ClinicalTrials.gov
ClinicalTrials.gov Menu

Pharmacokinetics of DMF and the Effects of DMF on Exploratory Biomarkers

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02683863
Recruitment Status : Completed
First Posted : February 17, 2016
Last Update Posted : March 22, 2017
Sponsor:
Collaborator:
Biogen
Information provided by (Responsible Party):
Multiple Sclerosis Center of Northeastern New York

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).

Condition or disease Intervention/treatment Phase
Multiple Sclerosis Drug: BG00012 (DMF) (Tecfidera®.) Phase 4

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open Label Study of the Pharmacokinetics of DMF and the Effects of DMF on Exploratory Biomarkers in Subjects With Secondary Progressive Multiple Sclerosis
Study Start Date : August 2015
Actual Primary Completion Date : January 31, 2017
Actual Study Completion Date : January 31, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Group 1

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

Group 2
2. Four subjects for CSF samples 5 hours after dosing
Drug: BG00012 (DMF) (Tecfidera®.)
Subjects will take DMF 120 mg BID for the first 4 weeks of treatment followed by DMF 240 mg BID for 24 weeks.

Group 3
3. Four subjects for CSF samples 7 hours after dosing
Drug: BG00012 (DMF) (Tecfidera®.)
Subjects will take DMF 120 mg BID for the first 4 weeks of treatment followed by DMF 240 mg BID for 24 weeks.

Group 4
4. Four subjects for predose CSF samples
Drug: BG00012 (DMF) (Tecfidera®.)
Subjects will take DMF 120 mg BID for the first 4 weeks of treatment followed by DMF 240 mg BID for 24 weeks.




Primary Outcome Measures :
  1. The primary objective of the study is to investigate the PK (drug level) of DMF(study drug) in CSF with SPMS. [ Time Frame: post-DMF treatment in Week 6 ]
    Concentration of DMF in CSF predose and at 3, 5, 7 hours post DMF treatment in week 6.

  2. The primary objective of the study is to investigate the PK (drug level) of DMF(study drug) in plasma in subjects with SPMS. [ Time Frame: treatment in week 6 ]
    Concentration of DMF in plasma predose and at 2,3,5,6, 7 and 8 hours post-DMF treatment at Week 6

  3. 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. [ Time Frame: treatment in week 6 ]
    Concentration of MMF in CSF predose and at 3, 5, 7 hours post DMF treatment in week 6.

  4. 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. [ Time Frame: treatment in week 6 ]
    Concentration of MMF in plasma predose and at 2,3,5,6, 7 and 8 hours post-DMF treatment at Week 6

  5. The primary objective of the study is to investigate the PK (drug level) of DMF conjugate (study drug) in CSF with SPMS. [ Time Frame: treatment in week 6 ]
    Concentration of DMF conjugate in CSF predose and at 3, 5, 7 hours post DMF treatment in week 6.

  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. [ Time Frame: treatment in week 6 ]
    Concentration of DMF conjugate in plasma predose and at 2,3,5,6, 7 and 8 hours post-DMF treatment at Week 6

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

  8. 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. [ Time Frame: treatment in week 6 ]
    Concentration of MMF conjugate in plasma predose and at 2,3,5,6, 7 and 8 hours post-DMF treatment at Week 6


Secondary Outcome Measures :
  1. A secondary objective is to assess the effects of DMF on PD biomarkers downstream of Nrf2 in the CSF of subjects with SPMS. [ Time Frame: at 28 weeks ]
    PD biomarkers downstream of Nrf2, such as NAD(P)H hydrogenase [quinone 1], heme oxygenase-1, and aldo-keto reductase family 1 member B8 that have not been evaluated in CNS.

  2. A secondary objective is to assess the effects of DMF on biomarkers of inflammation in the CSF of subjects with SPMS. [ Time Frame: at 28 weeks ]
    Biomarkers of inflammation (e.g., osteopontin, B cell activating factor, chemokines, and matrix metalloproteinase 9), which may reflect pathogenesis in SPMS.

  3. A secondary objective is to assess the effects of DMF on biomarkers of neuroaxonal damage in the CSF of subjects with SPMS. [ Time Frame: at 28 weeks ]
    Biomarkers of neuroaxonal damage (e.g., neurofilament, myelin basic protein, glial fibrillary acidic protein, and neural cell adhesion molecule), which may reflect pathogenesis in SPMS.

  4. A secondary objective is to assess the effects of DMF on biomarkers of oxidative stress in the CSF of subjects with SPMS. [ Time Frame: at 28 weeks ]
    Biomarkers of oxidative stress (e.g., myeloperoxidase, 8-Oxo-2'-deoxyguanosine and RNA biomarkers), which may reflect pathogenesis in SPMS

  5. A secondary objective is to assess the effects of DMF on myelin lipid biomarkers in the CSF of subjects with SPMS. [ Time Frame: at 28 weeks ]
    Myelin lipid biomarkers (e.g., cholesterol, galactoceramide, sulfatides, and sphingomyelin), which may correlate with disability progression in MS patients.

  6. A secondary objective is to assess the effects of DMF on pharmacogenomic biomarkers in the CSF of subjects with SPMS. [ Time Frame: at 28 weeks ]
    Pharmacogenomic biomarkers: DNA analysis from blood samples.

  7. A secondary objective is to assess the effects of DMF on RNA samples from CSF cellular pellet for transcriptionomics in the CSF of subjects with SPMS. [ Time Frame: at 28 weeks ]
    RNA samples from CSF cellular pellet for transcriptionomics.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   25 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria (MS Population):

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:

  1. 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.
  2. Aged 25 to 65 years-old, inclusive, at the time of informed consent.
  3. Male of female subject with a confirmed diagnosis of SPMS.
  4. EDSS score between 3 and 7, inclusive, at screening.
  5. Weight should be between 130 and 200 lb.

