Clinical trial NCT04788615: Open Label Randomized Multicenter to Assess Efficacy & Tolerability of Ofatumumab 20mg vs. First Line DMT in RMS
Official title: Open-Label Rater-Blind Randomized Multi-Center Parallel-Arm Active- Comparator Study to Assess the Efficacy and Tolerability of Ofatumumab 20mg SC Monthly vs. First Line DMT - Physician's Choice in the Treatment of Newly Diagnosed RMS
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Multiple Sclerosis
Keywords: Ofatumumab
relapsing multiple sclerosis
relapsing-remitting MS
MS therapy
RMS
Relapsing MS
Glatiramer acetate
IFNβ-1b
IFNβ-1a
peg-IFNβ-1a
Teriflunomide
Dimethyl fumarate
Diroximel fumarate
OMB157
adult
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2021-03-09
Enrollment: 185
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will compare ofatumumab vs. European approved platform first line self-administered disease modifying therapy (DMT) in newly diagnosed MS patients

Detailed description: The study is a randomized (1:1), open-label, rater-blind, multi-center, prospective, parallel-arm, active comparator study which will consist of 15 months treatment period and a 6 months observational safety extension period, for patients who withdraw ofatumumab for any reason, in 186 total patients with early relapsing multiple sclerosis (RMS) RMS patients are patients who are newly diagnosed or have never been on active treatment at the time of study entry with ≤ 5 years from first MS symptoms.

There is a screening period and patients are randomized to either ofatumumab or first line DMT at baseline. Patients will be treated until the end of study (EOS) or for a maximum duration of 15 months. Patients who prematurely discontinue study drug or comparator will have their end of treatment (EOT) visit and assessments at the time of discontinuation. After ofatumumab or the standard of care comparator (DMT) discontinuation, patients may initiate alternative MS therapy according to local standard of care, if clinically indicated.

Patients who for any reason withdraw from ofatumumab during treatment will be invited to participate in the observational extension safety period for 6 months or until patient re-starts MS treatment with a new DMT treatment. During this period, clinical efficacy after ofatumumab withdrawal will be assessed.

Eligibility criteria: 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

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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

Primary outcomes:
measure: Number of participants with no evidence of disease activity (NEDA-3)
timeFrame: Baseline to 15 month
Secondary outcomes:
measure: Number of relapses
timeFrame: Baseline to Month 15
measure: Annual relapse rate
timeFrame: Baseline to Month 15
measure: Percentage of relapse-free patients and proportion of relapse free patients with MRI activity free
timeFrame: Month 3, Month 9 and Month 15
measure: Time to 3 month Confirmed Disability Worsening (CDW) and time to 6-month Confirmed Disability Worsening (CDW)
timeFrame: Baseline to Month 3 and to Month 6
measure: Change in expanded disability status scale (EDSS)
timeFrame: Baseline to Month 15
measure: Percentage of disability-progression free patients
timeFrame: Baseline to Month 15
measure: Number of Gd+ T1 lesions of brain
timeFrame: Baseline to Month 15
measure: The number and percentage of patients with Treatment emergent adverse events (TEAE) or adverse events reports
timeFrame: Baseline to Month 15 and 6 months safety follow-up
measure: Volume of Gd+ T1 lesions of brain
timeFrame: Baseline to Month 15
measure: Number of new/enlarging T2 lesions of brain
timeFrame: Baseline to Month 15
measure: Volume of new enlarging T2 lesions of brain
timeFrame: Baseline to Month 15
measure: Mean time to first relapse
timeFrame: Baseline to Month 15
measure: Percentage of SAEs, and SAEs with hospitalizations
timeFrame: Baseline to Month 15 and 6 months safety follow-up
measure: Percentage of treatment compliance of participants
timeFrame: Baseline to Month 15
measure: Percentage of patient with AEs
timeFrame: Baseline to Month 15 and 6 months safety follow-up
measure: Percentage of withdrawn patients
timeFrame: Baseline to Month 15
measure: Percentage of treatment discontinuation or interruptions
timeFrame: Baseline to Month 15
Other outcomes:
Locations:
city: Bayonne
country: France
facility: Novartis Investigative Site
state: Bayonne Cedex
city: Amiens
country: France
facility: Novartis Investigative Site
city: Bordeaux Cedex
country: France
facility: Novartis Investigative Site
city: Clermont-Ferrand Cedex 1
country: France
facility: Novartis Investigative Site
city: Creteil
country: France
facility: Novartis Investigative Site
city: Gonesse
country: France
facility: Novartis Investigative Site
city: Grenoble
country: France
facility: Novartis Investigative Site
city: Montpellier
country: France
facility: Novartis Investigative Site
city: Nice
country: France
facility: Novartis Investigative Site
city: Nimes
country: France
facility: Novartis Investigative Site
city: Poissy
country: France
facility: Novartis Investigative Site
city: Rennes Cedex
country: France
facility: Novartis Investigative Site
city: Strasbourg
country: France
facility: Novartis Investigative Site
city: Frankfurt am Main
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Bayreuth
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Bielefeld
country: Germany
facility: Novartis Investigative Site
city: Dortmund
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Siegen
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Westerstede Oldenburg
country: Germany
facility: Novartis Investigative Site
city: Montichiari
country: Italy
facility: Novartis Investigative Site
state: BS
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Orbassano
country: Italy
facility: Novartis Investigative Site
state: TO
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Malaga
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Salt
country: Spain
facility: Novartis Investigative Site
state: Cataluna
city: Santiago De Compostela
country: Spain
facility: Novartis Investigative Site
state: Galicia
city: El Palmar
country: Spain
facility: Novartis Investigative Site
state: Murcia
city: Baracaldo
country: Spain
facility: Novartis Investigative Site
state: Vizcaya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: