Overview
Sponsor-declared trial summary
Phase
Therapeutic use (Phase IV)
Status
Ongoing, recruitment ended
Participants planned
200
Countries
1
Sites
21
multiple sclerosis
To study the non-inferiory of rituximab compared to ocrelizumab for the treatment of relapsing MS patients with an indication to start anti-CD20 therapy
Key facts
- Sponsor
- Amsterdam UMC
- Participant type
- Patients
- Age range
- 18-64 years
- Gender
- Male and Female
- Therapeutic area
- Diseases [C] - Nervous System Diseases [C10]
- Trial duration
- 1 May 2023 → ongoing
- Decision date (initial)
- 2023-03-03
- Transition trial
- No
- Low-intervention
- Yes
- Rare-disease indication
- No
- Vulnerable population
- No
- Funding sources
- Stichting Treatmeds
Trial design
CTIS Part I — objectives, methods, condition coding
Main objective
Scope: Therapy, Efficacy
To study the non-inferiory of rituximab compared to ocrelizumab for the treatment of relapsing MS patients with an indication to start anti-CD20 therapy
Conditions and MedDRA coding
multiple sclerosis
| Version | Level | Code | Term | System organ class |
|---|---|---|---|---|
| 20.1 | PT | 10028245 | Multiple sclerosis | 100000004852 |
Eligibility criteria
Principal inclusion / exclusion criteria as submitted by sponsor
Inclusion criteria 1
- 1. Men and women aged between 18 and 65 years (inclusive) 2. A diagnosis of relapsing MS according to the 2017 revised diagnostic criteria59 3. Indication to start treatment with anti-CD20 therapy according to the treating neurologist and the relevant label in the Netherlands for treatment of relapsing MS 4. Able to understand written and spoken Dutch or English 5. Capable of giving signed informed consent including compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. 6. Screening EDSS score ≤ 6.5 .
Exclusion criteria 1
- Medical Conditions 1. A known allergy or other intolerability to RTX, OCR, gadolinium-based MRI contrast agents, or corticosteroids. 2. A diagnosis of primary progressive MS according to the diagnostic criteria.59 3. A diagnosis of not-active secondary progressive MS.60 4. Not-active patients on natalizumab with JC-virus seroconversion 5. Chronic infectious diseases such as tuberculosis, VZV, hepatitis virus or HIV, as well as hepatitis B surface antigen positivity and/or hepatitis C PCR positivity verified at screening visit. 6. A history of proven inflammatory bowel disease such as M. Crohn or ulcerative colitis 7. Prior or current psychiatric illness, mental deficiency or cognitive dysfunction influencing the patient ability to make an informed consent or comply with the treatment and follow-up phases of this protocol. 8. Cardiac disease that makes treatment with OCR or RTX contra-indicated as stated by the most recent SmPC 9. Active malignancy or prior history of malignancy that makes treatment with OCR or RTX contra-indicated as stated by the most recent SmPC. 10. WBC < 1.5 x 109/L if not caused by a reversible effect of documented ongoing medication. If caused by a reversible effect of documented ongoing medication the WBC count must be > 1,5 x 109/L before start of study treatment. 11. Platelet (thrombocyte) count < 100 x 109/L 12. ALAT and/or ASAT more than 2 times the upper normal reference limit (ULN) 13. Serum creatinine > 200 μmol/L 14. Serum bilirubin > ULN 15. Serum IgG < LLN 16. Pregnant or breast-feeding women 17. Women of childbearing potential# (WOCBP) not able or willing to use highly effective methods of birth control## per ICH M3 (R2) that result in failure rate of ≤ 1% per year when used consistently and correctly for the duration of the study OR until 3 months after last dose administered. 18. History of serious or life-threatening infusion reaction to OCR or RTX 19. Treatment with glucocorticoids or ACTH within one month prior to start of study treatment Prior/Concomitant Therapy 20. Previous use of second line MS-therapies cladribine, RTX, alemtuzumab, OCR, ofatumumab, hematopoietic stem cell therapy (HSCT) or other immunosuppression therapies with long lasting effects. Mitoxantrone is allowed if used > 1 year before enrolment. If any of these medications have been used for indications other than MS, patients can be included if the medications have not been used the year before enrolment. Previous treatment with natalizumab is allowed (in for example cases that switch from natalizumab to anti-CD20 therapy because of JCV positivity). Prior/Concurrent Clinical Study Experience 21. Currently enrolled in another investigational device or drug study, or less than 30 days since ending of another investigational device or drug study (s), or receiving other investigational treatment(s). Patients participating in a purely observational studies will be allowed to participate. Lifestyle 22. Current alcohol or drug dependencies. Diagnostic assessments 23. Presence of metallic objects implanted in the body, that would preclude the ability of the patient to safely have MRI exams. 24. Not willing to undergo MRI scans with i.v. gadolinium injections
Endpoints
Primary and secondary outcome measures (English text)
Primary endpoints 1
- • The proportion of patients with no new or enlarged T2 lesions on brain MRI between month 6 and month 24 of treatment in each arm.