Exclusion Criteria (MS Population)

  • Candidates will be excluded from study entry if any of the following exclusion criteria exist at screening, or at the timepoint specified in the individual criterion listed:

    1. Unable or unwilling to provide informed consent. (Subjects must provide separate informed consent for this study.)
    2. 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.
    3. 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.
    4. Clinically significant brain MRI finding other than those related to MS, as judged by the Investigator, at screening.
    5. 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.
    6. Evidence of history of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, diabetes mellitus) with the exception of MS.
    7. Any sign of chronic active infection, requiring antibiotic treatment (refer to Exclusion 23) (e.g., urinary tract infection, bronchitis, hepatitis, and tuberculosis) except for those requiring topical medication for treatment (e.g., athletes foot), or screening laboratory evidence consistent with a significant chronic active acute infection requiring systemic treatment.
    8. 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.
    9. 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.
    10. 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.
    11. Positive Quantiferon-Tuberculosis Gold In-Tube test (QFT-GIT) at screening or known history of active tuberculosis not adequately treated.
    12. Any malignancy within 5 years, except for basal or squamous cell skin lesions which have been surgically excised, with no evidence of metastasis.
    13. Any clinical, CSF, or MRI evidence for progressive multifocal leukoencephalopathy, from historical MRI.
    14. 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.
    15. 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.
    16. History of drug or alcohol abuse (as defined by the Investigator) within 2 years prior to screening.

      Exclusion Criteria Related to Medication

    17. Previous exposure to DMF for disease management at any time in the past.
    18. History of severe allergic or anaphylactic reactions or known drug hypersensitivity to fumaric acid or fumaric acid esters.
    19. Treatment with methylprednisolone or other systemic corticosteroid for MS relapse or otherwise within 30 days prior to Day 1 of study treatment.
    20. Treatment with MS disease modifying therapies as follows:

      Beta interferons (interferon beta-1a [Avonex® or Rebif®] or interferon beta-1b [Betaseron®], or glatiramer acetate [Copaxone®] within 6 weeks prior to Baseline.

      Fingolimod (Gilenya®), teriflunomide (Aubagio®) within 6 months prior to Baseline, except teriflunomide washout with accelerated elimination and verification of zero serum levels of teriflunomide prior Baseline.

      Natalizumab (Tysabri®) within 6 months prior to Screening OR 1 month prior to screening if subject has a positive Nabs (neutralizing antibodies) to Tysabri® Treatment within the past 5 years or current treatment with any of the following agents: cyclosporine, cladribine, agents that are immunosuppressive (e.g., entanercept), murine protein, T-cell vaccination), or stem cell transplantation prior to Screening.

      Treatment within the past 2 years with rituximab, IVIG, or mycophenolate

    21. Receipt of any non-live vaccine within the previous 14 days or live vaccine within 30 days prior to first dose of study treatment.
    22. Treatment with an investigational drug within 30 days or 5 half-lives preceding the first dose of study treatment, whichever is longer.
    23. Use of antibiotics for any reason within 3 months of Screening. Inclusion Criteria (for Normal Control Volunteers Only)

To be eligible to participate in this study, normal control candidates must meet the following eligibility criteria at screening:

  1. 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.
  2. Male or female, aged 25 to 65 years-old, inclusive, at the time of informed consent.
  3. Weight should be between 130 and 200 lb. Exclusion Criteria (for Normal Control Volunteers Only)

Normal control candidates will be excluded from study entry if any of the following exclusion criteria exist at screening, or at the timepoint specified in the individual criterion listed:

  1. Unable or unwilling to provide informed consent. (Subjects must provide separate informed consent for this study.)
  2. 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.
  3. Evidence of history of autoimmune disease (e.g., rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, diabetes mellitus) with the exception of MS.
  4. Any sign of chronic active infection, requiring antibiotic treatment (refer to Exclusion 23) (e.g., urinary tract infection, bronchitis, hepatitis, and tuberculosis) except for those requiring topical medication for treatment (e.g., athletes foot), or screening laboratory evidence consistent with a significant chronic active acute infection requiring systemic treatment.
  5. 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.
  6. 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.
  7. 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.
  8. Positive Quantiferon-Tuberculosis Gold In-Tube test (QFT-GIT) at screening or known history of active tuberculosis not adequately treated.
  9. Any malignancy within 5 years, except for basal or squamous cell skin lesions which have been surgically excised, with no evidence of metastasis.
  10. Any clinical, CSF, or MRI evidence for progressive multifocal leukoencephalopathy, from historical MRI.
  11. 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.
  12. 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.
  13. History of drug or alcohol abuse (as defined by the Investigator) within 2 years prior to screening.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02683863


Locations
United States, New York
Multiple Sclerosis Center of Northeastern New York
Latham, New York, United States, 12110
Sponsors and Collaborators
Multiple Sclerosis Center of Northeastern New York
Biogen
Investigators
Principal Investigator: Keith Edwards, M.D MS Center of Northeastern NY

Publications:

Responsible Party: Multiple Sclerosis Center of Northeastern New York
ClinicalTrials.gov Identifier: NCT02683863     History of Changes
Other Study ID Numbers: BG12-001
First Posted: February 17, 2016    Key Record Dates
Last Update Posted: March 22, 2017
Last Verified: March 2017

Additional relevant MeSH terms:
Dimethyl Fumarate
Sclerosis
Multiple Sclerosis
Multiple Sclerosis, Chronic Progressive
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Dermatologic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs