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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04788615

Collaborator

(none)

236

Enrollment

Locations

Arms

35.7

Anticipated Duration (Months)

5.5

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: Ofatumumab Drug: First line DMT	Phase 3

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 in 236 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 ≤ 3 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

236 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Masking Description:

The independent EDSS (Expanded disability status scale) rater will be blind to the identity of the treatment throughout the study period. Patient MRI scans read by an independent central MRI reading center.

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jul 23, 2021

Anticipated Primary Completion Date :

Apr 15, 2024

Anticipated Study Completion Date :

Jul 15, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ofatumumab Oftatumumab 20mg auto injector syringes for subcutaneous injection on Day 1, Week 1 and 2, followed by subsequent monthly dosing, starting at Month 1.	Drug: Ofatumumab 20mg Subcutaneous injection Other Names: OMB157
Active Comparator: First line DMT Glatiramer acetate minimum dose 20mg or maximum dose 40mg twice a day or three times a week or Interferon minimum dose 22µg or maximum dose of 0.25mg 3 times a week or once a week or Every second week depending on preparation or Peg-Interferon beta-1a minimum dose of 63µg or maximum dose of 125µg every 2 weeks (14 days) or Teriflunomide 14 mg once a day or Dimethyl fumarate minimum dose of 120mg or maximum dose of 240mg twice a day	Drug: First line DMT any one of these based on availability at country given as First line DMT Glatiramer acetate 20mg or 40mg or Interferon 22µg or 0.25mg or Peg-Interferon beta-1a 63µg or 125µg or Teriflunomide 14mg or Dimethyl fumarate 120mg or 240mg Other Names: Glatiramer acetate or Interferon or Peg-Interferon beta-1a or Teriflunomide or Dimethyl fumarate

Arm

Intervention/Treatment

Experimental: ofatumumab

Oftatumumab 20mg auto injector syringes for subcutaneous injection on Day 1, Week 1 and 2, followed by subsequent monthly dosing, starting at Month 1.

Drug: Ofatumumab

20mg Subcutaneous injection

Other Names:

OMB157

Active Comparator: First line DMT

Glatiramer acetate minimum dose 20mg or maximum dose 40mg twice a day or three times a week or Interferon minimum dose 22µg or maximum dose of 0.25mg 3 times a week or once a week or Every second week depending on preparation or Peg-Interferon beta-1a minimum dose of 63µg or maximum dose of 125µg every 2 weeks (14 days) or Teriflunomide 14 mg once a day or Dimethyl fumarate minimum dose of 120mg or maximum dose of 240mg twice a day

Drug: First line DMT

any one of these based on availability at country given as First line DMT Glatiramer acetate 20mg or 40mg or Interferon 22µg or 0.25mg or Peg-Interferon beta-1a 63µg or 125µg or Teriflunomide 14mg or Dimethyl fumarate 120mg or 240mg

Other Names:

Glatiramer acetate or Interferon or Peg-Interferon beta-1a or Teriflunomide or Dimethyl fumarate

Outcome Measures

Primary Outcome Measures

Number of participants with no evidence of disease activity (NEDA-3) [Baseline to 15 month]
NEDA-3 (yes/no) is defined as: Absence of confirmed clinical relapse Absence of new MRI activity (Gd+ T1 lesion or new/enlarged T2 lesion) with MRI re-baselined at Month 3 Absence of 3-month confirmed disability worsening

Secondary Outcome Measures

Number of relapses [Baseline to 15 month]
Number of relapses will be summarized descriptively
Annual relapse rate [Baseline 15months]
Annual relapse rate will be analyzed by treatment group using negative binomial regression model with log-link and patient's time in study will be used as an offset.
Percentage of relapse-free patients and proportion of relapse free patients with MRI activity free [Baseline, Month 3 9 and 15]
Proportion of relapse-free patients and proportion of relapse-free patients with MRI activity free at Month 3, 9 and 15 will be summarized descriptively at each timepoint.
Time to 3 month Confirmed Disability Worsening (CDW) and time to 6-month Confirmed Disability Worsening (CDW) [Baseline, Month 3 and 6]
Time to 3 month Confirmed Disability Worsening (CDW) and time to 6-month CDW will be assessed by EDSS (Expanded disability status scale) score
Change in expanded disability status scale (EDSS) from baseline to end of study [Baseline, Month 15]
Change in expanded disability status scale (EDSS) from baseline to end of study will be summarized descriptively based on the expanded disability status scale (EDSS) score
Percentage of disability-progression free patients at end of study [Baseline, 15 month]
Proportion of disability-progression free patients at end of study will be summarized descriptively
Number of Gd+ T1 lesions of brain [Baseline to 15 month]
Number of Gd+ T1 lesions of brain will be summarized descriptively.
The number and percentage of patients with Treatment emergent adverse events (TEAE) or adverse events reports until safety follow-up [Base line to 15 month and 6 months safety follow-up]
Adverse will be collected at each patients visit including any clinically significant safety assessments determined to be an adverse event by the investigator
Volume of Gd+ T1 lesions of brain [Baseline to 15 month]
Volume of Gd+ T1 lesions of brain will be summarized descriptively.
Number of new/enlarging T2 lesions of brain [Baseline to 15 month]
Number of new/enlarging T2 lesions of brain will be summarized descriptively.
Volume of new enlarging T2 lesions of brain [Baseline to 15 month]
Volume of new enlarging T2 lesions of brain will be summarized descriptively.
Mean time to first relapse [Baseline to 15 month]
Mean time to first relapse will be summarized descriptively
Number of SAEs, and SAEs with hospitalizations [Baseline to 15 month]
Percentage of SAEs, and SAEs with hospitalizations between ofatumumab 20 mg s.c. and first line self-administered DMTs
Percentage of treatment compliance of participants [Baseline to 15 month]
Treatment compliance will be assessed by review of participant diary entries and counts of treatment (dispensed and returned)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 45 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria

Written informed consent obtained before any assessment
Male/female patients, 18 through 45 (inclusive) years of age.
Diagnosis of MS according to the 2017 revised McDonald criteria (Thompson et al 2018).
Relapsing MS: relapsing-course (RMS), as defined by Lublin et al 2014.
Treatment Naïve patients, ≤ 3 years since first MS symptom.
EDSS score 0-3 (inclusive).
Patient must be suitable to be treated with one of first line self-administered DMT-physician's choice (glatiramer acetate, IFNs, teriflunomide, DMF according to EMA SmPC) or ofatumumab depending on randomization and physician's choice
At least 1 relapse or 1 Gd+ enhanced lesion on T1in the year prior to Screening.
Able to obtain MRI assessment.
Neurologically stable within 1 month prior to first study drug administration Exclusion Criteria
Diseases other than multiple sclerosis responsible for the clinical or MRI presentation
Progressive MS phenotypes: Patients with primary progressive MS (Polman et al 2011) or SPMS (Lublin et al 2014).
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
Relapse between Screening and Baseline visits
Pregnancy or breastfeeding
Patients suspected of not being able or willing to cooperate or comply with study protocol requirements in the opinion of the Investigator
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.

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)
Patients with a chronic 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.
Patients with neurological findings consistent with Progressive Multifocal Leukoencephalopathy (PML), or confirmed PML
Patients at risk of developing or having reactivation of hepatitis. Positive results at Screening for serological markers for hepatitis (H) A, B, C, and E indicating acute or chronic infection: - anti-HA Immunoglobulin M (IgM)

HBs Ag and/or anti-HBc IgM and/or HB virus deoxyribonucleic acid (DNA)
anti-HBs negative and Anti-HBc positive
anti-HC IgG (if positive IgG, HCV-RNA PCR will be performed and if negative, patient can be enrolled)
anti-HE IgM (if positive IgG and/or IgM, perform HE-RNA PCR 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 patient.

Patients at risk of developing or having reactivation of syphilis or tuberculosis (e.g.

patients with known exposure to, or history of syphilis, or active or latent tuberculosis, even if previously treated). Testing for syphilis, HIV and tuberculosis will be done at Screening according to local clinical practice.

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Bayonne	Bayonne Cedex	France	64109
2	Novartis Investigative Site	Nantes	Cedex 1	France	44093
3	Novartis Investigative Site	Amiens		France	80054
4	Novartis Investigative Site	Bordeaux Cedex		France	33076
5	Novartis Investigative Site	Clermont-Ferrand Cedex 1		France	63003
6	Novartis Investigative Site	Creteil		France	94010
7	Novartis Investigative Site	Gonesse		France	95500
8	Novartis Investigative Site	Grenoble		France	38042
9	Novartis Investigative Site	Lille Cedex		France	59037
10	Novartis Investigative Site	Montpellier		France	34295
11	Novartis Investigative Site	Nice Cedex		France	06202
12	Novartis Investigative Site	Nimes		France	30029
13	Novartis Investigative Site	Poissy		France	78303
14	Novartis Investigative Site	Rennes Cedex		France	35033
15	Novartis Investigative Site	Strasbourg		France	67098
16	Novartis Investigative Site	Suresnes		France	92150
17	Novartis Investigative Site	Bayreuth		Germany	95445
18	Novartis Investigative Site	Berlin		Germany	12101
19	Novartis Investigative Site	Bielefeld		Germany	33647
20	Novartis Investigative Site	Heidelberg		Germany	69120
21	Novartis Investigative Site	Kassel		Germany	34121
22	Novartis Investigative Site	Siegen		Germany	57076
23	Novartis Investigative Site	Ulm		Germany	89073
24	Novartis Investigative Site	Ulm		Germany	89081
25	Novartis Investigative Site	Westerstede/Oldenburg		Germany	26655
26	Novartis Investigative Site	Montichiari	BS	Italy	25018
27	Novartis Investigative Site	Milano	MI	Italy	20132
28	Novartis Investigative Site	Roma	RM	Italy	00133
29	Novartis Investigative Site	Roma	RM	Italy	00189
30	Novartis Investigative Site	Malaga	Andalucia	Spain	29010
31	Novartis Investigative Site	Sevilla	Andalucia	Spain	41017
32	Novartis Investigative Site	Salt	Cataluna	Spain	17190
33	Novartis Investigative Site	Santiago de Compostela	Galicia	Spain	15706
34	Novartis Investigative Site	El Palmar	Murcia	Spain	30120
35	Novartis Investigative Site	Baracaldo	Vizcaya	Spain	48903
36	Novartis Investigative Site	Barcelona		Spain	08035
37	Novartis Investigative Site	Madrid		Spain	28009
38	Novartis Investigative Site	Madrid		Spain	28034
39	Novartis Investigative Site	Madrid		Spain	28040
40	Novartis Investigative Site	Valencia		Spain	46026
41	Novartis Investigative Site	Zaragoza		Spain	50009
42	Novartis Investigative Site	Exeter		United Kingdom	EX2 5DW
43	Novartis Investigative Site	Glasgow		United Kingdom	G51 4TF