| Eligibility |
Inclusion Criteria:
Patients eligible for inclusion in this Treatment Plan have to meet all of the following
criteria:
1. Adult patients who are able to provide written informed consent and have done so Note:
proof of efficacy in the Phase III EXPAND study (Kappos et al 2018) has been obtained
in patients who were aged 18 to 61 years (inclusive) at screening
2. Diagnosis of SPMS with active disease. The SPMS diagnosis must follow an initial
relapsing-remitting disease course of multiple sclerosis (MS) and align with the
diagnostic criteria published (Lublin and Reingold 1996, Rovaris et al 2006, Lublin et
al 2014)
3. Patient is ambulatory, i.e., has an EDSS score of =6.5
4. Patient has no comparable or satisfactory alternative therapy available for treatment
of SPMS Written patient informed consent must be obtained prior to start of treatment.
If consent cannot be expressed in writing, it must be formally documented and
witnessed, ideally via an independent trusted witness.
Exclusion Criteria:
Patients eligible for this Treatment Plan must not meet any of the following criteria:
1. Disease exclusions
1. Relapsing-remitting multiple sclerosis
2. Primary progressive multiple sclerosis
3. Secondary progressive multiple sclerosis without active disease
2. Medical conditions precluding inclusion such as lab abnormalities or underlying
diseases
1. Patients with an active or stable but treated chronic disease of the immune
system other than MS (e.g. rheumatoid arthritis, scleroderma, Sjogren's syndrome,
Crohn's disease, ulcerative colitis, etc.) or with a known immunodeficiency
syndrome (AIDS, hereditary immune deficiency, drug-induced immune deficiency)
2. Severe active infections Patients affected by severe infections should only be
included after full resolution of the condition
3. Second-degree AV block Mobitz type II or higher, sick-sinus syndrome, sino-atrial
heart block or significant QT prolongation (QTc =500 msec).
4. History of cardiac arrest, recurrent syncope, symptomatic bradycardia, severe
cerebrovascular disease, uncontrolled hypertension or severe untreated sleep
apnea.
5. Significant liver disease
6. Ongoing macular edema (patients with a history of resolved macular edema are
allowed to enter the program)
7. Patients homozygous for CYP2C9*3 (CYP2C9*3*3 genotype)
8. Patients without a health-care professional confirmed history of chickenpox or
documentation of a full course of vaccination with varicella vaccine. They have
to undergo antibody testing to varicella zoster virus (VZV) before initiating
treatment with siponimod. A full course of vaccination for antibody-negative
patients with varicella vaccine is required prior to commencing treatment with
siponimod. Initiation of treatment with siponimod has be postponed for one month
after completion of the vaccination course to allow full effect of vaccination to
occur.
9. History of hypersensitivity to any drugs or metabolites of similar chemical
classes as siponimod.
3. Prior therapy precluding enrollment:
1. Natalizumab, immunosuppressive/chemotherapeutic medications (e.g. azathioprine,
methotrexate) within 6 months prior to enrollment
2. Rituximab, ofatumumab, ocrelizumab, cladribine, or cyclophosphamide within one
year prior to enrollment
3. Any mitoxantrone during previous two years prior to enrollment or evidence of
cardiotoxicity following mitoxantrone or a cumulative life-time dose of more than
60 mg/m2
4. alemtuzumab, lymphoid irradiation, bone marrow transplantation or other
immunosuppressive treatments with effects potentially lasting over 6 months, at
any time
4. Concomitant therapy precluding enrollment:
1. Alemtuzumab, azathioprine, cyclophosphamide, cyclosporine, methotrexate,
mitoxantrone, natalizumab, rituximab, ofatumumab, or ocrelizumab as
immunosuppressive or immune-modulating therapies
2. Only during treatment initiation: Class Ia (e.g. quinidine, procainamide), Class
III anti-arrhythmic drugs (e.g. amiodarone, sotalol) during treatment initiation
5. Have any of the following out-of-range laboratory values:
1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST), or
gamma-glutamyl transferase (GGT) greater than 5 times the upper limit of normal
(ULN) range
2. White blood cell (WBC) count < 3,500/mm3 (< 3.5 x 109/L)
3. Lymphocyte count < 800/mm3 (< 0.8 x 109/L)
4. Serum potassium > ULN
6. Participation in a prior investigational study within 30 days prior to enrollment or
within five half-lives of the investigational study drug or until the expected
pharmacodynamic effect has returned to baseline, whichever is longer
7. Pregnancy statements and contraception requirements
1. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of
a female after conception and until the termination of gestation, confirmed by a
positive hCG laboratory test (> 5 mIU/mL).
2. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, UNLESS they are:
- Women whose partners have been sterilized by vasectomy or other means.
- Using a highly effective method of birth control for the duration of
treatment with siponimod and for at least ten days after stopping treatment
with siponimod. Highly effective method of birth control are such resulting
in a less than 1% per year failure rate when used consistently and
correctly, such as implants, injectables, combined oral contraceptives, and
some intrauterine devices (IUDs); periodic abstinence (e.g. calendar,
ovulation, symptothermal, post-ovulation methods) is not acceptable.
- Total abstinence from female-male intercourse (when this is in line with the
preferred and usual lifestyle of the subject, if accepted by local
regulation)
8. Not able to understand and to comply with treatment instructions and requirements.
|
