Intervention Review

You have free access to this content

Laquinimod for multiple sclerosis

  1. Dian He1,
  2. Kai Han2,
  3. Xiangdong Gao3,
  4. Shuai Dong3,
  5. Lan Chu1,*,
  6. ZhanHui Feng1,
  7. Shan Wu1

Editorial Group: Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group

Published Online: 6 AUG 2013

Assessed as up-to-date: 1 MAY 2013

DOI: 10.1002/14651858.CD010475.pub2


How to Cite

He D, Han K, Gao X, Dong S, Chu L, Feng Z, Wu S. Laquinimod for multiple sclerosis. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD010475. DOI: 10.1002/14651858.CD010475.pub2.

Author Information

  1. 1

    Affiliated Hospital of Guiyang Medical College, Department of Neurology, Guiyang, Guizhou Province, China

  2. 2

    Jinan No. 6 People's Hospital, Electrophysiology Center, Jinan, Shandong Province, China

  3. 3

    Jinan No. 6 People's Hospital, Department of Neurology, Jinan, Shandong Province, China

*Lan Chu, Department of Neurology, Affiliated Hospital of Guiyang Medical College, No. 28, Gui Yi Street, Guiyang, Guizhou Province, 550004, China. chulan8999@sohu.com.

Publication History

  1. Publication Status: New
  2. Published Online: 6 AUG 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Comi 2012a

MethodsThis was a double-blind, randomised, placebo-controlled, 24-month, phase 3 study involving a total of 1106 patients with relapsing–remitting multiple sclerosis, at 139 sites in 24 countries

Intervention group: 12.0% in the laquinimod group discontinued the study during the first year and an additional 8.5% discontinued the study during the second year. A total of 437 patients (79.5%) in the laquinimod group completed the 24-month study treatment. 113 (20.5%) in the laquinimod group discontinued over a period of 24 months.

Control group: 15.2% in the placebo group discontinued the study during the first year and an additional 7.9% discontinued the study during the second year. A total of 427 (76.8%) in the placebo group completed the 24-month study treatment. 129 (23.2%) in the placebo group discontinued over a period of 24 months. The most common reasons for discontinuation were the patient's decision not to sign the additional informed-consent form and withdrawal of consent after one relapse (8.0% of patients in the laquinimod group and 10.8% in the placebo group)."

Reason for discontinuation (G1: laquinimod group; G2: placebo group):

Due to AEs: G1 = 42 (7.6%), G2 = 28 (5.0%)

Refusal to re-consent: G1 = 12 (2.2%), G2 = 22 (4.0%)

Patient withdrew consent: G1 = 32 (5.8%), G2 = 38 (6.8%)

Physician request: G1 = 11 (2.0%), G2 = 14 (2.5%)

Protocol violation: G1 = 1 (0.2%), G2 = 6 (1.1%)

Pregnancy: G1 = 3 (0.5%), G2 = 8 (1.4%)

Lost to follow-up: G1 = 6 (1.1%), G2 = 5 (0.9%)

Other: G1 = 6 (1.1%), G2 = 6 (1.1%)

Deaths: G1 = 0 (0), G2 = 2 (0.4%)

Follow-up period: 24 months

Intention-to-treat analysis: the authors calculated the annualised relapse rate for the intention-to-treat cohort as the total number of confirmed relapses for all patients in each group, divided by the total patient-years in that group.


ParticipantsInclusion criteria: (1) diagnosis of multiple sclerosis according to the 2005 revised McDonald criteria; (2) relapsing–remitting course; (3) age of 18 to 55 years; (3) score of no more than 5.5 on the EDSS; (4) disease duration of at least 6 months before screening; (5) not received previous treatment; (6) received disease-modifying agents if they had had one or more documented relapses in the 12 months before screening, two or more documented relapses in the 24 months before screening, or one documented relapse between 12 and 24 months before screening with at least one gadolinium-enhancing lesion in the previous year.

