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Bacille Calmette-Guérin (BCG) Vaccine In Radiologically Isolated Syndrome (RIS)

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03888924
Recruitment Status : Not yet recruiting
First Posted : March 25, 2019
Last Update Posted : March 25, 2019
Sponsor:
Information provided by (Responsible Party):
Giovanni Ristori, S. Andrea Hospital

Brief Summary:

Multiple sclerosis (MS) witnessed relevant therapeutic progress in the last decade. Following the extraordinary progress in the treatment of relapsing-remitting (RR) multiple sclerosis (MS), two major unmet needs remain to be addressed by translational research in this field: progressive MS and the "dream" of a world free of MS. As far as the latter is concerned, the investigators can hope to make the dream come true by understanding the etiology of the disease and hence design definitive cures. A more realistic and pragmatic perspective may be the prevention of the clinical onset of the disease, a research field that promises to become increasingly important as the integration of genetic data with endophenotypes, magnetic resonance imaging and other biomarkers ameliorates the ability to predict the development of the disease under clinical circumstance. Bacille Calmette-Guerin (BCG) vaccine has been tested with encouraging results in early MS and clinically isolated syndrome (CIS). The knowledge that disease-modifying therapies work best when used early in the demyelinating process raises the question about whether to try this approach - which is safe, cheap and handy - in individuals with radiologically isolated syndrome (RIS).

Radiologically isolated syndrome is a new entity, diagnosed when the unanticipated magnetic resonance imaging (MRI) finding of brain spatial dissemination of focal white matter (WM) lesions highly suggestive of MS occurs in subjects without symptoms of MS, and with normal neurological examinations. Conversion to clinically isolated syndromes (CIS) were described in 84% of RIS individuals with spinal cord lesions over a median time of 1.6 years from the date of the first MRI. Whether or not to treat this condition remains currently a clinical conundrum. Bacille Calmette-Guérin (BCG) vaccine may have these characteristics since it resulted beneficial in early MS and first demyelinating episodes. Being safe, cheap and handy, the investigators propose to investigate its use to prevent progression of the demyelinating process in radiologically isolated syndrome. An approach such as BCG vaccine seems appropriate as a front-line immunomodulatory approach for RIS people. In a pilot study BCG vaccine was safe and effective in reducing disease activity at MRI, and the risk of developing persistent T1-hypointense lesions ('black holes' -BH- expression of tissue damage) in subjects with MS.


Condition or disease Intervention/treatment Phase
Multiple Sclerosis Drug: Bacille Calmette-Guerin vaccine Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a phase II, double blind, randomized, controlled, multicenter study with two parallel groups of subjects.
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: In order to guarantee a double blind design, participants, assessing neurologists and neuroradiologists will be masked to treatment allocation. A "two-physician-treating and assessing-model" will be used
Primary Purpose: Treatment
Official Title: Bacille Calmette-Guérin (BCG) Vaccine In Radiologically Isolated Syndrome (RIS)
Estimated Study Start Date : April 1, 2019
Estimated Primary Completion Date : April 1, 2022
Estimated Study Completion Date : August 1, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: BCG treated patients
a single dose of Bacille Calmette-Guerin vaccine
Drug: Bacille Calmette-Guerin vaccine

One dose (0.1 mL) contains 50 μg of the semi-dry mass of BCG bacilli, i.e. from 150,000 to 600,000 of live BCG bacilli (Bacillus Calmette-Guerin), the Brazilian Moreau substrain.

One ampoule or vial with the powder contains: 0.5 mg (from 1.5 mln to 6 mln) of live BCG bacilli (Bacillus Calmette-Guerin), the Brazilian Moreau substrain.

Powder: monosodium glutamate. Solvent: isotonic solution of sodium chloride.

Other Name: BCG 10 Anti-Tuberculosis Vaccine

Placebo Comparator: Placebo treated patients
a single dose of placebo.
Drug: Placebo
isotonic solution of sodium chloride (2mL vials).




Primary Outcome Measures :
  1. cumulative number of CUAL (new gadolinium T1-weighted lesions and non-enhancing new and newly enlarging T2-weighted lesions) on MRI scans over 1 year. [ Time Frame: 12 months ]

    To evaluate the cumulative number of new combined unique active lesions (CUAL; defined as new gadolinium T1-weighted lesions and non-enhancing new and newly enlarging T2-weighted lesions) on magnetic resonance imaging (MRI) scans over 1 year.

    Brain MRI will be acquired in all subjects at each centre using a magnet at 1.5T or 3T.

    • A sagittal survey image will be used to identify the anterior and posterior commissure (AC and PC).
    • A dual-echo, turbo spin-echo sequence (slice thickness: 3mm).
    • A high-resolution (3D, MPRAGE) T1- weighted image (slice thickness: 1mm).
    • A Magnetization Transfer (MT) sequence will be performed acquiring two 2-dimensional gradient-echo sequences, one without and one with MT saturation pulse (slice thickness: 3 mm).
    • A double inversion recovery (DIR) sequence
    • A T1-weighted scan, post-gadolinium injection, after 10-minute wait period.
    • A FLAIR sequence to be acquired between the DIR and the T1-weighted scans, after the gadolinium injection.


