Clinical trial NCT02273635: Efficacy, Safety and Tolerability of Andrographolides Versus Placebo in Patients With Progressive Forms of MS
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Primary Progressive Multiple Sclerosis
Multiple Sclerosis, Secondary Progressive
Lead sponsor: Innobioscience SpA
Sponsor class: INDUSTRY
Collaborators: name: Pontificia Universidad Catolica de Chile
name: University of Chile
name: Universidad Austral de Chile
First posted: 2014-10-24
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Brain atrophy in patients with progressive forms of MS
timeFrame: 24 months
Secondary outcomes:
measure: Expanded Disability Status Scale (EDSS)
timeFrame: 24 months
measure: Paced Auditory Serial Addition Test (PASAT)
timeFrame: 24 months
measure: Quality of life Multiple Sclerosis Impact Scale (MSIS 29)
timeFrame: 24 months
measure: Treatment Satisfaction Questionnaire for Medication (TSQM)
timeFrame: 24 months
measure: Number of new T2 lesions
timeFrame: 24 months
measure: New hypointense lesions in T1
timeFrame: 24 months
measure: Optical Coherence Tomography (OCT)
timeFrame: 24 months
measure: Record of adverse effects in daily symptoms and programmed interviews.
timeFrame: 24 months
measure: Multiple Sclerosis Functional Composite (MSFC)
timeFrame: 24 months
measure: Symbol Digit Modalities Test (SDMT)
timeFrame: 24 months
measure: Depression by Beck scale
timeFrame: 24 months
measure: Fatigue by Krupp scale
timeFrame: 24 months
measure: Number of new gadolinium enhancement lesions in T1 by MR
timeFrame: 24 months
measure: Visual field
timeFrame: 24 months
measure: Volume of new T2 lesions
timeFrame: 24 months
Other outcomes:
Locations:
city: Santiago
country: Chile
facility: Multiple Sclerosis Centre, Pontificia Universidad Catolica de Chile
state: Metropolitana
Study officials:
affiliation: Universidad Austral de Chile
name: Juan L Hancke, DVM, PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
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. doi: 10.1055/s-2005-864138.
citation: 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.
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.
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.
citation: 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.