Exclusion criteria: (1) progressive forms of multiple sclerosis; (2) an onset of relapse or receipt of any glucocorticoid treatment between screening and the baseline visit; (3) clinically significant or unstable medical or surgical conditions that would preclude safe and complete participation in the study; (4) use of investigative drugs or immunosuppressive agents (including mitoxantrone) within 6 months before screening; use of glatiramer acetate, any interferon, or intravenous immune globulin within 2 months before screening; (5) with use of glucocorticoids for at least 30 days within 2 months before screening; (6) any previous use of natalizumab, cladribine, or laquinimod; and use of inhibitors of CYP3A4 within 2 weeks before the baseline visit.

Of the 1106 patients who underwent randomisation, 550 were assigned to the laquinimod group and 556 to the placebo group.

There were no significant differences between the two groups in clinical or demographic characteristics. The clinical and demographic characteristics of the study groups at baseline were well balanced.

Summary of baseline characteristics of patients:

Women: G1 = 391 (71.1%), G2 = 368 (66.2%)

Age: G1 = 38.9±9.2 years, G2 = 38.5±9.1 years

Relapses within 1 year before screening: G1 = 1.2±0.7, G2 = 1.3±0.7

Relapses within 2 year before screening: G1 = 1.9±1.0, G2 = 1.9±1.0

EDSS score: G1 = 2.6±1.3 , G2 = 2.6±1.3

Time from first MS symptom to screening: G1 = 8.7±6.9 years, G2 = 8.7±6.7 years

Previous use of disease-modifying treatment: G1 = 210 (38.2%), G2 = 221 (39.7%); any interferon: G1 = 209 (38.0%), G2 = 208 (37.4%); Glatiramer acetate: G1 = 84 (15.3%), G2 = 89 (16.0%) and other disease-modifying treatments (antineoplastic agents; immune globulin or immune serum and immunosuppressive agents): G1 = 35(6.4%), G2 = 39(7.0%)

Gadolinium-enhancing lesions: G1 = 1.7±3.9, G2 = 2.0±5.7

Volume of lesions on T2-weighted images: G1 = 9.8±10.4 cm3, G2 = 9.7±10.5 cm3

Normalised brain volume: G1 = 1578.9±94.3 cm3, G2 = 1584.7±92.1 cm3


InterventionsExperimental group: a laquinimod capsule at a dose of 0.6 mg orally administered once daily

Control group: a matching placebo capsule at a dose of 0.6 mg orally administered once daily


OutcomesThe primary endpoints

(1) The annualised relapse rate during the 24-month period (defined as the total number of confirmed relapses for all patients in each group, divided by the total patient-years in that group). A relapse was defined as the appearance of one or more new neurologic abnormalities or the reappearance of one or more previously observed neurologic abnormalities lasting for at least 48 hours and occurring after an improved neurologic state for at least 30 days. An event was counted as a relapse if the patient's symptoms were accompanied by objective neurologic changes as indicated by at least one of the following: an increase of at least 0.5 points in the EDSS score, an increase of one grade in two or more of the seven functional systems that are graded in the EDSS (pyramidal, cerebellar, brain stem, sensory, bowel and bladder, visual, and cerebral), or an increase of two grades in one functional system.

(2) Safety assessments: measurement of vital signs and weight, physical examination, electrocardiography, clinical laboratory tests, and recording of adverse events. Adverse-event analysis was based on the percentage of patients who discontinued the study and the percentage of patients who discontinued the study owing to adverse events (the number of patients with at least one adverse event, number of discontinuation because of any adverse event , number of patients with any serious adverse event).

The secondary endpoints

(1) Disability progression as measured by scores on the EDSS and the MSFC. Confirmed disability progression was defined as an increase in the EDSS score of at least 1.0 point from baseline if the baseline score was between 0 and 5.0 or an increase of at least 0.5 points if the baseline score was 5.5. To confirm disability progression, these increases had to be sustained for at least 3 months. For the MSFC, the measure was the total z score at 24 months, and the analysis included the scores of all patients who completed the double-blind phase or discontinued the study after the 12-month visit.

(2) The cumulative number of gadolinium-enhancing lesions at 12 and 24 months confirmed disability progression (as measured by an increase of 2.0 or more points on the EDSS that was sustained for 3 months). (i.e., the sum of all gadolinium enhancing lesions on scans at 12 months plus all gadolinium-enhancing lesions on scans at 24 months).

(3) The cumulative number of new or enlarged lesions on T2-weighted images (>50% increase from the previous scan) at 12 and 24 months (i.e., the sum of all new or enlarged lesions on T2-weighted images at 12 months plus all new or enlarged lesions on T2-weighted images at 24 months).

(4) The per cent change in brain volume, measured with the use of the Structural Image Evaluation, Using Normalisation, of Atrophy (SIENA) and Cross-Sectional Structural Image Evaluation,Using Normalisation, of Atrophy (SIENAX) programs (version 2.3; FSL Release 3.2).


NotesThis was the Assessment of Oral Laquinimod in Preventing Progression in Multiple Sclerosis (ALLEGRO) trial, funded by Teva Pharmaceutical Industries.

The steering committee, in collaboration with the sponsor, Teva Pharmaceutical Industries, designed and monitored the study. The data were collected and analysed by the sponsor. All authors signed confidentiality agreements with the sponsor, had full access to the data, and vouch for the completeness and accuracy of the data analyses and interpretation.

An independent medical writing-services agency, paid by the sponsor, wrote the first draft of the Methods and Results sections of this article, the first author wrote the first draft of the introduction and the Discussion section, and all authors reviewed the first and subsequent drafts of the manuscript.

ClinicalTrials.gov number: NCT00509145

Other Study ID Numbers: MS-LAQ-301


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The randomisation list, stratified according to study centre, was computer-generated by the statistical data management department of the sponsor."

Comment: Sequence generation was adequate

Allocation concealment (selection bias)Low riskQuote: "The randomisation list was done by the statistical data management department of the sponsor."

Comment: Allocation concealment was adequate

Blinding of participants and personnel (performance bias)
All outcomes
Low riskQuote: "Patients and investigators were unaware of the study assignments."

Comment: The participants and personnel in this study were blinded to the allocated interventions

Blinding of outcome assessment (detection bias)
All outcomes
Low riskQuote: "Neurologic assessments and general medical evaluations were conducted by two neurologists in order to minimize the possibility of unblinding: an examining neurologist with special training and certification (www.neurostatus.net) assessed neurologic condition, and the treating neurologist determined, on the basis of the EDSS score, whether a patient had a relapse. Decisions regarding both hospitalization and treatment with glucocorticoids were made at the discretion of the treating neurologist, who was unaware of the study-group assignment."

Comment: The outcomes assessors in this study were blinded to the allocated interventions

Incomplete outcome data (attrition bias)
All outcomes
High riskQuote: "Of the 1106 patients who underwent randomisation, 13.7% discontinued the study during the first year and an additional 8.2% discontinued the study during the second year. 21.9% discontinued over a period of 24 months. A total of 437 patients (79.5%) in the laquinimod group completed the 24-month study treatment. A total of 427 (76.8%) in the placebo group completed the 24-month study treatment. The most common reasons for discontinuation were the patient's decision not to sign the additional informed-consent form and withdrawal of consent after one relapse (8.0% of patients in the laquinimod group and 10.8% in the placebo group)."

Comment: Missing data and reasons were carefully recorded but to a large degree, not balanced between groups. Although modified intention-to-treat principle was used for analyses, the high rate of drop-outs over a period of 24 months (20.5%, 23.2% in the laquinimod and placebo group, respectively) had potential impacts on the results. Generally, the higher the ratio of participants with missing data to participants with events, the greater potential there is for bias, especially for the high frequency of events. The potential impact of missing continuous outcomes increases with the proportion of participants with missing data. Both MS relapse and the occurrence of adverse events are common events, a high risk of attrition bias existed.

Selective reporting (reporting bias)Low riskAll listed outcomes were reported adequately

Other biasUnclear riskQuote:"The steering committee, in collaboration with the sponsor, Teva Pharmaceutical Industries, designed and monitored the study. The data were collected and analysed by the sponsor. An independent medical writing-services agency, paid by the sponsor, wrote the first draft of the Methods and Results sections of this article, the first author wrote the first draft of the introduction and the Discussion section."

