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Diseases other than multiple sclerosis responsible for the clinical or MRI presentation
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Progressive MS phenotypes: Patients with primary progressive MS (Polman et al 2011) or SPMS (Lublin et al 2014)
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Use of other experimental or investigational drugs at the time of enrollment (Screening) or within the prior 30 days, or 5 elimination half-lives, or until the expected pharmacodynamics effect has returned to baseline, whichever is longer
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Relapse between Screening and Baseline visits
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Pregnancy or breastfeeding
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Patients suspected of not being able or willing to cooperate or comply with study protocol requirements in the opinion of the Investigator
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Women of childbearing potential defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception (methods that result in less than 1% pregnancy rates) while receiving ofatumumab and for 6 months after the last administration. The requirements for contraception for the comparators should also be taken into consideration according to their SmPC
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Highly effective methods of contraception include
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Total abstinence (when this is in line with the preferred and usual lifestyle of the participant). Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception
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Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
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Male sterilization (at least 6 months prior to screening). For female participants on the study, the vasectomized male partner should be the sole partner for that participant
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(Vasectomized partner is a highly effective birth control method provided that partner
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is the sole sexual partner of the WOCBP trial participant and that the vasectomized
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partner has received medical assessment of the surgical success.)
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Use of combined, estrogen and progesterone containing (oral, intravaginal
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transdermal), hormonal methods of contraception or use of progesterone-only
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(oral, injectable, implantable) hormonal methods of contraception or placement of
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an intrauterine device (IUD) or intrauterine system (IUS), or other forms of
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hormonal contraception that have comparable efficacy (failure rate <1%), for
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example hormone vaginal ring or transdermal hormone contraception. In case of use
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of oral contraception women should have been stable on the same pill for a
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minimum of 3 months before taking study treatment. Women are considered
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post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea
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with an appropriate clinical profile (e.g. age appropriate history of vasomotor
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symptoms). Women are considered not of childbearing potential if they are
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post-menopausal or have had surgical bilateral oophorectomy (with or without
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hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks
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ago. In the case of oophorectomy alone, only when the reproductive status of the
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woman has been confirmed by follow up hormone level assessment is she considered
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not of childbearing potential. If local regulations deviate from the
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contraception methods listed above to prevent pregnancy, local regulations apply
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and will be described in the ICF
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Patients with an active chronic disease (or stable but treated with immune therapy) of
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the immune system other than MS (e.g. rheumatoid arthritis, scleroderma, Sjögren's
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syndrome, Crohn's disease, ulcerative colitis, etc.) or with immunodeficiency syndrome
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(hereditary immune deficiency, drug-induced immune deficiency)
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Patients with a chronic active infection (bacterial, fungal, or viral like hepatitis
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HIV or COVID), until the infection is resolved. Where local regulation requires it
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Sars-Cov-19 must be ruled out by the PCR test
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Patients with neurological findings consistent with Progressive Multifocal
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Leukoencephalopathy (PML), or confirmed PML
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Patients at risk of developing or having reactivation of hepatitis. Positive results
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at Screening for serological markers for hepatitis (H) A, B, C, and E indicating acute
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or chronic infection: - anti-HA Immunoglobulin M (IgM)
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HBs Ag and/or anti-HBc IgM and/or HB virus deoxyribonucleic acid (DNA)
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anti-HBs negative and Anti-HBc positive
