Efficacy Study of Andrographis Paniculata Purified Standardized Extract (ApE) in Patients With Multiple Sclerosis (MS)
Condition: Multiple Sclerosis, Relapsing-Remitting
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      To evaluate the efficacy of ApE coated tablets, on the relapse rate in a group of relapsing
      remitting multiple sclerosis (RRMS) patients, as compared to a placebo group in a period of
      12 months. This study will also determine the safety and tolerability of the drug
      administered over interferon beta vs. administration of a placebo formulation (also over
      interferon) during the evaluation period. Response will be assessed and measured by daily
      self patient recording, monthly clinical neurologist, and every three months serological and
      magnetic resonance parameters.

      Place of Study: National study in Chile with one center at the Regional Hospital in the city
      of Valdivia, including 30 patients enrolled by their respective neurologists.
    

Detailed description: 
      Introduction: Multiple sclerosis is a chronic inflammatory demyelinating disease of the
      central nervous system that predominantly affects young adults (1). Although its etiology has
      not yet been elucidated, evidence points to an autoimmune pathogenesis where it is thought
      that self-reactive and myelin-specific cluster of differentiation four and eight (CD4)and
      (CD8) T cells, play an important role by reacting and destroying the myelin sheath (2). No
      plasma biomarkers to determine disease activity by routine clinical measurements, the
      existence a pattern of pro-inflammatory cytokines has been described, with range increased
      Interferon (IFN), Tumoral Necrosis Factor alpha (TNFa) and Interleukin 12 (IL-12), as well as
      a decline in Interleukin10 (IL10) and Interleukin 4 (IL4) anti-inflammatory cytokines (3). To
      date, the most common treatment for MS is Interferon beta immunomodulation, although its cost
      / effectiveness has been questioned4.

      Regardless of the progressive form and the existence of outbreaks, the fatigue symptom is one
      of the most frequent and disabling one in patients with MS. The proposed pathogenic
      mechanisms are multiple, although its exact pathophysiology is unknown. Also, there is still
      no treatment that has proven to be completely effective in stopping the progression of the
      disease (5). Description of the botanical drug to be used in this clinical research: The
      botanical drug to be used in this clinical research, is a phytopharmaceutical tablet made by
      Good Manufacturing Practices (GMP) containing a purified, standardized and patented extract
      of Andrographis paniculata Nees (Acanthaceae) {U.S. Patent: 8,084,495 B2; Date: Dec. 27,
      2011} (ApE).

      This is a medicinal annual plant, native to India and China whose active compounds are bitter
      diterpenoid lactones such as and especially 14-deoxyandrographolide, Neoandrographolide and
      specially Andrographolide, which has proven particularly effective in regulating the immune
      response (7, 9).

      The cellular and molecular mechanisms responsible for the immunomodulatory and
      anti-inflammatory properties of Andrographolide, are for the most part still unknown.
      However, recent studies with in vitro and in vivo assays indicate that 10 micromol (µM) per
      liter inhibits Tumoral Necrosis Factor Beta (NF-kB). Specifically, Andrographolide at
      concentrations of 10 micromol (uM) per liter interferes with DNA binding of NF-kB (10), by
      reducing the expression of COX-2 in neutrophils induced with
      Formyl-Methionyl-Leucyl-Phenylalanine (fMLP) and Platelet Activating Factor (PAF). Moreover,
      Andrographolide reduces Interferon gamma (IFNg) and IL-2 production in Concanavalin A (Con A)
      induced T-cells, without affecting cell viability or inducing apoptosis, also diminishing
      thymocyte apoptosis induced by corticosteroids. Furthermore, Andrographolide and
      14-deoxyandrographolide are capable of inhibiting extracellular signal-regulated kinases 1/2
      (ERK1/2) phosphorylation in T cells and neutrophils, respectively (11, 12).

      Security settings: Toxicity and Tolerance Analysis of acute and sub-chronic toxicity of ApE
      in rodents and pigs, using the basic component of ApE have been carried out in our laboratory
      at the Institute of Pharmacology and Toxicology, Universidad Austral de Chile, and according
      to the guidelines of Good Laboratory Practice (GLP) of the Food Administration Agency (FDA).
      Also, clinical phase I and II clinical studies have been performed, plus controlled daily
      treatment of 12 patients with different rheumatoid conditions and other 8 patients with
      Recurrent Remitting Multiple Sclerosis (RRMS) for more than five years. All these
      observations have proven a wide range of dosage safety without any detected toxic effects at
      therapeutic dose of 2 milligrams per kilogram of body weight.

      Hypothesis: In experimental inflammatory and human autoimmune diseases, such as Rheumatoid
      arthritis and related conditions (17, 19), and also in animal models in which Experimental
      Autoimmune Encephalitis (EAE) is induced, we have recently shown that Andrographolide can
      significantly reduce the clinical symptoms and outcome of this diseases (6), for which we
      have now proposed this clinical study in RRMS.
    

Intervention name(s): 1 - Andrographis paniculata p/st extract; 2 - Excipients
Intervention type(s): Drug; Drug
Intervention description(s): Andrographis paniculata Extract (ApE), Oral tablets 650 mg, with 170 mg. of andrographolides active principles, three times per day, during a total of 365 continuous days.
Other Names:
• ApE tablets, EUROMED Specific. Santiago Chile.; Placebo 650mg tabs, 2/day, 365 days continuously.
Other Names:
• Excipients tablets EUROMED Specific. Santiago Chile
Other intervention name(s): Andrographolide; Verum formulation; Andrographis paniculata Extract ( ApE ); Paractin®; Placebo formulation
Intervention MeSH terms: Andrographolide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: MS; Demyelinating Autoimmune Diseases; CNS; Nervous System Diseases