Secondary endpoints 1
- • The annual relapse rate between baseline to month 24 • The annual relapse rate between month 6 to month 24 • Proportion of patients with no relapses from baseline to month 24 • Proportion of patients with no relapses from month 6 to month 24 • Time to first relapse • Proportion of patients with no contrast enhancing lesions between baseline and month 24 • Proportion of patients with no contrast enhancing lesions between month 6 and month 24 • The average number of new/enlarged T2 lesions betwe
Investigational products
Investigational medicinal products (IMPs), comparators, placebo, auxiliary
Test 11
Rixathon 500 mg concentrate for solution for infusion
PRD6060692 · Product
- Active substance
- Rituximab
- Substance synonyms
- CT-P10, PF-05280586, ABP 798, BI 695500, JHL1101, HLX01
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 1000 mg milligram(s)
- Max total dose
- 60000 mg milligram(s)
- Max treatment duration
- 1560 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01XC02 — RITUXIMAB
- Marketing authorisation
- EU/1/17/1185/003
- MA holder
- SANDOZ GMBH
- MA country
- Iceland
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
MabThera 500 mg concentrate for solution for infusion
PRD2154043 · Product
- Active substance
- Rituximab
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 1000 mg milligram(s)
- Max total dose
- 60000 mg milligram(s)
- Max treatment duration
- 1560 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01XC02 — RITUXIMAB
- Marketing authorisation
- EU/1/98/067/002
- MA holder
- ROCHE REGISTRATION GMBH
- MA country
- Iceland
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Rixathon 100 mg concentrate for solution for infusion
PRD6641103 · Product
- Active substance
- Rituximab
- Substance synonyms
- CT-P10, PF-05280586, ABP 798, BI 695500, JHL1101, HLX01
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 1000 mg milligram(s)
- Max total dose
- 60000 mg milligram(s)
- Max treatment duration
- 1560 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01XC02 — RITUXIMAB
- Marketing authorisation
- EU/1/17/1185/002
- MA holder
- SANDOZ GMBH
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Ruxience 100 mg concentrate for solution for infusion
PRD7980793 · Product
- Active substance
- Rituximab
- Substance synonyms
- CT-P10, PF-05280586, ABP 798, BI 695500, JHL1101, HLX01
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 1000 mg milligram(s)
- Max total dose
- 60000 mg milligram(s)
- Max treatment duration
- 1560 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01XC02 — RITUXIMAB
- Marketing authorisation
- EU/1/20/1431/001
- MA holder
- PFIZER EUROPE MA EEIG
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Truxima 500 mg concentrate for solution for infusion
PRD4797328 · Product
- Active substance
- Rituximab
- Substance synonyms
- CT-P10, PF-05280586, ABP 798, BI 695500, JHL1101, HLX01
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 1000 mg milligram(s)
- Max total dose
- 60000 mg milligram(s)
- Max treatment duration
- 1560 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01FA01 — -
- Marketing authorisation
- EU/1/16/1167/001
- MA holder
- CELLTRION HEALTHCARE HUNGARY KFT
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Rixathon 100 mg concentrate for solution for infusion
PRD6647925 · Product
- Active substance
- Rituximab
- Substance synonyms
- CT-P10, PF-05280586, ABP 798, BI 695500, JHL1101, HLX01
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 1000 mg milligram(s)
- Max total dose
- 60000 mg milligram(s)
- Max treatment duration
- 1560 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01XC02 — RITUXIMAB
- Marketing authorisation
- EU/1/17/1185/002
- MA holder
- SANDOZ GMBH
- MA country
- Iceland
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
MabThera 100 mg concentrate for solution for infusion
PRD2154041 · Product
- Active substance
- Rituximab
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 1000 mg milligram(s)
- Max total dose
- 60000 mg milligram(s)
- Max treatment duration
- 1560 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01XC02 — RITUXIMAB
- Marketing authorisation
- EU/1/98/067/001
- MA holder
- ROCHE REGISTRATION GMBH
- MA country
- Iceland
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Rixathon 100 mg concentrate for solution for infusion
PRD6641095 · Product
- Active substance
- Rituximab
- Substance synonyms
- CT-P10, PF-05280586, ABP 798, BI 695500, JHL1101, HLX01
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 1000 mg milligram(s)
- Max total dose
- 60000 mg milligram(s)
- Max treatment duration
- 1560 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01XC02 — RITUXIMAB
- Marketing authorisation
- EU/1/17/1185/001
- MA holder
- SANDOZ GMBH
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Rixathon 500 mg concentrate for solution for infusion
PRD6060651 · Product
- Active substance
- Rituximab
- Substance synonyms
- CT-P10, PF-05280586, ABP 798, BI 695500, JHL1101, HLX01
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 1000 mg milligram(s)
- Max total dose
- 60000 mg milligram(s)
- Max treatment duration
- 1560 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01XC02 — RITUXIMAB
- Marketing authorisation
- EU/1/17/1185/004
- MA holder
- SANDOZ GMBH
- MA country
- Norway
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Truxima 100 mg concentrate for solution for infusion
PRD5065907 · Product
- Active substance
- Rituximab
- Substance synonyms
- CT-P10, PF-05280586, ABP 798, BI 695500, JHL1101, HLX01
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 1000 mg milligram(s)
- Max total dose
- 60000 mg milligram(s)
- Max treatment duration
- 1560 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01FA01 — -
- Marketing authorisation
- EU/1/16/1167/002
- MA holder
- CELLTRION HEALTHCARE HUNGARY KFT
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Ruxience 500 mg concentrate for solution for infusion
PRD7980794 · Product
- Active substance
- Rituximab
- Substance synonyms
- CT-P10, PF-05280586, ABP 798, BI 695500, JHL1101, HLX01
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 1000 mg milligram(s)
- Max total dose
- 60000 mg milligram(s)
- Max treatment duration
- 1560 Week(s)
- Authorisation status
- Authorised
- ATC code
- L01XC02 — RITUXIMAB
- Marketing authorisation
- EU/1/20/1431/002
- MA holder
- PFIZER EUROPE MA EEIG
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Comparator 2
Ocrevus 300 mg concentrate for solution for infusion
PRD5771884 · Product
- Active substance
- Ocrelizumab
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS
- Max daily dose
- 1200 mg milligram(s)
- Max total dose
- 36000 mg milligram(s)
- Max treatment duration
- 1560 Week(s)
- Authorisation status
- Authorised
- ATC code
- L04AA36 — -
- Marketing authorisation
- EU/1/17/1231/002
- MA holder
- ROCHE REGISTRATION GMBH
- MA country
- Norway
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Ocrevus 300 mg concentrate for solution for infusion
PRD5771848 · Product
- Active substance
- Ocrelizumab
- Pharmaceutical form
- SOLUTION FOR INFUSION
- Route of administration
- INTRAVENOUS INFUSION
- Max daily dose
- 600 mg milligram(s)
- Max total dose
- 36000 mg milligram(s)
- Max treatment duration
- 1560 Week(s)
- Authorisation status
- Authorised
- ATC code
- L04AA36 — -
- Marketing authorisation
- EU/1/17/1231/001
- MA holder
- ROCHE REGISTRATION GMBH
- MA country
- EU
- Paediatric formulation
- No
- Orphan designation
- No
- Modified vs. Marketing Authorisation
- No
Sponsors and contacts
Sponsor organisations, regulatory contacts, third parties
Amsterdam UMC
- Sponsor organisation
- Amsterdam UMC
- Address
- P. O. Box 7057
- City
- Amsterdam
- Postcode
- 1007 MB
- Country