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anti-HC IgG (if positive IgG, HCV-RNA PCR will be performed and if negative
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patient can be enrolled)
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anti-HE IgM (if positive IgG and/or IgM, perform HE-RNA PCR and if negative
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patient can be enrolled) NOTE: If the Investigator suspects false positive
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hepatitis serology results such as an antibody pattern indicating acute hepatitis
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infection but no corresponding elevated liver enzymes and no signs or symptoms of
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liver disease, an infectious disease expert may be consulted. In the case the
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patient has a record of vaccination including HB, and there is no evidence of
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acute or chronic hepatitis infection (confirmed by an infectious disease expert)
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the Investigator must document (in source data and as a comment in the electronic
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Case Report Form (eCRF)) that the serology results are considered false positive
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and may then enroll the patient
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Patients at risk of developing or having reactivation of syphilis or tuberculosis
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(e.g
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patients with known exposure to, or history of syphilis, or active or latent
|
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tuberculosis, even if previously treated). Testing for syphilis, HIV and tuberculosis
|
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will be done at Screening according to local clinical practice
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Have received any live or live-attenuated vaccines within 4 weeks prior to first study
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drug administration
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Any other disease or condition that could interfere with participation in the study
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according to the study protocol, or with the ability of the patients to cooperate or
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comply with the study procedures
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Any of the following conditions or treatments that may impact the safety of the
|
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patient
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History of, or current, significant cardiac disease including cardiac failure (NYHA
|
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|
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functional class II-IV), myocardial infarction (within 6 months prior to screening)
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unstable angina (within 6 months prior to screening), transient ischemic attack
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(within 6 months prior to screening), stroke, cardiac arrhythmias requiring treatment
|
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or uncontrolled arterial hypertension
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Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular
|
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tachycardia and clinically significant second or third degree AV block without a
|
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pacemaker on screening electrocardiogram (ECG)
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|
|
History of or active severe respiratory disease, including Chronic Obstructive
|
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Pulmonary Disease, interstitial lung disease or pulmonary fibrosis
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Patients with asthma requiring regular treatment with oral steroids
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Severe hepatic impairment (Child-Pugh class C) or any chronic liver or biliary
|
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|
|
|
disease
|
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Patients with severe renal impairment (glomerular filtration rate < 30 ml/min/1.73
|
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|
|
m2)
|
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|
|
Any medically unstable condition as determined by the Investigator
|
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|
|
Any of the following abnormal laboratory values as confirmed by the central laboratory
|
|
|
|
|
|
prior to first study drug administration: - Total or direct bilirubin greater than 3
|
|
|
|
|
|
times upper limit of normal (ULN) range, unless in the context of Gilbert's syndrome
|
|
|
|
|
|
Alkaline phosphatase (ALP) greater than 5 times the ULN range
|
|
|
|
|
|
Alanine aminotransferase (ALT) between 1.5 and 5 times the ULN range and an
|
|
|
|
|
|
active infection with hepatotropic viruses (Herpes simplex virus, Cytomegalovirus
|
|
|
|
|
|
and Epstein-Barr Virus)
|
|
|
|
|
|
Serum IgG < 500mg/dL (according to central laboratory range)
|
|
|
|
|
|
Any other clinically significant laboratory assessment as determined by the
|
|
|
|
|
|
Investigator (e.g. significant anemia, neutropenia, thrombocytopenia, signs of
|
|
|
|
|
|
impaired bone marrow function)
|
|
|
|
|
|
Patients with severe hypoproteinemia e.g. in nephrotic syndrome
|
|
|
|
|
|
Patients with any of the following neurologic/psychiatric disorders prior to first
|
|
|
|
|
|
study drug administration
|
|
|
|
|
|
Score "yes" on item 4 or item 5 of the Suicidal Ideation section of the Columbia-
|
|
|
|
|
|
Suicide Severity Rating Scale (CSSRS) if this ideation occurred in the past 6
|
|
|
|
|
|
months OR
|
|
|
|
|
|
yes" on any item of the Suicidal Behavior section, except for the "Non-Suicidal
|
|
|
|
|
|
Self- Injurious Behavior" (item also included in the Suicidal Behavior section)
|
|
|
|
|
|
if this behavior occurred in the past 2 years
|
|
|
|
|
|
History of hypersensitivity to the study drug or any of the excipients or to drugs of
|
|
|
|
|
|
similar chemical classes
|
|
|
|