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

Multiple Sclerosis Clinical Trial

— ALLEGRO  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00509145
• Other study ID #: MS-LAQ-301
• Secondary ID: EUDRACT 2007-003
• Status: Completed
• Phase: Phase 3
• Start date: November 13, 2007
• Est. completion date: November 8, 2010

Study information

• Verified date: September 2021
• Source: Teva Branded Pharmaceutical Products R&D, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1106
• Est. completion date: November 8, 2010
• Est. primary completion date: November 8, 2010
• 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 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-ß (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.

Related Conditions & MeSH terms

• Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• Laquinimod
Laquinimod 0.6 mg capsule, oral, once daily

Other:
• Placebo
oral, once daily, capsule

Locations

Country	Name	City	State
Austria	Teva Investigational Site 3300	Klagenfurt
Austria	Teva Investigational Site 3303	Linz
Austria	Teva Investigational Site 3302	Sankt Polten
Austria	Teva Investigational Site 3301	Villach
Bulgaria	Teva Investigational Site 5901	Pleven
Bulgaria	Teva Investigational Site 5900	Sofia
Bulgaria	Teva Investigational Site 5903	Sofia
Bulgaria	Teva Investigational Site 5904	Sofia
Bulgaria	Teva Investigational Site 5905	Sofia
Bulgaria	Teva Investigational Site 5902	Varna
Canada	Teva Investigational Site 1130	Greenfield Park	Quebec
Canada	Teva Investigational Site 1132	Halifax	Nova Scotia
Canada	Teva Investigational Site 1126	London	Ontario
Canada	Teva Investigational Site 1129	Montreal	Quebec
Canada	Teva Investigational Site 1128	Ottawa	Ontario
Canada	Teva Investigational Site 1131	Sherbrooke	Quebec
Canada	Teva Investigational Site 1134	Toronto	Ontario
Czechia	Teva Investigational Site 5417	Olomouc
Czechia	Teva Investigational Site 5416	Ostrava - poruba
Estonia	Teva Investigational Site 5504	Tallinn
Estonia	Teva Investigational Site 5505	Tartu
France	Teva Investigational Site 3525	Besancon
France	Teva Investigational Site 3527	Bron Cedex
France	Teva Investigational Site 3526	Clermont-Ferrand Cedex 1
France	Teva Investigational Site 3524	Lille Cedex
France	Teva Investigational Site 3528	Marseille Cedex 5
France	Teva Investigational Site 3529	Rennes Cedex 9
Georgia	Teva Investigational Site 8100	Tbilisi
Georgia	Teva Investigational Site 8101	Tbilisi
Germany	Teva Investigational Site 3247	Bayreuth
Germany	Teva Investigational Site 3238	Berlin
Germany	Teva Investigational Site 3241	Berlin
Germany	Teva Investigational Site 3248	Bochum
Germany	Teva Investigational Site 3245	Dresden
Germany	Teva Investigational Site 3237	Emden
Germany	Teva Investigational Site 3242	Erbach
Germany	Teva Investigational Site 3240	Erfurt
Germany	Teva Investigational Site 3249	Freiburg
Germany	Teva Investigational Site 3236	Hamburg
Germany	Teva Investigational Site 3246	Hamburg
Germany	Teva Investigational Site 3239	Hannover
Germany	Teva Investigational Site 3243	Heidelberg
Germany	Teva Investigational Site 3251	Munster
Germany	Teva Investigational Site 3250	Trier
Germany	Teva Investigational Site 3244	Ulm
Hungary	Teva Investigational Site 5115	Budapest
Hungary	Teva Investigational Site 5114	Debrecen
Hungary	Teva Investigational Site 5116	Miskolc
Hungary	Teva Investigational Site 5117	Veszprem
Israel	Teva Investigational Site 8031	Haifa
Israel	Teva Investigational Site 8034	Haifa
Israel	Teva Investigational Site 8030	Jerusalem
Israel	Teva Investigational Site 8033	Ramat Gan
Israel	Teva Investigational Site 8032	Tel Aviv
Italy	Teva Investigational Site 3044	Catania
Italy	Teva Investigational Site 3045	Fidenza
Italy	Teva Investigational Site 3042	Gallarate
Italy	Teva Investigational Site 3046	Grosseto
Italy	Teva Investigational Site 3038	Milano
Italy	Teva Investigational Site 3039	Milano
Italy	Teva Investigational Site 3047	Milano
Italy	Teva Investigational Site 555	Milano
Italy	Teva Investigational Site 3041	Palermo
Italy	Teva Investigational Site 3040	Rome
Latvia	Teva Investigational Site 5604	Riga
Lithuania	Teva Investigational Site 5704	Kaunas
Lithuania	Teva Investigational Site 5705	Siauliai
Netherlands	Teva Investigational Site 3809	Groesbeek
Netherlands	Teva Investigational Site 3810	Nieuwegein
Netherlands	Teva Investigational Site 3811	Tilburg
Poland	Teva Investigational Site 5322	Czestochowa
Poland	Teva Investigational Site 5320	Gorzow Wielkopolski
