COMparison Between All immunoTherapies for Multiple Sclerosis. (COMBAT-MS)

COMparison Between All immunoTherapies for Multiple Sclerosis. An Observational Long-term Prospective Cohort Study of Safety, Efficacy and Patient's Satisfaction of MS Disease Modulatory Treatments in Relapsing-remitting Multiple Sclerosis

The overarching goal of this study is to determine whether rituximab (RTX) offers effectiveness and safety advantages over other commonly used approved Disease-Modifying Drugs (DMT) in the largest real-world population-based structured prospective follow-up cohort of Relapsing-Remitting Multiple Sclerosis (RRMS) patients. The study will include both treatment naïve patients starting their first DMT and patients switching from a previous first line DMT (escalation/second-line).

Study Overview

• Status: Completed
• Conditions: Relapsing-remitting Multiple Sclerosis
• Intervention / Treatment: Drug: Rituximab

Detailed Description

This is a prospective non-intervention observational prospective cohort study assessing the long-term safety and efficacy of RTX treatment in MS compared with other common MS DMTs regarding both clinical and radiological parameters in a real-life population of patients with MS.

A number of parameters will be assessed annually. These include baseline demographics, previous drug history and reasons for discontinuation, disability status (expanded disability status scale), relapses, safety and adverse events (AE), contrast enhancing T1 and newly appearing T2 lesions on magnetic resonance imaging, as well as a panel of patient reported outcome measures: Symbol Digit Modalities Test (SDMT); MS impact scale-29 (MSIS-29) Fatigue Scale for Motor and Cognitive Functions (FSMC), EuroQol-5 Dimensions (EQ-5D), the MS check scale and Treatment Satisfaction Questionnaire 9 (TSQM-9).

Retrospective data entered in medical charts and the Swedish MS registry will be included together with prospective annual structured follow up from inclusion into the study for a minimum of three years (three to nine years).

In a substudy - Covid Enhancement study - analyses will be performed regarding the effect of COVID-19 on people with MS as compared to non-MS individuals and also if there is any indication that a particular DMD is associated with a risk to contract a more severe COVID-19. The analyses will primarily be performed in official health care databases.

• Study Type: Observational
• Enrollment (Actual): 3526

Contacts and Locations

Study Locations

• Sweden
  • Stockholm, Sweden
    • Fredrik Piehl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

All patients initiated at their first or second disease-modifying drug between January 1 2011 and June 30 2018 will be included in the trial. Up to present date, study-related data will be retrospectively controlled via individual study of patient records. Patients will be identified through the Swedish MS registry. Inclusion into the COMBAT-MS core study will be subject to written informed consent. Given the non-intervention design of the study and very limited study-specific procedures outside of clinical practise, we expect participation rates to be very high. Based on preliminary calculations from the MS registry the projected number of participants will be 3700 patients, out of which at least 1000 are treated with rituximab first or second-line.

Description

INCLUSION CRITERIA:

The study population consists of all patients with Clinically Isolated Syndrome (CIS) or RRMS 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.

EXCLUSION CRITERIA:

