Pharmacokinetics of DMF and the Effects of DMF on Exploratory Biomarkers

NCT02683863 | Completed Phase 4

• 1 other identifier: BG12-001
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to explore whether DMF (Dimethyl Fumarate) or MMF (monomethyl fumarate) its main bioactive metabolite, is capable of entering the central nervous system in SPMS patients that are being treated with Tecfidera®. PK samples (pharmacokinetics - or the amount of study drug in blood) will be tested to compare with PK samples, the amount of study drug, in spinal fluid (CSF).

Conditions

Multiple Sclerosis

Outcome Measures

Primary Outcomes (8)

• The primary objective of the study is to investigate the PK (drug level) of DMF(study drug) in CSF with SPMS.

  Concentration of DMF in CSF predose and at 3, 5, 7 hours post DMF treatment in week 6.

  post-DMF treatment in Week 6

• The primary objective of the study is to investigate the PK (drug level) of DMF(study drug) in plasma in subjects with SPMS.

  Concentration of DMF in plasma predose and at 2,3,5,6, 7 and 8 hours post-DMF treatment at Week 6

  treatment in week 6

• The primary objective of the study is to investigate the PK (drug level) of MMF(the primary metabolite of study drug) in CSF with SPMS.

  Concentration of MMF in CSF predose and at 3, 5, 7 hours post DMF treatment in week 6.

  treatment in week 6

• The primary objective of the study is to investigate the PK (drug level) of MMF( the primary metabolite of study drug) in plasma in subjects with SPMS.

  Concentration of MMF in plasma predose and at 2,3,5,6, 7 and 8 hours post-DMF treatment at Week 6

  treatment in week 6

• The primary objective of the study is to investigate the PK (drug level) of DMF conjugate (study drug) in CSF with SPMS.

  Concentration of DMF conjugate in CSF predose and at 3, 5, 7 hours post DMF treatment in week 6.

  treatment in week 6

• The primary objective of the study is to investigate the PK (drug level) of DMF conjugate (study drug) in plasma in subjects with SPMS.

  Concentration of DMF conjugate in plasma predose and at 2,3,5,6, 7 and 8 hours post-DMF treatment at Week 6

  treatment in week 6

• The primary objective of the study is to investigate the PK (drug level) of MMF (the primary metabolite of study drug) conjugate in CSF with SPMS.

  Concentration of MMF conjugate in CSF predose and at 3, 5, 7 hours post DMF treatment in week 6.

  treatment in week 6

• The primary objective of the study is to investigate the PK (drug level) of MMF( the primary metabolite of study drug) conjugate in plasma in subjects with SPMS.

  Concentration of MMF conjugate in plasma predose and at 2,3,5,6, 7 and 8 hours post-DMF treatment at Week 6

  treatment in week 6

Secondary Outcomes (7)

• A secondary objective is to assess the effects of DMF on PD biomarkers downstream of Nrf2 in the CSF of subjects with SPMS.

  at 28 weeks

• A secondary objective is to assess the effects of DMF on biomarkers of inflammation in the CSF of subjects with SPMS.

  at 28 weeks

• A secondary objective is to assess the effects of DMF on biomarkers of neuroaxonal damage in the CSF of subjects with SPMS.

  at 28 weeks

• A secondary objective is to assess the effects of DMF on biomarkers of oxidative stress in the CSF of subjects with SPMS.

  at 28 weeks

• A secondary objective is to assess the effects of DMF on myelin lipid biomarkers in the CSF of subjects with SPMS.

  at 28 weeks

Study Arms (4)

Group 1

OTHER

There will be 4 CSF sampling groups at the Week 6 visit for PK assessment: 1\. Four subject for CSF samples 3 hours after dosing

Drug: BG00012 (DMF) (Tecfidera®.)

Group 2

OTHER

2\. Four subjects for CSF samples 5 hours after dosing

Drug: BG00012 (DMF) (Tecfidera®.)

Group 3

OTHER

3\. Four subjects for CSF samples 7 hours after dosing

Drug: BG00012 (DMF) (Tecfidera®.)

Group 4

OTHER

4\. Four subjects for predose CSF samples

Drug: BG00012 (DMF) (Tecfidera®.)

Interventions

BG00012 (DMF) (Tecfidera®.) DRUG

Subjects will take DMF 120 mg BID for the first 4 weeks of treatment followed by DMF 240 mg BID for 24 weeks.

Group 1; Group 2; Group 3; Group 4

Eligibility Criteria

• Age: 25 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• To be eligible to participate in this study, candidates must meet the following eligibility criteria at screening, or at the timepoint specified in the individual eligibility criterion listed:
• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local patient privacy regulations. Subjects must provide separate informed consent to participate in this CSF study.
• Aged 25 to 65 years-old, inclusive, at the time of informed consent.
• Male of female subject with a confirmed diagnosis of SPMS.
• EDSS score between 3 and 7, inclusive, at screening.
• Weight should be between 130 and 200 lb.

