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

Multiple Sclerosis, Relapsing-Remitting Clinical Trial

— PCNS-EM  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02280876
• Other study ID #: PaCRU-02/PCNS.EM/12
• Secondary ID: PCNS-EM
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: October 20, 2014
• Last updated: June 21, 2016
• Start date: January 2012
• Est. completion date: May 2015

Study information

• Verified date: January 2016
• Source: Universidad Austral de Chile
• Contact: n/a
• Is FDA regulated: No
• Health authority: Chile: Comisión Nacional de Investigación Científica y TecnológicaChile: Instituto de Salud Pública de ChileChile: Comité de Ética CientíficoChile: Ministry of Health
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: May 2015
• Est. primary completion date: February 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 55 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

Intervention

Drug:
• 1 - Andrographis paniculata p/st extract
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.
• 2 - Excipients
Placebo 650mg tabs, 2/day, 365 days continuously. Other Names: • Excipients tablets EUROMED Specific. Santiago Chile

Locations

Country	Name	City	State
Chile	Hospital Regional	Valdivia	Los Ríos

Sponsors (3)

Lead Sponsor	Collaborator
Universidad Austral de Chile	Comisión Nacional de Investigación Científica y Tecnológica, University of Chile

Country where clinical trial is conducted

Chile, 

References & Publications (18)

Bertoglio JC, Baumgartner M, Palma R, Ciampi E, Carcamo C, Cáceres DD, Acosta-Jamett G, Hancke JL, Burgos RA. Andrographis paniculata decreases fatigue in patients with relapsing-remitting multiple sclerosis: a 12-month double-blind placebo-controlled pil — View Citation

Burgos RA, Hancke JL, Bertoglio JC, Aguirre V, Arriagada S, Calvo M, Cáceres DD. Efficacy of an Andrographis paniculata composition for the relief of rheumatoid arthritis symptoms: a prospective randomized placebo-controlled trial. Clin Rheumatol. 2009 Aug;28(8):931-46. doi: 10.1007/s10067-009-1180-5. Epub 2009 Apr 29. — View Citation

Burgos RA, Hidalgo MA, Monsalve J, LaBranche TP, Eyre P, Hancke JL. 14-deoxyandrographolide as a platelet activating factor antagonist in bovine neutrophils. Planta Med. 2005 Jul;71(7):604-8. — View Citation

Burgos RA, Seguel K, Perez M, Meneses A, Ortega M, Guarda MI, Loaiza A, Hancke JL. Andrographolide inhibits IFN-gamma and IL-2 cytokine production and protects against cell apoptosis. Planta Med. 2005 May;71(5):429-34. — View Citation

Cabrera D, Gutiérrez J, Cabello-Verrugio C, Morales MG, Mezzano S, Fadic R, Casar JC, Hancke JL, Brandan E. Andrographolide attenuates skeletal muscle dystrophy in mdx mice and increases efficiency of cell therapy by reducing fibrosis. Skelet Muscle. 2014 Mar 21;4:6. doi: 10.1186/2044-5040-4-6. eCollection 2014. — View Citation

Cáceres DD, Hancke JL, Burgos RA, Sandberg F, Wikman GK. Use of visual analogue scale measurements (VAS) to asses the effectiveness of standardized Andrographis paniculata extract SHA-10 in reducing the symptoms of common cold. A randomized double blind-placebo study. Phytomedicine. 1999 Oct;6(4):217-23. — View Citation

Cáceres DD, Hancke JL, Burgos RA, Wikman GK. Prevention of common colds with Andrographis paniculata dried extract. A Pilot double blind trial. Phytomedicine. 1997 Jun;4(2):101-4. doi: 10.1016/S0944-7113(97)80051-7. — View Citation

Calabrese C, Berman SH, Babish JG, Ma X, Shinto L, Dorr M, Wells K, Wenner CA, Standish LJ. A phase I trial of andrographolide in HIV positive patients and normal volunteers. Phytother Res. 2000 Aug;14(5):333-8. — View Citation

Coon JT, Ernst E. Andrographis paniculata in the treatment of upper respiratory tract infections: a systematic review of safety and efficacy. Planta Med. 2004 Apr;70(4):293-8. Review. — View Citation

Gabrielian ES, Shukarian AK, Goukasova GI, Chandanian GL, Panossian AG, Wikman G, Wagner H. A double blind, placebo-controlled study of Andrographis paniculata fixed combination Kan Jang in the treatment of acute upper respiratory tract infections including sinusitis. Phytomedicine. 2002 Oct;9(7):589-97. — View Citation

Galboiz Y, Miller A. Immunological indicators of disease activity and prognosis in multiple sclerosis. Curr Opin Neurol. 2002 Jun;15(3):233-7. Review. — View Citation

Hidalgo MA, Romero A, Figueroa J, Cortés P, Concha II, Hancke JL, Burgos RA. Andrographolide interferes with binding of nuclear factor-kappaB to DNA in HL-60-derived neutrophilic cells. Br J Pharmacol. 2005 Mar;144(5):680-6. — View Citation

Iruretagoyena MI, Tobar JA, González PA, Sepúlveda SE, Figueroa CA, Burgos RA, Hancke JL, Kalergis AM. Andrographolide interferes with T cell activation and reduces experimental autoimmune encephalomyelitis in the mouse. J Pharmacol Exp Ther. 2005 Jan;312(1):366-72. Epub 2004 Aug 26. — View Citation

Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000 Sep 28;343(13):938-52. Review. — View Citation

Phillips JT, Rice G, Frohman E, Vande Gaer L, Scott T, Haas J, Eggenberger E, Freedman MS, Stuart W, Cunha L, Jacobs L, Oger J, Arnold D, Murray TJ, DiBiase M, Jethwa V, Goelz S. A multicenter, open-label, phase II study of the immunogenicity and safety of a new prefilled syringe (liquid) formulation of Avonex in patients with multiple sclerosis. Clin Ther. 2004 Apr;26(4):511-21. — View Citation

Rajagopal S, Kumar RA, Deevi DS, Satyanarayana C, Rajagopalan R. Andrographolide, a potential cancer therapeutic agent isolated from Andrographis paniculata. J Exp Ther Oncol. 2003 May-Jun;3(3):147-58. — View Citation

Thamlikitkul V, Dechatiwongse T, Theerapong S, Chantrakul C, Boonroj P, Punkrut W, Ekpalakorn W, Boontaeng N, Taechaiya S, Petcharoen S, et al. Efficacy of Andrographis paniculata, Nees for pharyngotonsillitis in adults. J Med Assoc Thai. 1991 Oct;74(10):437-42. — View Citation

Wingerchuk DM, Lucchinetti CF, Noseworthy JH. Multiple sclerosis: current pathophysiological concepts. Lab Invest. 2001 Mar;81(3):263-81. Review. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Central Nervous System (CNS) local inflammatory activity and anatomical damage parameters (functional and structural lesions) in RRMS patients treated with ApE and placebo administered over beta interferon.	CNS number, size, location and gadolinium uptaking of lesions in brain and / or spine will be measured by magnetic resonance (MR) at 0, 3, 6 and 12 months.	12 months	No
Other	Plasmatic inflammatory activity parameters (cytokines) in RRMS patients treated with ApE and placebo administered over beta interferon.	Plasmatic levels of IFNg, Interleukin 17 (IL17), Interleukin IL10, Interleukin 6 (IL6), IL4, TNFa, will be measured at 0, 3, 6 and 12 months	12 months	No
Primary	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	No
Secondary	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	Yes

External Links

•   Mari´a A. Hidalgo, Juan L. Hancke, Juan C. Bertoglio and Rafael A. Burgos. Andrographolide, a New Potential Drug for the Long Term Treatment of Rheumatoid Arthritis Disease. Innovative Rheumatology. International standard book (ISBN) 978-953-51-0916-7
•   Miller, Aaron E.; Coyle, Patricia K. CLINICAL FEATURES OF MULTIPLE SCLEROSIS. CONTINUUM: Lifelong Learning in Neurology. December 2004 - Volume 10 - Issue 6, Multiple Sclerosis - pp 38-73. doi: 10.1212/01.CON.0000293634.15851.7d