Efficacy, Safety and Tolerability of Andrographolides Versus Placebo in Patients With Progressive Forms of MS

Controlled, Randomized, Double-blind Clinical Trial, 24 Months Duration, to Compare the Efficacy, Safety and Tolerability of Andrographolide Versus Placebo in Patients With Progressive Forms of Multiple Sclerosis

The purpose of this study is to compare the efficacy and safety of andrographolide 140 mg administered twice a day orally versus a placebo as a modifying treatment of the disease in patients with the progressive forms of Multiple Sclerosis (MS).

The principal outcome is to determine the efficacy, of andrographolide in retarding the progression of brain atrophy in patients with progressive forms of MS.

Study Overview

• Status: Unknown
• Conditions: Multiple Sclerosis, Secondary Progressive; Primary Progressive Multiple Sclerosis
• Intervention / Treatment: Drug: Andrographolides; Drug: placebo

Detailed Description

1. Evaluate the clinical efficacy of andrographolide 140 mg administered orally twice a day versus a placebo in:

   • Delay in the disability capacity progression through the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) at 24 months compared to the baseline.
   • Delay in cognitive impairment by means of Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT) and depression (Beck) at 24 months compared to the baseline.
   • Quality of life Multiple Sclerosis Impact Scale (MSIS 29) and fatigue (Krupp) through parameters reported by the patients at at 24 months compared to the baseline.
   • Tolerability of andrographolide measured by the Treatment Satisfaction Questionnaire for Medication (TSQM) at 24 months.
   • Delay in the decrease in brain volume measured by Magnetic Resonance (MR) at 24 months compared to the baseline.
   • Number and volume of new lesions or larger size in T2 by MR at 24 months compared to the baseline.
   • Number of new hipointense lesions in T1 or (gadolinium captive) by MR at 24 months compared to the baseline.
   • Delay in the retineal thinning measured by Optical Coherence Tomography (OCT) and visual field at 24 months compared to the baseline.
   • Safety of andrographolide at 24 months through the record of adverse effects in symptom dairy and programmed interviews.

2. Explore the pharmacokinetic of andrographolide 140 mg administered orally twice day in:

   • bio availability and concentration of andrographolide in the patients with treatment.
   • half-life, maximum concentration, clearance of andrographolide in equilibrium state.

3. Determine the immunomodulatory effects of andrographolide 140 mg administered twice a day orally on lymphocyte populations in patients through the:

   • Determination of Th1, Th2, Th17 and Treg lymphocyte sub-populations.
   • Determination of cytokines IFNgama, TNFalpha, IL2, IL17alpha and TGFbeta.

Population: adult patients, men and women with progressive forms of MS. The number of patients to be selected will be 68, to randomly assign 34 patients to each group.

• Study Type: Interventional
• Enrollment (Anticipated): 68
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Chile
  • Metropolitana
    • Santiago, Metropolitana, Chile, 8330033
      • Recruiting
      • Multiple Sclerosis Centre, Pontificia Universidad Catolica de Chile
      • Contact: Claudia A Carcamo, MD, PhD.; Phone Number: 56 2 3546885; Email: ccarcamo@med.puc.cl
      • Contact: Ana C Reyes, Nurse; Phone Number: 56 2 3546885; Email: acreyes@med.puc.cl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed Informed Consent previous to the initiation of the study before any evaluation.
• Men and women > 18 years of age with Minimental > 24.
• Patients with diagnosis of secondary progressive MS without relapses or primary progressive MS according to the criteria of McDonald 2010.

Exclusion Criteria:

• Relapsing-remitting MS
• Current Immunomodulatory or immunosuppressive therapy
• Uncontrolled systemic diseases not controlled or treated with immunotherapy (i.e Rheumatoid Arthritis, Lupus Erythematosus).
• Pregnant women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: andrographolides; Coated tablets containing 140 mg andrographolides twice a day orally administered for a period of 24 months.	Drug: Andrographolides; 140 mg andrographolides coated tablets twice a day orally administered for 24 months.; Other Names: andrographolide, neoandrographolide, deoxyandrographolide; IB-MS 14
Placebo Comparator: sugar tablets; Coated tablets containing 140 mgs excipients twice a day orally administered for a period of 24 months.	Drug: placebo; 140 mg excipients coated tablets twice a day orally administered for 24 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain atrophy in patients with progressive forms of MS	Retarding the progression of brain atrophy as measured by MR quantified by the percentage of change in volume size utilizing SIENA.	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Expanded Disability Status Scale (EDSS)	Delay in the disability capacity progression through the Expanded Disability Status Scale (EDSS) at 24 months compared to the baseline.	24 months
Paced Auditory Serial Addition Test (PASAT)	Delay in cognitive impairment by means of Paced Auditory Serial Addition Test (PASAT) at 24 months compared to the baseline.	24 months
Quality of life Multiple Sclerosis Impact Scale (MSIS 29)	Quality of life Multiple Sclerosis Impact Scale (MSIS 29) through parameters reported by the patients at 24 months compared to the baseline.	24 months
Treatment Satisfaction Questionnaire for Medication (TSQM)	Tolerability of andrographolide measured by the Treatment Satisfaction Questionnaire for Medication (TSQM) at 24 months.	24 months
Number of new T2 lesions	Number of new lesions T2 by MR at 24 months compared to the baseline.	24 months
New hypointense lesions in T1	Number of new hypointense lesions in T1 by MR at 24 months compared to the baseline.	24 months
Optical Coherence Tomography (OCT)	Delay in the retinal thinning measured by Optical Coherence Tomography (OCT) at 24 months compared to the baseline.	24 months
Record of adverse effects in daily symptoms and programmed interviews.	Safety of andrographolide at 24 months through the record of adverse effects in daily symptoms and programmed interviews.	24 months
Multiple Sclerosis Functional Composite (MSFC)	Delay in the disability capacity progression through the Multiple Sclerosis Functional Composite (MSFC) at 24 months compared to the baseline.	24 months
Symbol Digit Modalities Test (SDMT)	Delay in cognitive impairment by means of Symbol Digit Modalities Test (SDMT) at 24 months compared to the baseline.	24 months
Depression by Beck scale	Evaluate mood disorders by means of Beck scale at 24 months compared to the baseline.	24 months
Fatigue by Krupp scale	Evaluate fatigue by Krupp scale reported by the patients at 24 months compared to the baseline.	24 months
Number of new gadolinium enhancement lesions in T1 by MR	Number of new gadolinium enhancement lesions in T1 by MR at 24 months compared to the baseline.	24 months
Visual field	Change in visual field at 24 months compared to the baseline.	24 months
Volume of new T2 lesions	Volume of size in T2 by MR at 24 months compared to the baseline.	24 months

Collaborators and Investigators

• Sponsor: Innobioscience SpA
• Collaborators: Pontificia Universidad Catolica de Chile; University of Chile; Universidad Austral de Chile
• Investigators: Study Director: Juan L Hancke, DVM, PhD, Universidad Austral de Chile

Publications and helpful links

General Publications

• Iruretagoyena MI, Tobar JA, Gonzalez PA, Sepulveda 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. doi: 10.1124/jpet.104.072512. Epub 2004 Aug 26.
• Hidalgo MA, Romero A, Figueroa J, Cortes 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. doi: 10.1038/sj.bjp.0706105.
• 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. doi: 10.1055/s-2005-864138.
• Cabrera D, Gutierrez 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.
• Burgos RA, Hancke JL, Bertoglio JC, Aguirre V, Arriagada S, Calvo M, Caceres 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.
• Iruretagoyena MI, Sepulveda SE, Lezana JP, Hermoso M, Bronfman M, Gutierrez MA, Jacobelli SH, Kalergis AM. Inhibition of nuclear factor-kappa B enhances the capacity of immature dendritic cells to induce antigen-specific tolerance in experimental autoimmune encephalomyelitis. J Pharmacol Exp Ther. 2006 Jul;318(1):59-67. doi: 10.1124/jpet.106.103259. Epub 2006 Apr 5.
• Carretta MD, Alarcon P, Jara E, Solis L, Hancke JL, Concha II, Hidalgo MA, Burgos RA. Andrographolide reduces IL-2 production in T-cells by interfering with NFAT and MAPK activation. Eur J Pharmacol. 2009 Jan 14;602(2-3):413-21. doi: 10.1016/j.ejphar.2008.11.011. Epub 2008 Nov 13.
• Sandborn WJ, Targan SR, Byers VS, Rutty DA, Mu H, Zhang X, Tang T. Andrographis paniculata extract (HMPL-004) for active ulcerative colitis. Am J Gastroenterol. 2013 Jan;108(1):90-8. doi: 10.1038/ajg.2012.340. Epub 2012 Oct 9.
• Tang T, Targan SR, Li ZS, Xu C, Byers VS, Sandborn WJ. Randomised clinical trial: herbal extract HMPL-004 in active ulcerative colitis - a double-blind comparison with sustained release mesalazine. Aliment Pharmacol Ther. 2011 Jan;33(2):194-202. doi: 10.1111/j.1365-2036.2010.04515.x. Epub 2010 Nov 30.
• Ciampi E, Uribe-San-Martin R, Carcamo C, Cruz JP, Reyes A, Reyes D, Pinto C, Vasquez M, Burgos RA, Hancke J. Efficacy of andrographolide in not active progressive multiple sclerosis: a prospective exploratory double-blind, parallel-group, randomized, placebo-controlled trial. BMC Neurol. 2020 May 7;20(1):173. doi: 10.1186/s12883-020-01745-w.

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Anticipated): November 1, 2016
• Study Completion (Anticipated): April 1, 2017

Study Registration Dates

• First Submitted: October 3, 2014
• First Submitted That Met QC Criteria: October 23, 2014
• First Posted (Estimate): October 24, 2014

Study Record Updates

• Last Update Posted (Estimate): October 27, 2014
• Last Update Submitted That Met QC Criteria: October 24, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis; Physiological Effects of Drugs; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Platelet Aggregation Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Andrographolide
• Other Study ID Numbers: 14PIE-26946CORFO; 14-391 (Other Identifier: Comite Etico Cientifico - CEC MED UC)