- Patients with progressive forms of MS at start of therapy are not eligible

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Other

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Confirmed Disease Progression in Patients With Expanded Disability Status Scale (EDSS) <2.5 at Baseline	Proportion of patients with baseline EDSS <2.5 progressing to 12 months confirmed EDSS ≥3 among those over 3 years of follow up. Expanded Disability Status Scale (EDSS) scale range: Minimum score: 0 (normal neurological examination). Maximum score: 10 (death due to multiple sclerosis) Lower scores indicate better outcomes (less disability). Higher scores indicate worse outcomes (more disability).	3 years
Confirmed Disease Progression in Patients With EDSS ≥2.5 at Baseline	- Proportion of patients with baseline EDSS ≥2.5 experiencing 12 months confirmed EDSS increase of 1 point among those over 3 years of follow up Expanded Disability Status Scale (EDSS) scale range: Minimum score: 0 (normal neurological examination). Maximum score: 10 (death due to multiple sclerosis) Lower scores indicate better outcomes (less disability). Higher scores indicate worse outcomes (more disability).	3 years
Disease-related Impact on Daily Life, Physical	- Change in the MSIS-29 physical subscale (change from baseline; mean value) The Multiple Sclerosis Impact Scale (MSIS-29) physical subscale measures patient-reported physical impact of multiple sclerosis. Scale range: Minimum score: 1 (least impact). Maximum score: 5 (highest impact). Lower scores indicate better outcomes. Higher scores indicate worse outcomes.	3 years
Disease-related Impact on Daily Life, Psychological	- Change in the MSIS-29 psychological subscale (change from baseline; mean value) The Multiple Sclerosis Impact Scale (MSIS-29) psychological subscale measures patient-reported psychological impact of multiple sclerosis. Scale range: Minimum score: 1 (least impact). Maximum score: 5 (highest impact). Lower scores indicate better outcomes. Higher scores indicate worse outcomes.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Annualized Relapse Rate	- Comparison of mean number of relapses per year between the different treatments	3 years
Remaining on Drug	- Proportion remaining on the index DMT after 3 years	3 years
Increase in EDSS	- Comparison of yearly increase in mean EDSS between the different treatments Expanded Disability Status Scale (EDSS) scale range: Minimum score: 0 (normal neurological examination). Maximum score: 10 (death due to multiple sclerosis) Lower scores indicate better outcomes (less disability). Higher scores indicate worse outcomes (more disability).	3 years
Proportion of Patients With at Least 1 Step Increase in EDSS	- Comparison of yearly proportion of patients with at least 1 step increase in EDSS between the different treatments Expanded Disability Status Scale (EDSS) scale range: Minimum score: 0 (normal neurological examination). Maximum score: 10 (death due to multiple sclerosis) Lower scores indicate better outcomes (less disability). Higher scores indicate worse outcomes (more disability).	3 years
Proportion of Patients With No Evidence of Disease Activity (NEDA) -2	- Comparison of yearly proportion of patients with No Evidence of Disease Activity (NEDA) -2 (free of exacerbations, new/enlarged T2-lesions and occurrence of CEL) between the treatments. Lower NEDA-2 scores indicate better outcomes. Higher NEDA-2 scores indicate worse outcomes.	3 years
Proportion of Patients With NEDA-3	- Comparison of yearly proportion of patients with NEDA-3 (NEDA-2 plus no confirmed worsening of EDSS from baseline). Lower NEDA-3 scores indicate better outcomes. Higher NEDA-3 scores indicate worse outcomes.	3 years
Quality of Life Assessments	Comparison of health-related quality of life measured by the European Quality of Life Five Dimensions (EQ-5D). Higher values indicate better health, and lower values indicate poorer health. The maximum theoretical value is 1. While there is no fixed minimum, scores can fall below 0, indicating health states worse than death. In this study, scores ranged from -0.59 to 1, which represent clinically relevant ranges of values.	3 years
Fatigue	Comparison of fatigue measured by the Fatigue Scale for Motor and Cognitive Functions (FSMC). The fatigue scale for motor and cognitive functions (FSMC) scale range: Minimum score: 20. Maximum score: 100. Lower scores indicate better outcomes. Higher scores indicate worse outcomes.	3 years
Treatment Satisfaction	Comparison of patient satisfaction with their treatment using the Treatment Satisfaction Questionnaire (TSQ), items 1-9, restricted to patients remaining on index DMT at 3 years. The Treatment Satisfaction Questionnaire (TSQ), items 1-9 scale range: Minimum score: 0. Maximum score: 100. Lower scores indicate worse outcomes. Higher scores indicate better outcomes.	3 years
Rate of Serious Infections	- Rate of serious infections, defined as hospitalizations where the main diagnosis included an ICD-10 diagnosis code in the national patient register in the 3 years after initiating index DMT	3 years
Rate of Major Adverse Cardiovascular Events (MACE)	- Rate of MACE, defined as acute coronary syndrome, stroke or death from any cardiovascular cause based on corresponding ICD-codes in the national patient and cause of death registries in the 3 years after initiating index DMT	3 years
Rate of Invasive Cancer	- Rate of incident invasive cancer, defined as invasive cancers based on corresponding ICD-codes in the national cancer registry in the 3 years after initiating index DMT.	3 years

Collaborators and Investigators

• Sponsor: Karolinska Institutet
• Collaborators: Patient-Centered Outcomes Research Institute; Kaiser Foundation Research Institute
• Investigators: Principal Investigator: Annette Langer-Gould, MD, PhD, Kaiser Permanent Southern California, Los Angeles, USA; Principal Investigator: Thomas Frisell, PhD, Karolinska Institutet; Principal Investigator: Fredrik Piehl, MD, PhD, Karolinska Institutet; Principal Investigator: Anders Svenningsson, MD, PhD, Karolinska Institutet; Principal Investigator: Anna Fogdell-Hahn, PhD, Karolinska Institutet; Principal Investigator: Ingrid Kockum, PhD, Karolinska Institutet

Study record dates

Study Major Dates

• Study Start (Actual): June 2, 2017
• Primary Completion (Actual): March 31, 2022
• Study Completion (Actual): March 31, 2022

Study Registration Dates

• First Submitted: April 20, 2017
• First Submitted That Met QC Criteria: June 18, 2017
• First Posted (Actual): June 21, 2017

Study Record Updates

• Last Update Posted (Actual): April 20, 2025
• Last Update Submitted That Met QC Criteria: March 31, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Cohort study; Rituximab; Natalizumab; Fingolimod; Dimethyl fumarate; Glatiramer acetate; Interferon-beta; Immunomodulating treatment
• Additional Relevant MeSH Terms: Nervous System Diseases; Pathologic Processes; Autoimmune Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Antineoplastic Agents, Immunological; Sphingosine 1 Phosphate Receptor Modulators; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Dermatologic Agents; Antiviral Agents; Adjuvants, Immunologic; Rituximab; Natalizumab; Fingolimod Hydrochloride; Alemtuzumab; Glatiramer Acetate; Dimethyl Fumarate; Interferons; Interferon-beta; (T,G)-A-L
• Other Study ID Numbers: COMBAT-MS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No