This is a long-term study of the safety, efficacy and patient satisfaction of the drug rituximab in comparison with other immunomodulatory treatments for multiple sclerosis. The study will use a national registry for both retrospective and prospective data retrieval.

• Register: EUCTR
• Last refreshed on: 4 December 2018
• Main ID: EUCTR2016-003587-39-SE
• Date of registration: 23/03/2017
• Prospective Registration: Yes
• Primary sponsor: Karolinska Institutet
• Public title: This is a long-term study of the safety, efficacy and patient satisfaction of the drug rituximab in comparison with other immunomodulatory treatments for multiple sclerosis. The study will use a national registry for both retrospective and prospective data retrieval.
• Scientific title: COMBAT-MS (COMparison Between All immunoTherapies for Multiple Sclerosis) A prospective long-term cohort study of safety, efficacy and patient’s satisfaction of MS disease modulatory treatments in relapsing-remitting multiple sclerosis - COMparison Between All immunoTherapies for Multiple Sclerosis (COMBAT-MS)
• Date of first enrolment: 22/05/2017
• Target sample size: 3700
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003587-39
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: yes; Other trial design description: Prospective cohort trial; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 5
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): yes

Countries of recruitment

Sweden

Contacts

• Name: Dept of Clinial Neuroscience
• Affiliation: Karoloinska Institutet

• Name: Dept of Clinial Neuroscience
• Affiliation: Karoloinska Institutet

Key inclusion & exclusion criteria

Inclusion criteria:
The study population consists of all patients with CIS/RRMS diagnosed with the 2010 revised McDonald criteria who;
• Initiate a first MS DMT (treatment naïve), or
Initiate a second ever DMT, of a different drug class than the first, regardless of time between drugs or reason for discontinuation(“switchers”) from 1st Jan 2011 to 30st June 2018, and
• Are followed at any of the University clinics of Sweden, and
• Consent to participation in COMBAT-MS core, and
• Are expected to be capable to follow study assessments and have decision-making capacity, e.g. lucid and oriented x 4 as judged by the investigator; and
• Are aged =18 years and = 75 years at the day of signing the informed consent for inclusion into the prospective study (i.e. no age limit for retrospective data), and
In case of fertile women, have been given information on potential DMT-related teratogenic effects and what type of contraception is considered safe according to respective SmPC.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 3700
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 100

Exclusion criteria:
Patients who at inclusion have the following characteristics are excluded from study participation;
• progressive forms of MS at start of the inclusion therapy (first bullet above).
• other neurological or other conditions that may interfere with follow study assessments or decision-making capacity.
• subjects with conditions listed as contraindications to the use of medicinal products used in the trial, e.g. gadolinium used for MRI scans.
ongoing participation in other trials with blinded study medication or that interfere with the study protocol.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Relapsing-remitting multiple sclerosis (RRMS) that has started on their first or second immunomodulatory drug at the earliest 2011-01-01 and at the latest 2018-06-30. The clinical course and response to treatment is thereafter followed until 2021-06-30

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Trade Name: Mabthera
Pharmaceutical Form: Infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 500-1000

Trade Name: Tysabri
Pharmaceutical Form: Infusion
INN or Proposed INN: NATALIZUMAB
CAS Number: 189261-10-7
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 300-

Trade Name: Tecfidera
Pharmaceutical Form: Capsule
INN or Proposed INN: DIMETHYL FUMARATE
CAS Number: 624-49-7
Other descriptive name: DIMETHYL FUMARATE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 240-

Trade Name: Gilenya
Pharmaceutical Form: Tablet
INN or Proposed INN: FINGOLIMOD
CAS Number: 162359-55-9
Other descriptive name: FINGOLIMOD
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-

Trade Name: Copaxone
Pharmaceutical Form: Injection
INN or Proposed INN: GLATIRAMER ACETATE
CAS Number: 147245-92-9
Other descriptive name: GLATIRAMER ACETATE
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 20-40

Trade Name: Betaferon
Pharmaceutical Form: Injection
INN or Proposed INN: INTERFERON BETA-1B
CAS Number: 145155-23-3
Other descriptive name: INTERFERON BETA-1B
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.25-

Trade Name: Extavia
Pharmaceutical Form: Injection
INN or Proposed INN: INTERFERON BETA-1B
CAS Number: 145155-23-3
Other descriptive name: INTERFERON BETA-1B
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.25-