Comment: Conflicts of interest may exist

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Comi 2008An RCT (LAQ/5062;NCT00349193) with a length of follow-up shorter than one year

Comi 2010This study (LAQ/5063) was the double-blind extension phase of the placebo-controlled phase IIb study of laquinimod (LAQ/5062) without placebo treatment as a control, and the length of follow-up was shorter than one year

Comi 2011This article was one of multiple reports from the same study (Comi 2012a)

Comi 2012bThis article was one of multiple reports with pooled analyses from the two studies (Vollmer 2011; Comi 2012a)

Filippi 2011This article was one of multiple reports from the same study (Comi 2012a)

Polman 2005bAn RCT with a length of follow-up shorter than one year

Vollmer 2012This article was one of multiple reports with pooled analyses from the two studies (Vollmer 2011; Comi 2012a)

 
Characteristics of studies awaiting assessment [ordered by study ID]
Vollmer 2011

MethodsA Multinational, Multicenter, Randomized, Parallel-group Study Performed in Subjects With RRMS to Assess the Efficacy, Safety and Tolerability of Laquinimod Over Placebo in a Double-blind Design and a Reference Arm of Interferon β-1a (Avonex®) in a Rater-blinded Design

ParticipantsInclusion criteria:

(1) Subjects must have a confirmed and documented MS diagnosis as defined by the Revised McDonald criteria [Ann Neurol 2005: 58:840-846], aged 18 to 55 years, with a relapsing-remitting disease course and a disease duration of at least 6 months (from first symptom) prior to screening.

(2) Subjects must be ambulatory with converted EDSS score of 0-5.5 and in a stable neurological condition between screening (month -1) and baseline visits (month 0) and be willing and able to comply with the protocol requirements for the duration of the study.

(3) Subjects must have had experienced at least one documented relapse in the 12 months prior to screening, at least two documented relapses in the 24 months prior to screening, or 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.

(4) Women of child-bearing potential must practice 2 acceptable methods of birth control.

Exclusion criteria:

(1) Subjects who suffer from any form of progressive MS.

(2) Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation or any condition which the investigator feels may interfere with participation in the study.

(3) Subjects treated with any investigational medication, immunosuppressives or cytotoxic agents within 6 months prior to screening or immunomodulators within two months prior to screening.

(4) Pregnancy or breastfeeding.

InterventionsIntervention group: 0.6 mg oral laquinimod once daily

Placebo comparator: oral placebo once daily

Active comparator: interferon β-1a (Avonex®) 30 mcg IM once weekly

OutcomesPrimary outcome measures: assess efficacy, as measured by number of confirmed relapses

Secondary outcome measures:

(1) Accumulation of physical disability. Measured by the time to confirmed progression of EDSS

(2) The cumulative number of enhancing lesions on T1-weighted images or new hypointense lesions on enhanced T1 scans (Images taken at months 12 and 18)

(3) General health status using Short Form (SF-36) survey subject-reported questionnaire obtained at month 0 and every 6 months thereafter

NotesStudy name: BRAVO Study: Laquinimod Double Blind Placebo Controlled Study in RRMS Patients With a Rater Blinded Reference Arm of Interferon β-1a (Avonex®)

Sponsors and Collaborators: Teva Pharmaceutical Industries

Principal Investigator: Timothy L. Vollmer; St. Joseph's Hospital & Medical Center

ClinicalTrials.gov number: NCT00605215

Other Study ID Numbers:MS-LAQ-302

http://www.clinicaltrials.gov/ct2/show/NCT00605215

This trial started in April 2008 and had been completed in December 2011, but the full article was not published. We wrote to the principal investigator (Timothy.Vollmer@UCD.edu and timothy.vollmer@uchsc.edu) and the Teva Americas-Medical Information (http://www.tevapharm.com/Pages/Contact-Us.aspx) for the information about this trial, but we got no reply. However, there was an abstract presentation at the 5th Joint triennial congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis, which was held in Amsterdam, the Netherlands during 19-22 October 2011. This abstract was included in the Multiple Sclerosis Journal 2011;17:S507-S524, Abstract 148. 

