| Eligibility |
- INCLUSION CRITERIA:
In order to be eligible to participate in this study, an individual must meet all of the
following criteria:
Tolebrutinib Cohorts Inclusion Criteria
1. Able to provide informed consent
2. Willingness to comply with all study procedures and availability for the duration of
the study
3. Male or female, aged greater than or equal to 18
4. Diagnosed with multiple sclerosis according to the 2017 revision of the McDonald
diagnostic criteria, with no new lesion formation by comparison of baseline MRI scan
with a historical MRI scan at least 6 months prior
5. On anti-CD20 antibody treatment for at least 6 months, with the most recent dose at
most 6 months prior to enrollment.
6. Willing to forego further anti-CD20 antibody treatment for the duration of the study
7. Fully vaccinated against SARS-CoV-2 by Day 0. At the time of this writing, Fully
vaccinated is defined as:
- Two weeks out from the second dose of a two-dose vaccine series (Moderna,
Pfizer-BioNTech); or
- Two weeks out from a single-dose vaccine (Johnson & Johnson/Janssen)
- Note: Should guidelines change, we will amend these inclusion criteria
accordingly
8. Has a prior 7-tesla MRI scan, no more than 1 year prior to enrollment, demonstrating
at least one white matter lesion with a paramagnetic rim
9. For females of reproductive potential: agrees to use highly effective contraception
for at least 1 month prior to dosing and to use such a method during study
participation and for an additional 12 weeks after the end of tolebrutinib
administration
10. For males of reproductive potential: agrees to use condoms or other methods to ensure
effective contraception with partner; agrees not to donate sperm from the inclusion up
to 12 weeks after the last dose
11. QuantiFERON-TB Gold negative; skin testing (e.g., tuberculin skin test) will be
allowed if blood testing is not available or the blood test result is indeterminate
12. Agrees to adhere to Lifestyle Considerations throughout study duration
13. Agrees not to participate in any other interventional study while participating in
this protocol
Control Cohort Inclusion Criteria:
1. Able to provide informed consent
2. Willingness to comply with all study procedures and availability for the duration of
the study
3. Male or female, aged greater than or equal to 18
4. Diagnosed with multiple sclerosis according to the 2017 revision of the McDonald
diagnostic criteria, with no new lesion formation by comparison of baseline MRI scan
with a historical MRI scan at least 6 months prior
5. On anti-CD20 antibody treatment for at least 6 months, with the most recent dose at
most 6 months prior to enrollment. (Participants in this cohort should remain on their
baseline anti-CD20 treatment at least through week 48.)
6. Has a prior 7-tesla MRI scan, no more than 1 year prior to enrollment, demonstrating
at least one white matter lesion with a paramagnetic rim
7. For females of reproductive potential: agrees to use highly effective contraception
during study participation
8. Agrees not to participate in any other interventional study while participating in
this protocol
EXCLUSION CRITERIA:
An individual who meets any of the following criteria will be excluded from participation
in this study:
Tolebrutinib Cohorts Exclusion Criteria
1. Pregnancy or lactation
2. MS relapse in the 6 months prior to dosing
3. Febrile illness within 4 weeks prior to dosing, or persistent chronic or active
infection requiring treatment with systemic antibiotics, antivirals, or antifungals.
4. Treatment with another investigational drug or other investigational intervention
within 3 months prior to baseline
5. Contraindications for 7-tesla MRI
6. Presence of screening laboratory or ECG values outside normal limits that are
considered in the PI or MAI s judgment to be clinically significant, including but not
limited to:
1. Presence of liver injury defined as underlying hepatobiliary disease or screening
alanine aminotransferase (ALT) more than 1.5 times the upper limit of normal
(ULN)
2. At screening, positive for hepatitis B surface antigen and/or hepatitis B core
antibody and/or positive for hepatitis C antibody
3. Any of the following:
- Bleeding disorder or known platelet dysfunction at any time prior to the
first screening visit
- Platelet count less than 150,000/microL at the screening visit
4. Lymphocyte count less than 1000 cells/dL at the screening visit
7. Is HIV-positive
8. Has received any live (attenuated) vaccine (including but not limited to varicella
zoster, oral polio, and nasal influenza) within 2 months before dosing
9. Has received any of the following medications/treatments within the specified time
frame before baseline assessment:
- Medication: Systemic corticosteroids, adrenocorticotropic hormone (other than
used for premedication); Exclusionary if used/used within required wash-out
period: 1 month prior to baseline MRI scan
- Medication: Dimethyl fumarate; Exclusionary if used/used within required wash-out
period: 6 months prior to dosing
- Medication: Intravenous immunoglobulin, fingolimod, natalizumab; Exclusionary if
used/used within required wash-out period: 6 months prior to dosing
- Medication: Teriflunomide; Exclusionary if used/used within required wash-out
period: 2 years prior to dosing or 1 month prior to dosing
if participant undergoes an accelerated elimination procedure and has documented
teriflunomide plasma level below 0.02 mg/L
before dosing
- Medication: Mildly to moderately immunosuppressive/chemotherapeutic medications
such azathioprine and methotrexate; Exclusionary if used/used within required
wash-out period: 6 months prior to dosing
- Medication: Highly immunosuppressive/chemotherapeutic medications: mitoxantrone
up to 120 mg/m2 body surface area, cyclophosphamide, cladribine; Exclusionary if
used/used within required wash-out period: 2 years prior to dosing
- Medication: Alemtuzumab; Exclusionary if used/used within required wash-out
period: 4 years prior to dosing
- Medication: Lymphoid irradiation, bone marrow transplantation, mitoxantrone (with
evidence of cardiotoxicity following treatment, or cumulative lifetime dose >120
mg/m2), other strongly immunosuppressive treatments with very long-lasting
effects; Exclusionary if used/used within required wash-out period: Any time
- Medication: Any BTK inhibitor; Exclusionary if used/used within required wash-out
period: Any time
10. Is receiving potent and moderate inducers and inhibitors of cytochrome P450 3A (CYP3A)
or potent inhibitors of CYP2C8 hepatic enzymes.
