Non-inferiority study of ocrelizumab and rituximab in active multiple sclerosis

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Rigshospitalet

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

28 Apr 2021 → ongoing

Decision date (initial)

2024-08-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Danske regioner - Regionernes medicin- og behandlingspulje

External identifiers

EU CT number

2024-514287-84-00

EudraCT number

2020-002981-15

ClinicalTrials.gov

NCT04688788

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Safety, Pharmacogenetic, Therapy, Pharmacoeconomic, Pharmacodynamic, Efficacy

The primary aim of the study is to test whether rituximab treatment is non-inferior to ocrelizumab treatment in active forms of multiple sclerosis, which will be evaluated with the primary endpoint percentage of patients with no new or enlarging T2 white matter lesions from month 6 to month 24. Patients completing the core-study of 24 months treatment, will be asked to continue in the extension study of additional 36 months duration.The extension long-term phase of the study (month 24 to month 60) willevaluate the long term efficacy and safety of rituximab and ocrelizumab therapy given as either standard dosing or extended interval dosing. The long-term phase of the study will examine whether extended interval dosing may be a preferable dosing strategy for patients who have been stable on well-established CD20-depleting therapy.

Secondary objectives 1

1. Secondary aims include evaluation of other standard efficacy and safety endpoints and tertiary, explorative endpoints related to assessment of efficacy and safety (blood flow cytometry, whole blood gene expression, genotyping of Fcγ-receptor or complement genes, serum NFL, IgG concentrations) in the 24-month core study period.

Conditions and MedDRA coding

Multiple sclerosis

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. Inclusion criteria for core study: • Age ≥18 and ≤65 years • MS diagnosis and definition of disease course according to the 2017 McDonald criteria • Expanded disability status scale (EDSS) ≤6.5 • Fulfilling criteria for active MS: o Treatment naïve RRMS patients (never treated, or no DMT the previous 3 months):≥2 relapse previous 12 months OR ≥1 relapse previous 12 months AND ≥9 T2 lesions on brain and/or spinal MRI AND ≥1 contrast-enhancing lesion or ≥1 new or enlarging T2 lesion on brain and/or spinal MRI previous 12 month o Previously treated RRMS patients: ≥1 relapse previous 12 months OR ≥1 contrast-enhancing lesion or ≥2 new/enlarging T2 lesions on brain MRI previous 12 months o Progressive MS patients: ≥1 relapse previous 12 months OR ≥1 contrast-enhancing lesion previous 12 months or ≥1new/enlarging T2 lesions on brain MRI previous 12 months or ≥2 new or enlarging T2 lesion on brain MRI previous 24 months OR Increased levels of neurofilament light chain in serum or cerebrospinal on sample collected previous 12 months Progressive MS patients not fulfilling the clinical/MRI criteria for active disease, may qualify for inclusion in the study if sNFL or CSF NFL levels is elevated: • Signed written informed consent long-term follow-up phase of the study: Inclusion criteria for extended interval dosing sub-study though randomisation • Completed the first 24 months of the study • No signs of active disease the previous 18 months • Signed written informed consent Inclusion criteria for extended interval dosing outside the randomisation process • Completed the first 24 months of the study • Recommended by physician to switch to extended interval dosing due to Low IgG (<6,1 g/L) or Frequent infections • No signs of active disease the previous 18 months • Signed written informed consent

Exclusion criteria 1

1. • Pregnancy or breast feeding • Lack of effective contraception (failure rate <1%) for women of child-bearing potential • Receipt of a live or live-attenuated vaccine within 6 weeks prior to randomization • Active malignant disease in the previous 5 years • Positive test for HIV, hepatitis B or C, or tuberculosis • Negative test for varicella zoster • Lymphopenia grade 2 (0.5 to 0.8 × 109/L) or higher grades of lymphopenia (in case of switching from fingolimod, siponimod or ozanimod lymphopenia is accepted at screening visit (note that treatment with interferon-beta can induce transient lymphopenia) • Neutropenia grade 2 (1.0 to 1.5 × 109/L) or higher grades • Thrombocytopenia grade 2 (50 to 75 × 109/L) or higher grades • Previous treatment with alemtuzumab or hematopoietic stem-cell transplantation • Previous treatment with cladribine, CD20-depleting antibodies, daclizumab or other immune suppressive treatment which is judged to still exert immune suppressive effect by treating physician • Methylprednisolone treatment 4 weeks within baseline visit and baseline MRI scan • Findings on the screening MRI (for patients without MRI scan of the brain the previous 12 months the baseline MRI scan is also used as screening MRI) judged to preclude participation by the treating physician • Other diseases judged to be relevant by the treating physician • Contraindication to MRI • Known allergy or hypersensitivity to rituximab or ocrelizumab

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Percentage of patients with no new or enlarging T2 white matter lesions from month 6 to month 24

Secondary endpoints 1

1. Percentage of patients with 6-month confirmed disease worsening (CDW) in EDSS from baseline to month 24 (m24) • ARR based on cumulative number of confirmed relapses from baseline to m24 • Percentage of patients with 6-months CDW in T25FW, 9HPT and SDMT from baseline to m24 • Change in MSIS-29, FSMC, EQ-5D from baseline to m24 • Percentage of patients without GdEL on m6 and m24 scans • Change in T2 and T1 white matter lesion volume from m6 to m24 • Difference in serum NFL from baseline to m24

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Rigshospitalet

Sponsor organisation

Rigshospitalet

Address

Valdemar Hansens Vej 1-23

City

Glostrup

Postcode

2600

Country

Denmark

Scientific contact point

Organisation

Rigshospitalet

Contact name

DMSC - Finn Sellebjerg

Public contact point

Organisation

Rigshospitalet

Contact name

DMSC - Finn Sellebjerg

Third parties 6

Locations

1 EU/EEA country · 11 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 14 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications