Open Label Randomized Multicenter to Assess Efficacy & Tolerability of Ofatumumab 20mg vs. First Line DMT in RMS

Inclusion Criteria

1. Written informed consent obtained before any assessment

2. Male/female patients, 18 through 55 (inclusive) years of age.

3. Diagnosis of MS according to the 2017 revised McDonald criteria (Thompson et al
2018).

4. Relapsing MS: relapsing-course (RMS), as defined by Lublin et al 2014.

5. Treatment Naïve patients, ≤ 5 years since first MS symptom.

6. EDSS score 0-4.0 (inclusive).

7. Patient must be suitable to be treated with one of first line self-administered
DMT-physician's choice (glatiramer acetate, IFNs, teriflunomide, DMF, diroximel
fumarate according to EMA SmPC) or ofatumumab depending on randomization and
physician's choice

8. At least 1 relapse or 1 Gd+ enhanced lesion on T1 in 1 year prior to Screening.

9. Able to obtain MRI assessment.

10. Neurologically stable within 1 month prior to first study drug administration
Exclusion Criteria

1. Diseases other than multiple sclerosis responsible for the clinical or MRI
presentation

2. Progressive MS phenotypes: Patients with primary progressive MS (Polman et al 2011)
or SPMS (Lublin et al 2014).

3. 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

4. Relapse between Screening and Baseline visits

5. Pregnancy or breastfeeding

6. Patients suspected of not being able or willing to cooperate or comply with study
protocol requirements in the opinion of the Investigator

7. 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.

Highly effective methods of contraception include:

- 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.

- 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.

- 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.

(Vasectomized partner is a highly effective birth control method provided that
partner is the sole sexual partner of the WOCBP trial participant and that the
vasectomized partner has received medical assessment of the surgical success.) - Use
of combined, estrogen and progesterone containing (oral, intravaginal, transdermal),
hormonal methods of contraception or use of progesterone-only (oral, injectable,
implantable) hormonal methods of contraception or placement of an intrauterine
device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception
that have comparable efficacy (failure rate <1%), for example hormone vaginal ring
or transdermal hormone contraception. In case of use of oral contraception women
should have been stable on the same pill for a minimum of 3 months before taking
study treatment. Women are considered post-menopausal if they have had 12 months of
natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age
appropriate history of vasomotor symptoms). Women are considered not of childbearing
potential if they are post-menopausal or have had surgical bilateral oophorectomy
(with or without hysterectomy), total hysterectomy or bilateral tubal ligation at
least six weeks ago. In the case of oophorectomy alone, only when the reproductive
status of the woman has been confirmed by follow up hormone level assessment is she
considered not of childbearing potential. If local regulations deviate from the
contraception methods listed above to prevent pregnancy, local regulations apply and
will be described in the ICF.

8. Patients with an active chronic disease (or stable but treated with immune therapy)
of the immune system other than MS (e.g. rheumatoid arthritis, scleroderma,
Sjögren's syndrome, Crohn's disease, ulcerative colitis, etc.) or with
immunodeficiency syndrome (hereditary immune deficiency, drug-induced immune
deficiency)

9. Patients with an active infection (bacterial, fungal, or viral like hepatitis, HIV
or COVID), until the infection is resolved. Where local regulation requires it,
Sars-Cov-19 must be ruled out by the PCR test.

10. Patients with neurological findings consistent with Progressive Multifocal
Leukoencephalopathy (PML), or confirmed PML

11. Positive results at Screening for serological markers for hepatitis (H) B and C
indicating acute or chronic infection:

- Hepatitis B virus (HBV) screening should be performed before initiation of
treatment.

At a minimum, screening should include hepatitis B surface antigen (HBsAg) and
hepatitis B core antibody (HBcAb) testing. These can be complemented with other
appropriate markers as per local guidelines. Patients with positive hepatitis B
serology (either HBsAg or HBcAb) should consult a liver disease expert before the
start of treatment and should be monitored and managed following local medical
standards to prevent hepatitis B reactivation.

- Hepatitis C risk must be ruled out via anti-HC IgG (if positive IgG, HCV-RNA
PCR will be performed and if negative, patient can be enrolled) NOTE: If the
Investigator suspects false positive hepatitis serology results such as an
antibody pattern indicating acute hepatitis infection but no corresponding
elevated liver enzymes and no signs or symptoms of liver disease, an infectious
disease expert may be consulted. In the case the patient has a record of
vaccination including HB, and there is no evidence of acute or chronic
hepatitis infection (confirmed by an infectious disease expert), the
Investigator must document (in source data and as a comment in the electronic
Case Report Form (eCRF) that the serology results are considered false positive
and may then enroll the subject.

12. Have received any live or live-attenuated vaccines within 4 weeks prior to first
study drug administration

13. Any other disease or condition that could interfere with participation in the study
according to the study protocol, or with the ability of the patients to cooperate or
comply with the study procedures

14. Any of the following conditions or treatments that may impact the safety of the
patient:

- History of, or current, significant cardiac disease including cardiac failure
(NYHA functional class II-IV), myocardial infarction (within 6 months prior to
screening), unstable angina (within 6 months prior to screening), transient
ischemic attack (within 6 months prior to screening), stroke, cardiac
arrhythmias requiring treatment or uncontrolled arterial hypertension

- Concomitant clinically significant cardiac arrhythmias, e.g. sustained
ventricular tachycardia and clinically significant second or third degree AV
block without a pacemaker on screening electrocardiogram (ECG)

- History of or active severe respiratory disease, including Chronic Obstructive
Pulmonary Disease, interstitial lung disease or pulmonary fibrosis

- Patients with asthma requiring regular treatment with oral steroids

- Severe hepatic impairment (Child-Pugh class C) or any chronic liver or biliary
disease

- Patients with severe renal impairment (glomerular filtration rate < 30
ml/min/1.73 m2)

- Any medically unstable condition as determined by the Investigator

15. Any of the following abnormal laboratory values prior to first study drug
administration:

- Total 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

- 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)

16. Patients with severe hypoproteinemia e.g. in nephrotic syndrome

17. 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.

18. History of hypersensitivity to the study drug or any of the excipients or to drugs
of similar chemical classes