A Prospective Biomarker Study in Active SPMS Subjects Treated With Cladribine Tablets

The purpose of this study is to explore the concept that biomarker sensitivity will detect activity in Multiple Sclerosis (MS) subjects and allow appropriate change in treatment to prevent dysfunction.

After being informed about the study and potential risks, all patients giving written informed consent will undergo a screening period. Maximum allowable time between first screening procedure and first administration of study treatment will be 42 days.

Subjects will have a 28 day run-in period consisting of 2 visits at week -4 and week -2.

Subjects will have a Baseline day 1 visit. Study medication will commerce on the day following this visit.

Additional visits will be at the following time points: week 4, week 8, week 12, week 16, week 24, week 36, week 48, week 52, week 56, week 60, week 72, week 84 and week 96.

Eligibility Criteria:
Inclusion Criteria:

1. Male or female between 21 and 65 years old, inclusive.
2. Must be capable of understanding and providing written informed consent, including subject authorization under the health insurance portability and accountability act (HIPPA), prior to any study related procedures that are not part of routine medical care.
3. Has an EDSS score at the screening visit of 2.0 to 7.0 inclusive.
4. Have a diagnosis of clinically definite SPMS. (Lublin, 2014)
5. Are considered neurologically stable for \> 30 days prior to both screening, baseline and week 48.
6. Must be otherwise healthy without confounding diseases.
7. Subject has decided to pursue cladribine tablets as their disease modifying therapy (DMT) of choice, and have signed a study specific informed consent form.
8. Must be willing and physically able to comply with all required protocol visits and complete all assessments.
9. Must be willing to complete 2 years of routine clinic follow-ups after study completion as per cladribine tablets FDA guidelines.
10. Must have read the FDA approved patient labeling (medication guide) and be counseled, risk of teratogenicity, lactation, lymphopenia and other hematologic toxicity, infections, liver injury, hypersensitivity, cardiac failure and treatment handling and administration.
11. If female: must have a negative serum pregnancy test at screen and week 48 and a negative urine pregnancy test at baseline. All females must agree to notify us immediately if they have concern of possible pregnancy.
12. If female: be neither pregnant or breastfeeding, nor attempting to conceive AND

    • Use a highly effective method of contraception throughout the entire duration of the study and for 6 months (5 menstrual cycles) following completion of the last dose of study medication. As it is currently unknown whether cladribine tablets may reduce the effectiveness of systemically acting hormonal contraceptives, a barrier method of contraception should be implemented for the duration of the study.
13. If Male: must be willing to use contraception to avoid contributing to pregnancies 6 months following the last dose of study medication.

Exclusion Criteria:

1. Subjects with a diagnosis of a sub-type of MS other than PMS active (clinically definite SPMS)
2. Have MRI findings other than MS that are considered significant per the P.I.
3. Have a clinical condition or medical history noted as a contraindication as per the FDA/US package insert guidelines.
4. Have a history of chronic disease(s) of the immune system, other than MS or a known immunodeficiency syndrome.
5. Have comorbid conditions that preclude participation, including any condition that might increase brain biomarkers such as traumatic brain injury (TBI), meningitis, stroke, or drug abuse in the last 12 months or any other medical condition deemed significant for increased biomarkers by the investigator.
6. Have an active/acute infection (bacterial, viral, fungal, etc.) at the time of screen AND/OR baseline or within 4 weeks prior to or at the start of course 2 year 2 that would interfere with the safety of the study.
7. Have a current or past significant history of poorly controlled diabetes mellitus, obesity (BMI over 35) or anorexia (BMI under 18), hypertension or hyperlipidemia as determined by the investigator.
8. Have a history or presence of malignancy other than basal cell epithelioma (BCE) or cervical cancer in-situ following a complete excision. Cancer that has been absent for more than 10 years and considered to be cured is allowed.

   a. All standard cancer screening guidelines should be followed for subjects that are treated with cladribine tablets during the course of the study.
9. Known liver conditions including the following:

   1. History or current hepatic impairment considered moderate or severe. Subjects with mild hepatic impairment can be considered at the investigator's discretion.
   2. Current or known history of alcohol abuse
   3. Chronic liver or biliary diseases
   4. Total or conjugated bilirubin greater than the upper limit of normal range
   5. Alkaline phosphatase (AP) greater than 1.5 times the upper limit of the normal range
   6. Aspartate transaminase (AST/ aka SGOT) and/or an alanine transaminase (ALT/aka SGPT) greater than 2 times the upper limit of normal range.
   7. Gamma-glutamyl-transferase (GGT) greater than 3 times the upper limit of normal.
10. History of or current renal Impairment that is considered moderate to severe. (creatinine clearance below 50 mL per minute)
11. Any other significant medical condition that in the opinion of the investigator that could potentially cause interference of complications of subject taking study Investigational Product (IP).
12. Have a contraindication to a lumbar puncture. (i.e. abnormal coagulation panel, skin infection at the location of Lumbar Puncture (LP), increased cranial pressure, etc.)
13. Any laboratory results at screen and/or prior to course 2 that are considered significant, such as but not limited to, abnormal lymphocyte count, positive hepatitis B and/or C screen, positive HIV test, etc. Any abnormal lab results must be approved by the investigator prior to initiating the first AND second course of IP therapy.
14. Have a lymphocyte count that is not at least 800 cells per microliter before initiating the second treatment course at week 48. If necessary, the second treatment course can be delayed as per FDA/US package insert guidelines.
15. Unable to undergo the required MRI scans for any reason, including claustrophobia and a history of hypersensitivity to Gd+.
16. Females who are pregnant, plan to become pregnant or who are breastfeeding during the study or plan on becoming pregnant or breastfeeding within 6 months of the last dose of cladribine tablets.
17. Males whose partner plans to become pregnant during the study or become pregnant within 6 months of the last dose of cladribine tablets.
18. Screening labs may be repeated in 2-6 weeks if an abnormality is felt to be due to a transient, reversible condition
19. Subjects that have previously been treated with cladribine in any dosing form (intravenous, subcutaneous, oral) are not allowed.
20. Subjects with a history of any of the following:

    1. Prior alemtuzumab treatment
    2. Prior or current investigational or non-FDA approved DMT or procedure
    3. Prior or current stem cell transplant for any reason
    4. Treatment with ocrelizumab or rituximab within 12 months of last dose to baseline
    5. Treatment with natalizumab within 1 year of screen. If subject has a prior history of treatment with natalizumab, the subject must also be JCV (John Cunningham virus) negative or have JCV index of 0.5 or lower. A past JCV index over 0.5 is exclusionary.
    6. Treatment with fingolimod, teriflunomide or dimethyl fumarate (DMF) within 4 weeks prior to baseline
    7. Treatment with interferon(IFN) or glatiramer acetate(GA) within 4 weeks of baseline
    8. Treatment with Intravenous immune globulin (IVIG) or plasmapheresis within 12 weeks prior to screening
    9. Treatment with an immunosuppressant such as cyclophosphamide, mitoxantrone, azathioprine, mycophenolate within 3 years prior to screening.
    10. Systemic corticosteroid within 2 weeks prior to screening. The screening period may be extended up to 4 weeks for patients who have used systemic corticosteroids but for a patient to be eligible for enrollment, no corticosteroids should be administered between screening and baseline
21. Treatment with concomitant drugs used for symptomatic treatment of spasticity or neuropathic pain, (i.e. baclofen, lorazepam, or gabapentin) as long as they have been stable dose for at least 30 days prior to screen. Medical Marijuana is allowed per investigator discretion and where allowed by state law. Medical Marijuana must not interfere with the subject's function.