Efficacy Study of Andrographis Paniculata Purified Standardized Extract (ApE) in Patients With Multiple Sclerosis (MS)

Study Overview
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Brief Summary
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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
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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.

Official Title
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Randomized, Comparative, Double Blind Controlled Phase II Clinical Trial, to Evaluate the Efficacy of ApE in Patients With Multiple Sclerosis (MS).

Conditions
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Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
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* Drug: 1 - Andrographis paniculata p/st extract
* Drug: 2 - Excipients


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients diagnosed with MS according to McDonald scale Relapsing Remitting Forms of MS (subtypes of Lublin) Minor or less incapacity according to EDSS scale At least one relapse in the last 2 years Sign an informed consent Exclusion Criteria: Primary and Secondary Progressive MS patients. Use of corticosteroids up to one month previous to enrollment Use of immunosuppressors up to one month previous to enrollment Use of drugs that induce hepatic metabolism Pregnancy, contraception, breast feeding. Psychiatric disorders Systemic diseases Chronic renal failure Diabetes mellitus Cardiac failure Respiratory failure Cancer

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1 - Andrographis paniculata p/st extract<br>1 - Andrographis paniculata extract. Active comparator, consists of 15 adult patients with active Recurrent Remitting Multiple Sclerosis, randomly assigned, taking the active test product (Andrographis paniculata p/st extract, oral lozenges, one BID, for 12 months), in addition to base medication (Interferon). | Drug: 1 - Andrographis paniculata p/st extract<br>* 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.<br>* Other names: Paractin®;|
| Placebo Comparator: 2 - Excipients<br>2 - Excipients. Placebo comparator, consists of 15 adult patients with active Recurrent Remitting Multiple Sclerosis, randomly assigned, taking the placebo formulation (Only the excipients of the active test product, in oral lozenges of same shape, one BID, for 12 months), in addition to base medication (Interferon). | Drug: 2 - Excipients<br>* Placebo 650mg tabs, 2/day, 365 days continuously. Other Names: • Excipients tablets EUROMED Specific. Santiago Chile<br>* Other names: Placebo formulation;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical inflammatory (stamina) and disability score parameters (sensorial, neurosensitive, neuromotor and cognitive function) in patients with RRMS, treated with ApE and placebo administered over beta interferon. | Clinical parameters (stamina, sensorial, neurosensitive, neuromotor and cognitive function), will be measured by the Fatigue Severity Scale (FSS) and Expanded Disability Scale (EDSS) in patients with RRMS treated with ApE and placebo. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety, tolerability and efficacy of ApE and placebo administered over beta interferon in RRMS treated patients (adverse symptoms, general clinical laboratory and comparative statistical parameters) | Patients dairy of possible adverse symptoms, general clinical laboratory and comparative statistical parameters | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MS, Demyelinating Autoimmune Diseases, CNS, Nervous System Diseases