Trade Name: Avonex
Pharmaceutical Form: Injection
INN or Proposed INN: INTERFERON BETA-1A
CAS Number: 220581-49-7
Other descriptive name: INTERFERON BETA-1A
Concentration unit: µg microgram(s)
Concentration type: equal
Concentration number: 30-

Trade Name: Rebif
Pharmaceutical Form: Injection
INN or Proposed INN: INTERFERON BETA-1A
CAS Number: 220581-49-7
Other descriptive nam

Primary Outcome(s)

Secondary Objective: The secondary objectives of the study are
• To compare the long-term safety of RTX with the most commonly used escalation agents, DMF, NTZ and FGL, in RRMS patients who have experienced disease activity on first-line DMTs
• To compare the long-term safety of treatment with RTX with IFN, GA, NTZ, FGL and DMF in treatment-naïve RRMS patients
• To compare drug survival, as a compound measure of effectiveness, side-effects and patient satisfaction, between RTX and IFN, GA, NTZ, FGL, DMF and NTZ
• To compare patient satisfaction, fatigue and health related quality of life between treatment with RTX and IFN, GA, NTZ, FGL, DMF and NTZ
• To study the occurrence of anti-drug antibodies (ADA) against RTX and their effect on B-lymphocyte levels and treatment efficacy.
To compare the effectiveness on preventing MRI CELs between treatment with RTX and IFN, GA, NTZ, FGL, DMF and NTZ in first-line and second-line settings, respectively.

Timepoint(s) of evaluation of this end point: The primary endpoints will be checked for data validity and demographics on a semiyearly basis.
Effectiveness of therapy will be assessed primarily at an evaluation point 3 years after treatment initiation.
Final data analysis including long-term effectiveness will be done after study closure by 2021-06-30

Main Objective: The two co-primary objectives of this study are
1. To compare the long-term effectiveness for preventing disability and reduced QoL of RTX with the most commonly used escalation agents, DMF, NTZ and FGL, in RRMS patients who have experienced disease activity on first-line DMTs
2. To compare the long-term effectiveness for preventing disability and reduced QoL of RTX with IFN, GA, NTZ, FGL and DMF in treatment-naïve RRMS patients

Primary end point(s): The primary endpoints in this study are:
• Proportion of patients with baseline EDSS =2.5 progressing to 12 months confirmed EDSS =3 over 3 years of follow up.
• Proportion of patients with baseline EDSS =2.5 experiencing 12 months confirmed EDSS change +1 point over 3 years of follow up.
• Change in MSIS-29 over 3 years of follow up (change from baseline; mean value ±SD).

End points will be tested in -First line RTX vs DMF/GA/IFN/NTZ/FGL and Second line/escalation (switching from DMF/GA/IFN) RTX vs NTZ/FGL/DMF.

Secondary Outcome(s)

Secondary end point(s): Secondary analyses comprise comparisons between the different treatment regimens concerning:
• Rate of malignancy, cardiovascular disease, serious infections and all-cause mortality in populations on therapy and ever treated, respectively. Data on safety outcomes will be obtained through linkage to the national Cancer, Patient, Prescribed Drug, and Causes of Death registers.
• Annual relapse rate.
• Mean number of CELs on yearly MRI.
• Drug survival and reason to terminate treatment.
• Yearly increase in mean and median EDSS.
• Yearly proportion of patients with at least 1 step increase in EDSS.
• Evaluation of frequency, titre, kinetics and clinical relevance of anti-RTX ADA.
• Yearly proportion of patients with No Evidence of Disease Activity (NEDA) -2 (free of exacerbations, new/enlarged T2-lesions and occurrence of CEL) as well as NEDA-3 (NEDA-2 plus no worsening of EDSS from baseline).
• Mean levels of NFL in serum.
• Yearly brain atrophy rate measured as brain parenchymal fraction (BPF) for different DMTs in a sub-population of patients and in relation to baseline values.
• Estimation of total societal costs per year after initiating treatment.
• Evaluation of health related QoL, fatigue and patient satisfaction during the treatment.
• Evaluation of work ability.

Timepoint(s) of evaluation of this end point: The secondary endpoints will be checked for data validity and demographics on a semiyearly basis.
Effectiveness of therapy will be assessed primarily at an evaluation point 3 years after treatment initiation.
Final data analysis including long-term effectiveness will be done after study closure by 2021-06-30

Secondary ID(s)

COMBAT-MS

Source(s) of Monetary Support

Dept of Clinical Neuroscience, Karolinska Instituet