11. Is receiving anticoagulant/antiplatelet therapies, including:
1. Acetylsalicylic acid (aspirin); half-life elimination: Parent drug: Plasma
concentration: 15 to 20 minutes; Salicylates (dose dependent): 3 hours at lower
doses (300 to 600 mg), 5 to 6 hours (after 1 g), 10 hours with higher doses
2. Antiplatelet drugs (eg, clopidogrel); half-life: 6 hours
3. Warfarin (vitamin K antagonist); half-life: 20-60 hours
4. Heparin, including low molecular weight heparin (antithrombin agents); half-life:
60-90 minutes
5. Dabigatran (direct thrombin inhibitor); half-life:12-17 hours
6. Apixaban (IV half-life: approximately 5 hours, oral half-life: approximately 12
hours), edoxaban (half-life: 10-14 hours), rivaroxaban (half-life: 5-9 or 11-13
hours in younger or elderly individuals, respectively) (direct factor Xa
inhibitors)
Note: All above drugs need to be stopped at least 5 half-lives before study drug
administration except for aspirin, which needs to be stopped at least 8 days before.
12. Has a history or presence of significant other concomitant illness that, according to
the PI or MAI s judgment, would adversely affect participation in this study; examples
include but are not limited to clinically significant cardiovascular, renal, hepatic,
or metabolic
disease.
- Acute liver disease, cirrhosis, chronic liver disease (unless considered stable
for >6 months)
- Has untreated hepatitis C
- Has chronic hepatitis B unless stable on oral suppression and/or followed by a
local hepatologist to monitor for reactivation
- Has active alcohol use disorder
- Has an alcohol intake greater than 2 drink per day for men, and greater than 1
drink per day for women (1 drink = approximately 14 grams of alcohol = 350 ml
beer = 140 mL wine = 40 mL of spirits)
- Has aspartate transaminase (AST) or alanine transaminase (ALT) levels greater
than 1.5x ULN
- Has a total bilirubin level greater than 1.5x ULN unless due to Gilbert s or
non-liver related disorder
- Has an alkaline phosphatase level greater than 2x ULN unless caused by non-liver
related disorder or explained by a stable chronic liver disorder
- At baseline, elevated transferrin saturation (>50% in males and >40% in females)
and/or with elevated ferritin levels >500 microgram/L.
13. Unwilling to allow coded samples to be processed offsite
14. Unwilling to have coded samples and/or data saved or used in other studies.
Control Cohort Exclusion Criteria:
1. Pregnancy or lactation
2. MS relapse in the 6 months prior to baseline
3. Treatment with another investigational drug or other investigational intervention
within 3 months prior to baseline
4. Contraindications for 7-tesla MRI
5. Has received any of the following medications/treatments within the specified time
frame before baseline assessment:
- Medication: Systemic corticosteroids, adrenocorticotropic hormone (other than
used for premedication); Exclusionary if used/used within required wash-out
period: 1 month prior to baseline MRI scan
- Medication: Dimethyl fumarate; Exclusionary if used/used within required wash-out
period: 6 months prior to dosing
- Medication: Intravenous immunoglobulin, fingolimod, natalizumab; Exclusionary if
used/used within required wash-out period: 6 months prior to dosing
- Medication: Teriflunomide; Exclusionary if used/used within required wash-out
period: 2 years prior to dosing or 1 month prior to dosing if participant
undergoes an accelerated elimination procedure and has documented teriflunomide
plasma level below 0.02 mg/L before dosing
- Medication: Mildly to moderately immunosuppressive/chemotherapeutic medications
such azathioprine and methotrexate; Exclusionary if used/used within required
wash-out period: 6 months prior to dosing
- Medication: Highly immunosuppressive/chemotherapeutic medications: mitoxantrone
up to 120 mg/m2 body surface area, cyclophosphamide, cladribine; Exclusionary if
used/used within required wash-out period: 2 years prior to dosing
- Medication: Alemtuzumab; Exclusionary if used/used within required wash-out
period: 4 years prior to dosing
- Medication: Lymphoid irradiation, bone marrow transplantation, mitoxantrone (with
evidence of cardiotoxicity following treatment, or cumulative lifetime dose >120
mg/m2), other strongly immunosuppressive treatments with very long-lasting
effects; Exclusionary if used/used within required wash-out period: Any time
- Medication: Any BTK inhibitor; Exclusionary if used/used within required wash-out
period: Any time
6. Has a history or presence of significant other concomitant illness that, according to
the PI or MAI s judgment, would adversely affect participation in this study; examples
include but are not limited to clinically significant cardiovascular, renal, hepatic,
or metabolic
disease.
7. Unwilling to allow coded samples to be processed offsite
8. Unwilling to have coded samples and/or data saved or used in other studies
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