Trial document





This trial has been registered retrospectively.
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  DRKS00020132

Trial Description

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Title

Explorative study of emerging blood biomarkers in progressive multiple sclerosis

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Trial Acronym

EmBioProMS

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URL of the Trial

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Brief Summary in Lay Language

In recent years, progress in the field of multiple sclerosis has been more rapid than in any other field of neurology. The therapeutic possibilities of the relapsing form are numerous and effective. Nevertheless, the treatment of patients with the progressive course of the disease (PMS) remains challenging. What is the reason for this? Why do PMS patients respond only moderately to available therapies?

The complex interacting mechanisms that drive progression remain partially understood. The so-called glial cells, the supporting cells of the brain, could play an important role in the decline of the nerve cells and thus lead to the accumulation of disability. Of particular relevance are the astrocytes (spider cells), where many studies have shown a malfunction in MS, especially in PMS. Activated astrocytes are numerous in the demyelination sites in the brain of PMS patients. They can recruit immune cells, influence the metabolism of nerve cells, release nerve-poisonous substances, and finally form scar tissue, thus preventing the repair of nerve fibers.
The application of novel, cutting-edge technology enables the determination of astrocyte-spicy molecules, e.g., the acid glial fiber protein (GFAP), in the blood of MS patients. Our preliminary work showed exciting results; the GFAP was particularly high in the blood of PMS patients and correlated with different aspects of progression. Based on these results, we launched our EmBioProMS network initiative (Explorative study of emerging blood biomarkers in progressive multiple sclerosis) with the support of the DMSG. Within this framework, a multicenter observational study will be initiated at the university clinics of Ulm, Munich (LMU), Tübingen, the Fachklinik Dietenbronn, and the Marianne-Strauß-Klinik. This will enable us to validate our previous results and possibly discover innovative biomarkers. In addition, the establishment of a disease activity marker in the blood instead of the previous time-consuming investigations will make life much easier for patients.

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Brief Summary in Scientific Language

Progressive multiple sclerosis (PMS) affects more than half of all people with MS over the course of the disease, with either a primary (PPMS) or secondary progressive (SPMS) clinical course. An unmet need in the research and care of PMS patients is a practical, highly accessible biomarker of disease progression. Such a biomarker could help to define at what time a patient transits to a progressive form of the disease and also serve as an outcome measure in future clinical trials. Astrocyte-specific glial fibrillary acidic protein (GFAP) and the neuroaxonal neurofilament light chain (NfL) might be such markers for disease progression as demonstrated by our previous work, in which we retrospectively analysed CSF and serum specimens from multiple centers. Using the Single Molecule Array (SIMOA) technology, the sensitivity of biomarker analysis could be increased and it became possible to measure GFAP and NfL in the blood. The opportunity to detect brain-specific proteins related to MS disease mechanisms (gliosis and axonal damage) in the blood warrants a prospective assessment of these emerging biomarkers in PMS. Our exploratory pilot project aims to explore a possible role of GFAP and NfL as biomarkers of disease progression by determining their blood levels and correlating them to clinical, imaging, and neurochemical features in patients with PMS. A cohort of 200 patients with PMS (SPMS and PPMS) will be recruited by a collaborative network consisting of clinicians and scientists from five German centers specialised in care and research of MS. The aim of the first phase is to compare levels of GFAP and NfL among patients with relapsing-remitting MS (RRMS) and PMS, and to examine serum GFAP and NfL levels as potential markers of clinical disease progression in a cross-sectional multicenter cohort of patients with progressive vs non-progressive PMS. In the second, prospective part, the patients will be followed at six months intervals to evaluate the role of GFAP and NfL as longitudinal parameters in blood samples. Other secondary objectives as measured by magnetic resonance imaging and optical coherence tomography will be explored in a subgroup of patients. Following successful completion of this exploratory pilot project, the long-term goal of our collaborative network is to establish the basis for a larger prospective multicenter cohort of PMS patients that will allow us: a) to improve clinical tools to monitor disease progression in concert with biomarkers, b) to improve the real-world assessment of the emerging blood biomarkers, and c) to provide a basis for data-driven decisions on meaningful endpoints for clinical trials. Our project has obvious limitations, including the small sample size, focus on selected biomarkers where we have preliminary supportive evidence, and limitation of MRI to a subgroup. However, we feel that the goals, novelty of the markers and method, experience of the participating centers, as well as the prospects of a long-term real-world data collection are strengths of this pragmatic, explorative proposal. Also, the cohorts will be expanded and results will be validated in future research projects, if the preliminary findings of this study are encouraging.

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Do you plan to share individual participant data with other researchers?

No

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Description IPD sharing plan:

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Organizational Data

  •   DRKS00020132
  •   2019/12/19
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  •   yes
  •   Approved
  •   270/17 , Ethik-Kommission der Universität Ulm
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Secondary IDs

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Health Condition or Problem studied

  •   G35 -  Multiple sclerosis
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Interventions/Observational Groups

  •   Levels of serum NfL and GFAP will be assessed in patients with progressive MS over a follow-up period of 18 months
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Characteristics

  •   Non-interventional
  •   Other
  •   Other
  •   Open (masking not used)
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  •   Other
  •   Prognosis
  •   Parallel
  •   N/A
  •   N/A
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Primary Outcome

examine serum GFAP as a marker of disease progression by comparing PMS patients with progressive vs non-progressive disease course.

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Secondary Outcome

• examine serum NfL as a marker of disease progression by comparing PMS patients with progressive vs non-progressive disease course.
• examine serum GFAP as a marker of disease activity by comparing PMS Patients with active vs non-active disease course.
• examine serum NfL as a marker of disease activity by comparing PMS Patients with active vs non-active disease course.
• examine the ability of GFAP to distinguish between RRMS and PMS.
• examine the ability of NfL to distinguish between RRMS and PMS.
• examine different OCT-parameters (whole retinal thickness, GCL, RNFL, INL) as a marker of disease progression by comparing PMS patients with progressive vs non-progressive disease course.
• examine different OCT-parameters (whole retinal thickness, GCL, RNFL, INL) as a marker of disease activity by comparing PMS Patients with active vs non-active disease course.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
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Recruitment

  •   Actual
  •   2018/06/01
  •   240
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   65   Years
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Additional Inclusion Criteria

Patients with progressive multiple sclerosis (PMS)

- Duration of the progressive phase of at least 12 months
- Cranial MRI scan within the last three months of baseline-Visit*
- EDSS between 1 and 6,5+
* not obligatory in 50% of the study population (100 patients)
+ a cap of 25% will be applied as the upper limit of patients with EDSS > 5.5

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Exclusion Criteria

- Patients with relapsing-remitting multiple sclerosis.
- Acute exacerbation in the last 3 months
- Treatment with*:
• Methylprednisolone in the last 30 days
• Interferon, Glatiramer acetate, Natalizumab, Dimethyl fumarate, Fingolimod and Teriflunomide in the last 3 months
• Ocrelizumab, Rituximab or Mitoxantrone in the last 12 months
• With Cladribine or alemtuzumab in the last 24 months
- Contraindication for MRI or for Gadolinium injection
- Inflammatory diseases of the central nervous system

* not obligatory in 50% of the study population (100 patients)

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Addresses

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Sources of Monetary or Material Support

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    • Deutsche Multiple Sklerose Bundeverband e.V.
    • Krausenstr. 50
    • 30171  Hannover
    • Germany
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.