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

Primary Progressive Multiple Sclerosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02273635
• Other study ID #: 14PIE-26946CORFO
• Secondary ID: 14-391
• Status: Recruiting
• Phase: Phase 1/Phase 2
• First received: October 3, 2014
• Last updated: October 24, 2014
• Start date: September 2014
• Est. completion date: April 2017

Study information

• Verified date: October 2014
• Source: Innobioscience SpA
• Contact: Claudia A Carcamo, MD, PhD
• Phone: +56223546885
• Email: ccarcamo[@]med.puc.cl
• Is FDA regulated: No
• Health authority: Chile: Instituto de Salud Pública de Chile
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 68
• Est. completion date: April 2017
• Est. primary completion date: November 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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 Design

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Chronic Progressive
• Multiple Sclerosis, Secondary Progressive
• Primary Progressive Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• Andrographolides
140 mg andrographolides coated tablets twice a day orally administered for 24 months.
• placebo
140 mg excipients coated tablets twice a day orally administered for 24 months

Locations

Country	Name	City	State
Chile	Multiple Sclerosis Centre, Pontificia Universidad Catolica de Chile	Santiago	Metropolitana

Sponsors (4)

Lead Sponsor	Collaborator
Innobioscience SpA	Pontificia Universidad Catolica de Chile, Universidad Austral de Chile, University of Chile

Country where clinical trial is conducted

Chile, 

References & Publications (9)

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, 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

Carretta MD, Alarcón 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. — 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, Sepúlveda SE, Lezana JP, Hermoso M, Bronfman M, Gutiérrez 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. Epub 2006 Apr 5. — 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

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	Treatment Satisfaction Questionnaire for Medication (TSQM)	Tolerability of andrographolide measured by the Treatment Satisfaction Questionnaire for Medication (TSQM) at 24 months.	24 months	Yes
Secondary	Number of new T2 lesions	Number of new lesions T2 by MR at 24 months compared to the baseline.	24 months	No
Secondary	New hypointense lesions in T1	Number of new hypointense lesions in T1 by MR at 24 months compared to the baseline.	24 months	No
Secondary	Optical Coherence Tomography (OCT)	Delay in the retinal thinning measured by Optical Coherence Tomography (OCT) at 24 months compared to the baseline.	24 months	No
Secondary	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	Yes
Secondary	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	No
Secondary	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	No
Secondary	Depression by Beck scale	Evaluate mood disorders by means of Beck scale at 24 months compared to the baseline.	24 months	Yes
Secondary	Fatigue by Krupp scale	Evaluate fatigue by Krupp scale reported by the patients at 24 months compared to the baseline.	24 months	No
Secondary	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	No
Secondary	Visual field	Change in visual field at 24 months compared to the baseline.	24 months	No
Secondary	Volume of new T2 lesions	Volume of size in T2 by MR at 24 months compared to the baseline.	24 months	No