Secondary Outcome Measures :
  1. Time to the first clinical event. [ Time Frame: 36 months ]

    The secondary endpoint will be the time to the first clinical event over the 3 years period.

    Five visits (including physical and neurological examinations) per subject are planned:

    • Visit 1 - from day -3 to day +1
    • Visit 2 - 6 months (±7 days)
    • Visit 3 - 12 months (±7 days)
    • Visit 4 - 24 months (±7 days)
    • Visit 5 - 36 months (±7 days)


Other Outcome Measures:
  1. number of cortical lesions [ Time Frame: 6, 12, 24, 36 months ]
    To evaluate the number of cortical lesions on magnetic resonance imaging (MRI) scans at 6 months, as well as at 1, 2 and 3 years: Cortical lesions will be assessed on the DIR sequence and defined as those focal hyperintensities entirely or partly located in the cortical GM.

  2. Percentage of Brain Volume Changes (PBVC) [ Time Frame: 6, 12, 24, 36 months ]
    Brain atrophy (global and regional) will be assessed on the 3D T1-weighted images using the software SIENA/SIENAX (Structural Image Evaluation, using Normalization, of Atrophy) method.

  3. Cortical and white matter Volume Changes [ Time Frame: 6, 12, 24, 36 months ]
    Brain atrophy (global and regional) will be assessed on the 3D T1-weighted images using the software SIENA/SIENAX (Structural Image Evaluation, using Normalization, of Atrophy) method. To avoid GM misclassification due to WM lesions, the latter will be masked out and refilled with intensities matching the surrounding normal-appearing WM before segmentation analysis. Volume in the subcortical grey matter will be assessed with FMRIB's Integrated Registration and Segmentation Tool (FIRST).

  4. Magnetization Transfer ratio (MTr) in lesions [ Time Frame: 6, 12, 24, 36 months ]
    Magnetization Transfer (MT) sequence will be performed acquiring two 2-dimensional gradient-echo sequences, one without and one with MT saturation pulse, which allows to obtain MT ratio in lesions, and normal-appearing brain.

  5. Magnetization Transfer ratio (MTr) in normal-appearing brain [ Time Frame: 6, 12, 24, 36 months ]
    Magnetization Transfer (MT) sequence will be performed acquiring two 2-dimensional gradient-echo sequences, one without and one with MT saturation pulse, which allows to obtain MT ratio in lesions, and normal-appearing brain.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male and female of any race and > 18 years old.
  2. Diagnosis of RIS (4) within the last five years.
  3. Signed Informed Consent.

Exclusion Criteria:

  1. Pregnancy or lactation.
  2. Concomitant or previous use of immunosuppressive or immunomodulating treatment (except sporadic use of corticosteroids) within the last five years.
  3. Subjects with a clinically significant or unstable medical or surgical condition that would preclude safe and complete study participation. Such conditions may include cardiovascular, pulmonary, hepatic, renal, severe systemic mycotic infections, metabolic diseases or malignancies, primary or secondary immunodeficiencies as determined by medical history, physical exam, laboratory tests, chest X-ray, electrocardiogram (ECG), and Mantoux reaction.
  4. Any medical or psychiatric condition that may affect the subjects ability to give informed consent, or to complete the study, or if the subject is considered by the treating neurologist to be, for any other reason, an unsuitable candidate for this study.
  5. Subjects with inability to successfully undergo MRI scans.
  6. Concomitant radiotherapy.
  7. Known hypersensitivity to any component of the vaccine.
  8. Past bone marrow stem cell transplantation and organ transplantation.
  9. Other vaccinations in the previous 4 weeks.

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): NCT03888924


Contacts
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Contact: Giovanni Ristori, MD +390633776044 ext 6044 giovanni.ristori@uniroma1.it

Locations
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Italy
Center for Experimental Neurological Therapies (CENTERS), S. Andrea Hospital, Faculty of Medicine and Psychology, "Sapienza" University of Rome
Rome, Italy, 00139
Sponsors and Collaborators
S. Andrea Hospital
Investigators
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Principal Investigator: Giovanni Ristori S.Andrea Hospital, University of Roma La Sapienza
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Responsible Party: Giovanni Ristori, Medical director, PhD, S. Andrea Hospital
ClinicalTrials.gov Identifier: NCT03888924    
Other Study ID Numbers: BCG-RIS-01
First Posted: March 25, 2019    Key Record Dates
Last Update Posted: March 25, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Giovanni Ristori, S. Andrea Hospital:
BCG Vaccine
Radiologically Isolated Syndrome
Additional relevant MeSH terms:
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Multiple Sclerosis
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Vaccines
BCG Vaccine
Immunologic Factors
Physiological Effects of Drugs
Adjuvants, Immunologic