Efficacy of andrographolide in not active progressive multiple sclerosis: a prospective exploratory double-blind, parallel-group, randomized, placebo-controlled trial

Ethel Ciampi, Reinaldo Uribe-San-Martin, Claudia Cárcamo, Juan Pablo Cruz, Ana Reyes, Diego Reyes, Carmen Pinto, Macarena Vásquez, Rafael A Burgos, Juan Hancke, Ethel Ciampi, Reinaldo Uribe-San-Martin, Claudia Cárcamo, Juan Pablo Cruz, Ana Reyes, Diego Reyes, Carmen Pinto, Macarena Vásquez, Rafael A Burgos, Juan Hancke

Abstract

Background: Multiple sclerosis (MS) is a chronic immune mediated disease and the progressive phase appears to have significant neurodegenerative mechanisms. The classification of the course of progressive MS (PMS) has been re-organized into categories of active vs. not active inflammatory disease and the presence vs. absence of gradual disease progression. Clinical trial experience to date in PMS with anti-inflammatory medications has shown limited effect. Andrographolide is a new class of anti-inflammatory agent, that has been proposed as a potential drug for autoimmune disorders, including MS. In the present trial, we perform an exploratory pilot study on the efficacy and safety of andrographolide (AP) compared to placebo in not active PMS.

Methods: A pilot clinical trial using 140 mg oral AP or placebo twice daily for 24 months in patients with not active primary or secondary progressive MS was conducted. The primary efficacy endpoint was the mean percentage brain volume change (mPBVC). Secondary efficacy endpoints included 3-month confirmed disability progression (3-CDP) and mean EDSS change.

Results: Forty-four patients were randomized: 23 were assigned to the AP group, and 21 were assigned to the placebo group. The median baseline EDSS of both groups was 6.0. Annualized mPBVC was - 0.679% for the AP group and - 1.069% for the placebo group (mean difference: -0.39; 95% CI [- 0.836-0.055], p = 0.08, relative reduction: 36.5%). In the AP group, 30% had 3-CDP compared to 41% in the placebo group (HR: 0.596; 95% CI [0.200-1.777], p = 0.06). The mean EDSS change was - 0.025 in the AP group and + 0.352 in the placebo group (mean difference: 0.63, p = 0.042). Adverse events related to AP were mild rash and dysgeusia.

Conclusions: AP was well tolerated and showed a potential effect in reducing brain atrophy and disability progression, that need to be further evaluated in a larger clinical trial.

Trial registration: ClinicalTrials.gov NCT02273635 retrospectively registered on October 24th, 2014.

Keywords: Andrographolide; Brain atrophy; Disability progression; Multiple sclerosis; Progressive multiple sclerosis.

Conflict of interest statement

EC received the ECTRIMS Clinical Fellowship (2013–2014), ECTRIMS travel grant awards, and academic travel support from Novartis, Genzyme, Merck, Biogen and Roche, has been a member of advisory boards at Genzyme, Biogen, Merck and Novartis, has received sub-investigator fees from the ISS “Social Cognition in MS” project at Teva and sub-investigator fees from project CORFO 14PIE-26946 - InnoBioscience SpA.

RUSM received academic travel support from Novartis, Genzyme, Merck, Biogen and Roche, has been a member of advisory boards at Genzyme, Biogen, Merck and Novartis.

CC received academic travel support from Novartis, Genzyme, Merck, Biogen and Roche, has been a member of advisory boards at Genzyme, Biogen, Merck and Novartis, has received PI fees from the ISS “Social Cognition in MS” project at Teva, and PI fees from project CORFO 14PIE-26946 - InnoBioscience SpA.

AR received study coordinator fees from project CORFO 14PIE-26946 - InnoBioscience SpA and speaker fees from Roche.

JPC, DR, CP, MV: nothing to disclose.

JH and RA have two patents related to the drug of study US8084495B2 granted 2011-12-27 and US9060994B2 granted 2015-06-23.

JH is the scientific advisor of Innobioscience Spa, Santiago, Chile.

Figures

Fig. 1
Fig. 1
Flow chart. SAE serious adverse event, MRI magnetic resonance imaging
Fig. 2
Fig. 2
Endpoint results. Brain Atrophy endpoints (per-protocol population). Panel a shows percentage brain volume change (PBVC) as measured by SIENA comparing baseline and 24-month Magnetic Resonance Imaging (MRI). P value was calculated using a generalized linear model (GLM) adjusted for the baseline Multiple Sclerosis Functional Composite (MSFC). I bars indicate standard deviation. Panel b shows Brain Parenchymal Fraction (BPF) change comparing baseline and 24-month MRI. P value was calculated using GLM adjusted for the baseline Multiple Sclerosis Functional Composite (MSFC). I bars indicate standard deviation. Three-month confirmed disability progression endpoint (intention-to-treat population). Panel c shows cumulative probability of clinical disability progression as defined by an increase in the Expanded Disability Status Scale that was confirmed after 3 months of follow-up, in a time-to-event analysis. P value calculated with the use of the log-rank test. Cox proportional regression was used for calculation hazard ratio using baseline Multiple Sclerosis Functional Composite (MSFC), sex, phenotype and baseline progression as covariates

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