You may not qualify if:

• Unable or unwilling to provide informed consent. (Subjects must provide separate informed consent for this study.)
• A MS relapse, as determined by the Investigator, which occurred within 90 days prior to screening, or the subject has not stabilized from a previous relapse prior to screening.
• Any contraindication to having a brain magnetic resonance imaging (MRI) (e.g., pacemaker, MRI-incompatible aneurysm clips, artificial heart valves, or other metal foreign body; claustrophobia that cannot be medically managed) or contraindication for administration of gadolinium-contrast agent.
• Clinically significant brain MRI finding other than those related to MS, as judged by the Investigator, at screening.
• Any contraindications to having a LP (e.g., aspirin greater than 325 mg/day, warfarin, clopidrogel, decreased platelet count, prolonged PT or PTT more than 1 ½ over normal) as determined by history and Investigator decision.
• Evidence of history of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, diabetes mellitus) with the exception of MS.
• Pregnant; or breastfeeding females; or males of fathering potential or females of childbearing potential who are unwilling or unable to use an effective method of contraception as outlined in this protocol (Section 12.5) for the duration of the study and for at least 28 days after the last dose of DMF use in this protocol. For females of childbearing potential, a positive pregnancy test at any time within the protocol.
• Known positive human immunodeficiency virus antibody, hepatitis B surface antigen, hepatitis B core antibody, or hepatitis C antibody tests indicative of present or prior infection.
• Any abnormal hematology values or clinical chemistry values judged by the Investigator or Sponsor as clinically significant, including white blood cell count (WBC) 3500/mm3, or absolute lymphocyte count lower limit of normal.
• Positive Quantiferon-Tuberculosis Gold In-Tube test (QFT-GIT) at screening or known history of active tuberculosis not adequately treated.
• Any malignancy within 5 years, except for basal or squamous cell skin lesions which have been surgically excised, with no evidence of metastasis.
• Any clinical, CSF, or MRI evidence for progressive multifocal leukoencephalopathy, from historical MRI.
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.
• Subjects participating in or expecting to participate in other interventional clinical trials, except those participating in Study US-BGT-US-10766 at the same site.
• History of drug or alcohol abuse (as defined by the Investigator) within 2 years prior to screening.

Sponsors & Collaborators

• Multiple Sclerosis Center of Northeastern New York: lead
• Biogen: collaborator

Study Sites (1)

Multiple Sclerosis Center of Northeastern New York

Latham, New York, 12110, United States

Location

Related Publications (13)

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• Calkins MJ, Johnson DA, Townsend JA, Vargas MR, Dowell JA, Williamson TP, Kraft AD, Lee JM, Li J, Johnson JA. The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal. 2009 Mar;11(3):497-508. doi: 10.1089/ars.2008.2242.

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• Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, Zeng W, Hronowsky X, Buko A, Chollate S, Ellrichmann G, Bruck W, Dawson K, Goelz S, Wiese S, Scannevin RH, Lukashev M, Gold R. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011 Mar;134(Pt 3):678-92. doi: 10.1093/brain/awq386.

  PMID: 21354971 BACKGROUND

• Scannevin RH, Chollate S, Jung MY, Shackett M, Patel H, Bista P, Zeng W, Ryan S, Yamamoto M, Lukashev M, Rhodes KJ. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther. 2012 Apr;341(1):274-84. doi: 10.1124/jpet.111.190132. Epub 2012 Jan 20.

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• Ellrichmann G, Petrasch-Parwez E, Lee DH, Reick C, Arning L, Saft C, Gold R, Linker RA. Efficacy of fumaric acid esters in the R6/2 and YAC128 models of Huntington's disease. PLoS One. 2011 Jan 31;6(1):e16172. doi: 10.1371/journal.pone.0016172.

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• Ghoreschi K, Bruck J, Kellerer C, Deng C, Peng H, Rothfuss O, Hussain RZ, Gocke AR, Respa A, Glocova I, Valtcheva N, Alexander E, Feil S, Feil R, Schulze-Osthoff K, Rupec RA, Lovett-Racke AE, Dringen R, Racke MK, Rocken M. Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med. 2011 Oct 24;208(11):2291-303. doi: 10.1084/jem.20100977. Epub 2011 Oct 10.

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MeSH Terms

Conditions

Multiple Sclerosis

Interventions

Dimethyl Fumarate

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Fumarates; Dicarboxylic Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals

Study Officials

• Keith Edwards, M.D

  MS Center of Northeastern NY

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 14, 2016
• First Posted: February 17, 2016
• Study Start: August 1, 2015
• Primary Completion: January 31, 2017
• Study Completion: January 31, 2017
• Last Updated: March 22, 2017

Record last verified: 2017-03

Locations

US (1)