 
Characteristics of ongoing studies [ordered by study ID]
NCT01707992

Trial name or titleThe Efficacy and Safety and Tolerability of Laquinimod in Subjects With Relapsing Remitting Multiple Sclerosis (RRMS) (CONCERTO)

MethodsRandomised, double-blind, parallel group, placebo-controlled study

ParticipantsInclusion criteria:

(1) Subjects must have a confirmed and documented MS diagnosis as defined by the Revised McDonald criteria, aged 18 to 55 years at screening, with relapse onset disease or a relapsing-remitting disease course and a disease duration of at least 6 months, but not more than 12 years (from the first symptom) prior to randomisation.

(2) Subjects must be ambulatory with EDSS score of 0- 5.5 in both screening and randomisation visits, and be in a stable neurological condition, relapse-free and free of any corticosteroid treatment [IV, IM and/or PO] or adrenocorticotrophic hormone (ACTH), 60 days prior to randomisation.

(3) Subjects must have experienced at least one documented relapse in the 12 months prior to randomisation, and be able to sign and date a written informed consent prior to entering the study and comply with the protocol requirements for the duration of the study.

(4) Women of child-bearing potential must practice an acceptable method of birth control until 30 days after the last dose of treatment was administered

Exclusion criteria:

(1) Subjects with progressive forms of MS or Neuromyelitis Optica (NMO).

(2) Use of experimental or investigational drugs and/or participation in drug clinical studies, or use of immunosuppressive agents including fingolimod or cytotoxic agents within 6 months prior to randomisation, or use of natalizumab, rituximab, ocrelizumab, atacicept, belimumab, or ofatumumab within 2 years prior to screening visit, or use of moderate/strong inhibitors of CYP3A4 or inducers of CYP3A4 within 2 weeks prior to randomisation.

(3) Previous treatment with glatiramer acetate, interferon-β, intravenous immunoglobulin, or chronic (more than 30 consecutive days) systemic (IV, IM or PO) corticosteroid treatment within 2 months prior to randomisation, or previous use of mitoxantrone, cladribine, alemtuzumab or laquinimod.

(4) Previous total body irradiation, total lymphoid irradiation, stem cell treatment, autologous bone marrow transplantation or allogenic bone marrow transplantation.

(5) Pregnancy or breastfeeding.

(6) Serum levels ≥3xULN of either ALT or AST or serum direct bilirubin which is ≥2xULN at screening.

(7) Subjects with a clinically significant or unstable medical or surgical condition or any other condition that cannot be well-controlled by the allowed medications permitted in the study protocol that would preclude safe and complete study participation, as determined by medical history, physical examinations, ECG, laboratory tests MRI or chest X-ray.

(8) Any malignancies, excluding basal cell carcinoma, in the 5 years prior to randomisation.

(9) A known history of sensitivity to gadolinium or inability to successfully undergo MRI scanning.

(10) GFR ≤ 60 mL/min at the screening visit or known hypersensitivity that would preclude administration of laquinimod capsule, such as hypersensitivity to: mannitol, meglumine or sodium stearyl fumarate.

(11) Subjects who underwent endovascular treatment for Chronic Cerebrospinal Venous Insufficiency (CCSVI) within 3 months prior to randomisation.

InterventionsIntervention group: 0.6 mg oral laquinimod once daily

Intervention group: 1.2 mg oral laquinimod once daily

Placebo comparator: matching oral placebo once daily

OutcomesPrimary outcome measures: time to confirmed disease progression (CDP). CDP is defined as an increase in EDSS of 1 point or more from baseline for subjects with baseline EDSS of ≤5.0, or an increase 0.5 points or more from baseline for subjects with baseline EDSS of 5.5

Secondary outcome measures:

(1) Percent change in brain volume. Brain atrophy is defined as the percent change in brain volume from baseline to month 15

(2) Number of participants with adverse events, abnormal vital signs, abnormal ECG findings or abnormal clinical laboratory parameters

Starting dateFebruary 2013

Contact informationContact: Teva US Medical Information 1-800-896-5855

NotesSponsor: Teva Pharmaceutical Industries

Other Study ID Numbers: LAQ-MS-305

http://www.clinicaltrials.gov/ct2/show/NCT01707992