Intrathecal Methotrexate for Progressive Multiple Sclerosis: An Open Label Single Arm Study

NCT02644044 | Unknown Early Phase 1 DMC

• 1 other identifier: 0166-15-TLV
• Study Type: interventional
• Target: 30
• Locations: 0 countries
• Sites: N/A

Brief Summary

Multiple sclerosis (MS) is characterized pathologically by demyelination, axonal loss, and glial scar formation. Clinically, most patients have a relapsing-remitting course of MS (RRMS) that over time may become progressive without remissions - a secondary progressive MS (SPMS). About 15% of patients have a progressive course from onset which is called primary progressive (PP). Currently, there is no approved treatment for PPMS and for SPMS only therapy with mitoxantrone showed mild effect. Thus, more effective therapies need to be developed for treatment of SPMS and PPMS. Methotrexate (MTX), an anti-metabolite, has been in clinical use since 1948 when it was found to produce temporary remission of acute childhood leukemia. There are accumulating evidences that in progressive MS patients there are follicular lymphoid structures in the meninges and in the Virchow-Robin spaces. Therefore, intrathecal therapy may target the pathological follicular lymphoid activity. The safety of intrathecal MTX (ITMTX) has been demonstrated by its widespread use in treating lymphoproliferative diseases and leptomeningeal metastases. Sadik et. Al. reported about the feasibility and safety of using intrathecal methotrexate (ITMTX) as a treatment for unresponsive patients with progressive forms of MS. In their open label study they found that ITMTX may have a beneficial effect in progressive forms of MS and that it was well tolerated with no serious adverse events. The investigators aim is to evaluate the efficacy , safety and tolerability of intrathecal methotrexate administration every 3 months in progressive 30 patients with progressive MS. The investigators will evaluate clinical, laboratory evaluation of the blood and cerebrospinal fluid as well as the MRI scans of the participants. Each patient will be treated 4 times for 1 year with the option to continue for another 1 more year with the same protocol.

Conditions

To Evaluate the Effect of Therapy With IT MTX on the Disease Course of Patients With Progressive MS

Keywords

Progressive multiple sclerosis; methotrexate

Outcome Measures

Primary Outcomes (2)

• The change in disability ( Multiple Sclerosis Functional Composite (MSFC)

  Disability will be measured every visit by the Multiple Sclerosis Functional Composite (MSFC)

  1 year

• Safety and tolerability (adverse events)

  adverse events will be followed until resolution. Serious adverse events will be reported to the IRB within 24 hours of noticed.

  each adverse event will be followed up until resolution

Secondary Outcomes (2)

• Changes in brain MRI measurements

  1 year

• Laboratory measurements

  1 year

Study Arms (1)

Treatment

EXPERIMENTAL

Treatment with IT methotrexate

Drug: Intrathecal methotrexate

Interventions

Intrathecal methotrexate DRUG

12.5 mg of methotrexate diluted to a concentration of up to 4 mg/mL in 0.9 percent sodium chloride with 4 mg Dexamethasone via lumbar puncture needle.

Treatment

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-75 years
• Clinically definite diagnosis of MS according to McDonald criteria 2010.
• Progressive disease form defined by confirmed expanded disability status scale (EDSS) progression without relapse by at least 0.5 point or greater in the six months prior to enrollment.

You may not qualify if:

• Pregnancy
• Active infection
• Significant associated medical condition such as malignancy, heart disease or concurrent other autoimmune condition.
• Known allergy to MTX.
• WBC\<4000 cells/µL
• Lym\<800 cells/µL
• Treated with fingolimod or natalizumab 3 months prior to enrollment

Sponsors & Collaborators

• Tel-Aviv Sourasky Medical Center: lead

Related Publications (10)

• Sadiq SA (2005) Multiple sclerosis. In: Rowland LP (ed) Merritt's neurology, 11th edn. Lippincott Williams and Wilkins, Philadelphia, pp 941-963

  BACKGROUND

• Goodkin DE, Rudick RA, VanderBrug Medendorp S, Daughtry MM, Schwetz KM, Fischer J, Van Dyke C. Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol. 1995 Jan;37(1):30-40. doi: 10.1002/ana.410370108.

  PMID: 7818255 BACKGROUND

• Hartung HP, Gonsette R, Konig N, Kwiecinski H, Guseo A, Morrissey SP, Krapf H, Zwingers T; Mitoxantrone in Multiple Sclerosis Study Group (MIMS). Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002 Dec 21-28;360(9350):2018-25. doi: 10.1016/S0140-6736(02)12023-X.

  PMID: 12504397 BACKGROUND

• American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum. 2002 Feb;46(2):328-46. doi: 10.1002/art.10148. No abstract available.

  PMID: 11840435 BACKGROUND

• Ashtari F, Savoj MR. Effects of low dose methotrexate on relapsing-remitting multiple sclerosis in comparison to Interferon beta-1alpha: A randomized controlled trial. J Res Med Sci. 2011 Apr;16(4):457-62.

  PMID: 22091259 BACKGROUND

• Currier RD, Haerer AF, Meydrech EF. Low dose oral methotrexate treatment of multiple sclerosis: a pilot study. J Neurol Neurosurg Psychiatry. 1993 Nov;56(11):1217-8. doi: 10.1136/jnnp.56.11.1217.

  PMID: 8229034 BACKGROUND

• Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, Reynolds R, Aloisi F. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2007 Apr;130(Pt 4):1089-104. doi: 10.1093/brain/awm038.

  PMID: 17438020 BACKGROUND

• Siegal T, Lossos A, Pfeffer MR. Leptomeningeal metastases: analysis of 31 patients with sustained off-therapy response following combined-modality therapy. Neurology. 1994 Aug;44(8):1463-9. doi: 10.1212/wnl.44.8.1463.

  PMID: 8058150 BACKGROUND

• Sadiq SA, Simon EV, Puccio LM. Intrathecal methotrexate treatment in multiple sclerosis. J Neurol. 2010 Nov;257(11):1806-11. doi: 10.1007/s00415-010-5614-4. Epub 2010 Jun 10.

  PMID: 20532907 BACKGROUND

• Kolb H, Shachaf Y, Fainberg K, Golan M, Regev K, Vigiser I, Fuchs L, Gadoth A, Kestenbaum M, Omer N, Shopin L, Ash EL, Artzi M, Ben Bashat D, Aizenstein O, Karni A. Intrathecal methotrexate in progressive multiple sclerosis: a phase 1 open-label study with long-term follow-up. J Neurol. 2025 May 4;272(5):374. doi: 10.1007/s00415-025-13114-z.

  PMID: 40319416 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis, Chronic Progressive

Condition Hierarchy (Ancestors)

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Arnon Karni, MD

CONTACT

052-4266733; arnonk@tlvmc.gov.il

Oren Weintraub, MPHA

CONTACT

03-6915138; orenw@tlvmc.gov.il

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director R&D Division

Study Record Dates

• First Submitted: March 23, 2015
• First Posted: December 31, 2015
• Study Start: January 1, 2016
• Primary Completion: December 1, 2017
• Study Completion: January 1, 2018
• Last Updated: December 31, 2015

Record last verified: 2015-12