Publications and helpful links

General Publications

• 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.
• Filippi M, Rocca MA, Pagani E, De Stefano N, Jeffery D, Kappos L, Montalban X, Boyko AN, Comi G; ALLEGRO Study Group. Placebo-controlled trial of oral laquinimod in multiple sclerosis: MRI evidence of an effect on brain tissue damage. J Neurol Neurosurg Psychiatry. 2014 Aug;85(8):851-8. doi: 10.1136/jnnp-2013-306132. Epub 2013 Sep 12.
• Comi G, Jeffery D, Kappos L, Montalban X, Boyko A, Rocca MA, Filippi M; ALLEGRO Study Group. Placebo-controlled trial of oral laquinimod for multiple sclerosis. N Engl J Med. 2012 Mar 15;366(11):1000-9. doi: 10.1056/NEJMoa1104318.

Helpful Links

• Teva's Allegro Clinical Trials website

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 13, 2007
• Primary Completion (ACTUAL): November 8, 2010
• Study Completion (ACTUAL): November 8, 2010

Study Registration Dates

• First Submitted: July 27, 2007
• First Submitted That Met QC Criteria: July 30, 2007
• First Posted (ESTIMATE): July 31, 2007

Study Record Updates

• Last Update Posted (ACTUAL): November 2, 2021
• Last Update Submitted That Met QC Criteria: October 5, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Relapsing; Remitting
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis
• Other Study ID Numbers: MS-LAQ-301; EUDRACT 2007-003226-19