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Abstract
Objective To evaluate efficacy, safety, and tolerability of laquinimod in patients with primary progressive multiple sclerosis (PPMS).
Methods In the randomized, double-blind, placebo-controlled, phase 2 study, ARPEGGIO (A Randomized Placebo-controlled Trial Evaluating Laquinimod in PPMS, Gauging Gradations in MRI and Clinical Outcomes), eligible patients with PPMS were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 mg or 1.5 mg or matching placebo. Percentage brain volume change (PBVC; primary endpoint) from baseline to week 48 was assessed by MRI. Secondary and exploratory endpoints included clinical and MRI measures. Efficacy endpoints were evaluated using a predefined, hierarchical statistical testing procedure. Safety was monitored throughout the study. The laquinimod 1.5 mg dose arm was discontinued on January 1, 2016, due to findings of cardiovascular events.
Results A total of 374 patients were randomized to laquinimod 0.6 mg (n = 139) or 1.5 mg (n = 95) or placebo (n = 140). ARPEGGIO did not meet the primary endpoint of significant treatment effect with laquinimod 0.6 mg vs placebo on PBVC from baseline to week 48 (adjusted mean difference = 0.016%, p = 0.903). Laquinimod 0.6 mg reduced the number of new T2 brain lesions at week 48 (risk ratio 0.4; 95% confidence interval, 0.26–0.69; p = 0.001). Incidence of adverse events was higher among patients treated with laquinimod 0.6 mg (83%) vs laquinimod 1.5 mg (66%) and placebo (78%).
Conclusions Laquinimod 0.6 mg did not demonstrate a statistically significant effect on brain volume loss in PPMS at week 48.
Clinicaltrials.gov identifier NCT02284568.
Classification of evidence This study provides Class I evidence that, although well tolerated, laquinimod 0.6 mg did not demonstrate a significant treatment effect on PBVC in patients with PPMS.
Glossary
- 9HPT=
- 9-Hole Peg Test;
- AE=
- adverse event;
- ALLEGRO RRMS=
- Assessment of Oral Laquinimod in Preventing Progression in Multiple Sclerosis;
- ARPEGGIO=
- A Randomized Placebo-controlled Trial Evaluating Laquinimod in PPMS, Gauging Gradations in MRI and Clinical Outcomes;
- BICAMS=
- Brief International Cognitive Assessment for MS;
- BRAVO=
- Laquinimod Double Blind Placebo Controlled Study in RRMS Patients With a Rater Blinded Reference Arm of Interferon β-1a (Avonex®);
- CDP=
- confirmed disability progression;
- CI=
- confidence interval;
- CONCERTO=
- The Efficacy, Safety, and Tolerability of Laquinimod in Participants With Relapsing Remitting Multiple Sclerosis;
- DMC=
- data monitoring committee;
- EDSS=
- Expanded Disability Status Scale;
- ET=
- early termination;
- FSS=
- Functional System Score;
- Gd+=
- gadolinium-enhancing;
- INFORMS=
- Open-label, Single-arm Extension Study (CFTY720D2306E1) to a Double-blind, Randomized Multicenter, Placebo-controlled, Parallel-group Core Study (CFTY720D2306) in PPMS;
- ITT=
- intention-to-treat;
- LCVA=
- low-contrast visual acuity;
- mITT1=
- modified intention-to-treat 1 population;
- mITT2=
- modified intention-to-treat 2 population;
- MS=
- multiple sclerosis;
- MSWS-12=
- 12-Item Multiple Sclerosis Walking Scale;
- MTR=
- magnetization transfer ratio;
- PBVC=
- percent brain volume change;
- PPMS=
- primary progressive multiple sclerosis;
- RRMS=
- relapsing-remitting multiple sclerosis;
- SDMT=
- Symbol Digit Modalities Test;
- SPRINT-MS=
- A Phase 2 Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Tolerability and Activity of Ibudilast (MN-166) in Subjects With Progressive Multiple Sclerosis;
- T25FW=
- Timed 25-Foot Walk
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Class of Evidence: NPub.org/coe
- Received July 9, 2019.
- Accepted in final form February 20, 2020.
- © 2020 American Academy of Neurology
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