Poland	Teva Investigational Site 5316	Katowice
Poland	Teva Investigational Site 5318	Kielce
Poland	Teva Investigational Site 5319	Konskie
Poland	Teva Investigational Site 5317	Krakow
Poland	Teva Investigational Site 5315	Lodz
Poland	Teva Investigational Site 5325	Warszawa
Romania	Teva Investigational Site 5208	Bucharest
Romania	Teva Investigational Site 5210	Cluj-Napoca
Romania	Teva Investigational Site 5212	Constanta
Romania	Teva Investigational Site 5211	Targu-Mures
Romania	Teva Investigational Site 5209	Timisoara
Russian Federation	Teva Investigational Site 5029	Ekaterinburg
Russian Federation	Teva Investigational Site 5031	Kemerovo
Russian Federation	Teva Investigational Site 5021	Moscow
Russian Federation	Teva Investigational Site 5028	Nizhny Novgorod
Russian Federation	Teva Investigational Site 5027	Novosibirsk
Russian Federation	Teva Investigational Site 5030	Perm
Russian Federation	Teva Investigational Site 5022	Saint Petersburg
Russian Federation	Teva Investigational Site 5026	Saint-Petersburg
Russian Federation	Teva Investigational Site 5023	St. Petersburg
Russian Federation	Teva Investigational Site 5024	St. Petersburg
Russian Federation	Teva Investigational Site 5025	St. Petersburg
Serbia	Teva Investigational Site 6100	Belgrade
Serbia	Teva Investigational Site 6102	Nis
Spain	Teva Investigational Site 3132	Barcelona
Spain	Teva Investigational Site 3134	Barcelona
Spain	Teva Investigational Site 3144	Barcelona
Spain	Teva Investigational Site 3140	Beade-Vigo
Spain	Teva Investigational Site 3142	Getafe
Spain	Teva Investigational Site 3136	Girona
Spain	Teva Investigational Site 3135	Lleida
Spain	Teva Investigational Site 3133	Madrid
Spain	Teva Investigational Site 3146	Madrid
Spain	Teva Investigational Site 3137	Murcia
Spain	Teva Investigational Site 3138	Pontevedra
Spain	Teva Investigational Site 3139	Santiago de Compostela
Spain	Teva Investigational Site 3143	Valencia
Sweden	Teva Investigational Site 4204	Stockholm
Sweden	Teva Investigational Site 4205	Stockholm
Sweden	Teva Investigational Site 4206	Stockholm
Turkey	Teva Investigational Site 8201	Izmir
Ukraine	Teva Investigational Site 5803	Dnipropetrovsk
Ukraine	Teva Investigational Site 5802	Kyiv
Ukraine	Teva Investigational Site 5804	Kyiv
Ukraine	Teva Investigational Site 5800	Lviv
Ukraine	Teva Investigational Site 5801	Vinnytsya
United Kingdom	Teva Investigational Site 3425	Liverpool
United Kingdom	Teva Investigational Site 3424	London
United Kingdom	Teva Investigational Site 3422	Sheffield
United States	Teva Investigational Site 1090	Centennial	Colorado
United States	Teva Investigational Site 1084	Dayton	Ohio
United States	Teva Investigational Site 1083	Des Moines	Iowa
United States	Teva Investigational Site 1097	Fargo	North Dakota
United States	Teva Investigational Site 1096	Farmington Hills	Michigan
United States	Teva Investigational Site 1088	Fort Collins	Colorado
United States	Teva Investigational Site 1081	Fort Wayne	Indiana
United States	Teva Investigational Site 1100	Hershey	Pennsylvania
United States	Teva Investigational Site 1086	Kansas City	Kansas
United States	Teva Investigational Site 1101	Lexington	Kentucky
United States	Teva Investigational Site 1075	Lubbock	Texas
United States	Teva Investigational Site 1085	Milwaukee	Wisconsin
United States	Teva Investigational Site 1093	Minneapolis	Minnesota
United States	Teva Investigational Site 1094	New Haven	Connecticut
United States	Teva Investigational Site 1082	New York	New York
United States	Teva Investigational Site 1102	Northbrook	Illinois
United States	Teva Investigational Site 1092	Oklahoma City	Oklahoma
United States	Teva Investigational Site 1087	Philadelphia	Pennsylvania
United States	Teva Investigational Site 1076	Phoenix	Arizona
United States	Teva Investigational Site 1079	Rochester	New York
United States	Teva Investigational Site 1098	Saint Louis	Missouri
United States	Teva Investigational Site 1078	San Antonio	Texas
United States	Teva Investigational Site 1073	Winston-Salem	North Carolina

Sponsors (1)

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

Countries where clinical trial is conducted

United States,  Austria,  Bulgaria,  Canada,  Czechia,  Estonia,  France,  Georgia,  Germany,  Hungary,  Israel,  Italy,  Latvia,  Lithuania,  Netherlands,  Poland,  Romania,  Russian Federation,  Serbia,  Spain,  Sweden,  Turkey,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
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

External Links

•   Teva's Allegro Clinical Trials website