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

• ClinicalTrials.gov Identifier: NCT03193866
• Recruitment Status: Active, not recruiting
• First Posted: June 21, 2017
• Last Update Posted: August 22, 2022
• Sponsor: Karolinska Institutet
• Collaborators: Patient-Centered Outcomes Research Institute; Kaiser Foundation Research Institute
• Information provided by (Responsible Party): Fredrik Piehl, Karolinska Institutet

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment
Relapsing-remitting Multiple Sclerosis	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 Design

• Study Type: Observational [Patient Registry]
• Actual Enrollment: 3526 participants
• Observational Model: Cohort
• Time Perspective: Other
• Target Follow-Up Duration: 3 Years
• Official Title: 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
• Actual Study Start Date: June 2, 2017
• Estimated Primary Completion Date: December 31, 2022
• Estimated Study Completion Date: December 31, 2022

Groups and Cohorts

Intervention Details:

• Drug: Rituximab
  Comparisons of efficacy and safety between rituximab and all other frequently used immunomodulating drugs against multiple sclerosis
  Other Names:

  • Natalizumab
  • Fingolimod
  • Alemtuzumab
  • Interferon-beta
  • Glatiramer acetate
  • Dimethyl Fumarate

Outcome Measures

Primary Outcome Measures :

1. Confirmed disease progression in patients with Expanded Disability Status Scale (EDSS) ≤2.5 at baseline [ Time Frame: 3 years ]
   - Proportion of patients with baseline EDSS ≤2.5 progressing to 12 months confirmed EDSS ≥3 among those over 3 years of follow up
2. Confirmed disease progression in patients with EDSS ≥2.5 at baseline [ Time Frame: 3 years ]
   - Proportion of patients with baseline EDSS ≥2.5 experiencing 6 months confirmed EDSS increase of 1 point among those over 3 years of follow up
3. Disease-related impact on daily life [ Time Frame: 3 years ]
   - Change in MSIS-29 over 3 years of follow up (change from baseline; mean value ±SD)

Secondary Outcome Measures :

1. Risk and side effect assessments [ Time Frame: 3-9 years ]
   - Rate of malignancy, cardiovascular disease, serious infections and all-cause mortality in populations on therapy and ever treated, respectively
2. Occurence of Serious Adverse Reactions [ Time Frame: 3-9 years ]
   - The occurrence of serious adverse events (SAE) of all types that are possibly or likely related to DMT treatment
3. Annual relapse rate [ Time Frame: 3-9 years ]
   - Comparison of mean number of relapses per year between the different treatments
4. Number of Contrast-enhancing lesions (CEL) [ Time Frame: 3-9 years ]
   - Comparison of mean number of CEL on yearly MRI between the different treatments
5. Increase in EDSS [ Time Frame: 3-9 years ]
   - Comparison of yearly increase in mean and median EDSS between the different treatments
6. Proportion of patients with at least 1 step increase in EDSS [ Time Frame: 3-9 years ]
   - Comparison of yearly proportion of patients with at least 1 step increase in EDSS between the different treatments
7. Proportion of patients with No Evidence of Disease Activity (NEDA) -2 [ Time Frame: 3-9 years ]
   - Comparison of early 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
8. Proportion of patients with NEDA-3 [ Time Frame: 3-9 years ]
   - Comparison of early proportion of patients with NEDA-3 (NEDA-2 plus no worsening of EDSS from baseline) between the treatments
9. Levels of Neurofilament-Light chain (NFL) in serum [ Time Frame: 3-9 years ]
   - Comparison of mean levels of Neurofilament-Light chain (NFL) in serum between the different treatments
10. Brain atrophy rate [ Time Frame: 3-9 years ]
    - Comparison of yearly brain atrophy rate measured as per cent brain parenchymal fraction (BPF) loss in relation to baseline values between the different treatments
11. Time on drug [ Time Frame: 3-9 years ]
    - Comparison of time to drug discontinuation between the different treatments. Separate analyses will be performed depending on reason to drug discontinuation, mainly side effects and lack of efficacy
12. Treatment satisfaction [ Time Frame: 3-9 years ]
    Comparison of patient satisfaction with their treatment using the Treatment Satisfaction Questionnaire (TSQ) between the treatments
13. Quality of life assessments [ Time Frame: 3-9 years ]
    - Comparison of health related QoL measured by EQ-5D between the treatments
14. Fatigue [ Time Frame: 3-9 years ]
    Comparison of fatigue measured by the Fatigue Scale for Motor and Cognitive Functions (FSMC) between the treatments
15. Health economy [ Time Frame: 3-9 years ]
    - Estimation of total societal costs per year after initiating treatment
16. Occurrence of Anti-drug antibodies (ADA) [ Time Frame: 3-9 years ]
    - Proportion of patients treated with RTX developing high-titer anti-RTX ADA
17. Employment rate [ Time Frame: 3-9 years ]
    - Comparison of mean number of working hours per week between the treatments.
18. Severity assessments of COVID-19 in MS [ Time Frame: 1-2 years after COVID-19 epidemic ]
    Number of hospital and ICU admittance in people with MS compared to population
19. Severity assessments of COVID-19 in MS in relation to DMD [ Time Frame: 1-2 years after COVID-19 epidemic ]
    Number of hospital and ICU admittance in people with MS in relation to DMD

Biospecimen Retention:   Samples Without DNA

Serum samples will be taken yearly for analysis of anti-drug antibodies. These samples will be saved in biobank.

Additional blood samples will be taken for analyses of SARS-CoV-2 serologic response.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• 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.

Criteria

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

Contacts and Locations

Locations

Sweden

Fredrik Piehl

Stockholm, Sweden

Sponsors and Collaborators

Karolinska Institutet

Patient-Centered Outcomes Research Institute

Kaiser Foundation Research Institute

Investigators

• Principal Investigator: Fredrik Piehl, MD, PhD; Karolinska Institutet, Stockholm, Sweden
• Principal Investigator: Anders Svenningsson, MD, PhD; Karolinska Institutet, Stockholm, Sweden
• Principal Investigator: Anna Fogdell-Hahn, PhD; Karolinska Institutet, Stockholm, Sweden
• Principal Investigator: Ingrid Kockum, PhD; Karolinska Institutet, Stockholm, Sweden
• Principal Investigator: Thomas Frisell, PhD; Karolinska Institutet, Stockholm, Sweden
• Principal Investigator: Annette Langer-Gould, MD, PhD; Kaiser Permanent Southern California, Los Angeles, USA

More Information

Additional Information:

• Responsible Party: Fredrik Piehl, Professor, Karolinska Institutet
• ClinicalTrials.gov Identifier: NCT03193866
• Other Study ID Numbers: COMBAT-MS
• First Posted: June 21, 2017
• Last Update Posted: August 22, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Fredrik Piehl, Karolinska Institutet:

Immunomodulating treatment; Cohort study; Dimethyl fumarate; Fingolimod; Interferon-beta; Natalizumab; Rituximab; Glatiramer acetate

Additional relevant MeSH terms:

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Pathologic Processes; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Interferons; Interferon-beta; Rituximab; Alemtuzumab; Glatiramer Acetate; Dimethyl Fumarate; Natalizumab; Fingolimod Hydrochloride; (T,G)-A-L; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antiviral Agents; Anti-Infective Agents; Sphingosine 1 Phosphate Receptor Modulators; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Dermatologic Agents