- Netherlands
Scientific contact point
- Organisation
- Amsterdam UMC
- Contact name
- Dr. E.M.M. Strijbis
Public contact point
- Organisation
- Amsterdam UMC
- Contact name
- Dr. E.M.M. Strijbis
Locations
1 EU/EEA country · 21 investigational sites
By country
| Country | MS status | Planned subjects | Sites |
|---|---|---|---|
| Netherlands | Ongoing, recruitment ended | 200 | 21 |
| Rest of world | — | 0 | — |
Investigational sites
Groene Hart Ziekenhuis
Neurology, Bleulandweg 10, 2803 HH, Gouda
Flevoziekenhuis Stichting
Neurology, Hospitaalweg 1, 1315 RA, Almere
Zuyderland Medisch Centrum Stichting
Neurology, Henri Dunantstraat 5, 6419 PC, Heerlen
Haga Hospital
Neurology, Els Borst-Eilersplein 275, 2545 AA, 's-Gravenhage
Alrijne Zorggroep Stichting
Neurology, Simon Smitweg 1, 2353 GA, Leiderdorp
Reinier de Graaf Groep
Neurology, Reinier De Graafweg 5, 2625 AD, Delft
Albert Schweitzer Ziekenhuis
Neurology, Albert Schweitzerplaats 25, 3318 AT, Dordrecht
Noordwest Ziekenhuisgroep Stichting
Neurology, Wilhelminalaan 12, 1815 JD, Alkmaar
Stichting Treant Ziekenhuiszorg
Neurology, Boermarkeweg 60, 7824 AA, Emmen
Stichting Viecuri Medisch Centrum voor Noord-Limburg
Neurology, Tegelseweg 210, 5912 BL, Venlo
Universitair Medisch Centrum Groningen
Neurology, Hanzeplein 1, 9713 GZ, Groningen
Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
neurology, Dr. Molewaterplein 60, 3015 GJ, Rotterdam
St. Antonius Ziekenhuis
Neurology, Soestwetering 1, 3543 AZ, Utrecht
Amsterdam UMC
Neurology, De Boelelaan 1117, 1081 HV, Amsterdam
Rijnstate Ziekenhuis Stichting
Neurology, Wagnerlaan 55, 6815 AD, Arnhem
Zaans Medisch Centrum Stichting
Neurology, Koningin Julianaplein 58, 1502 DV, Zaandam
Meander Medisch Centrum
Neurology, Maatweg 3, 3813 TZ, Amersfoort
Amphia Hospital
Neurology, Molengracht 21, 4818 CK, Breda
Jeroen Bosch Ziekenhuis Stichting
Neurology, Henri Dunantstraat 1, 5223 GZ, 'S-Hertogenbosch
Maasstad Ziekenhuis Stichting
Neurology, Maasstadweg 21, 3079 DZ, Rotterdam
Deventer Ziekenhuis
Neurology, Nico Bolkesteinlaan 75, 7416 SE, Deventer
Country notifications
Trial-start, recruitment-start, end and early-termination notifications submitted per Member State
| Country | Trial start | Trial end | Recruitment start | Recruitment end | Early termination |
|---|---|---|---|---|---|
| Netherlands | 2023-05-01 | 2023-05-12 | 2025-12-08 |
Oversight and notifications
Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77
Serious breaches 1 · Art. 52 CTR
Serious breach SB-80251
- Sponsor became aware
- 2025-04-18
- Date of breach
- 2024-12-31
- Submission date
- 2025-04-24
- Member states concerned
- Netherlands
- Categories
- Regulation
- Areas impacted
- Subject rights
- Benefit-risk balance changed
- No
- Description
- Participant has been randomised to study arm on 31DEC2024, before the informed consent form was signed on 02JAN2025. No impacts on study data or trial.
- Sponsor actions
- Study team was informed that no study tasks can be performed before informed consent is signed.
| Organisation | City | Country | Type |
|---|---|---|---|
| Universitair Medisch Centrum Groningen | Groningen | Netherlands | Clinical facility BE/BA |
Results and documents
Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial
Documents 26 files
Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.
| Type | Title | Version |
|---|---|---|
| Protocol (for publication) | D1_Protocol_NoisyRebels_20225026642100 | 9 |
| Protocol (for publication) | D4_EQ-5D-5L_20225026642100 | 1 |
| Protocol (for publication) | D4_iMCQ_20225026642100 | 1 |
| Protocol (for publication) | D4_iPCQ_20225026642100 | 1 |
| Protocol (for publication) | D4_MSIS29_20225026642100 | 1 |
| Protocol (for publication) | D4_RAPID3HAQ2_20225026642100 | 1 |
| Protocol (for publication) | D4_TSQM_20225026642100 | 1 |
| Protocol (for publication) | D4_Wearing_off_ocrelizumab_20225026642100 | 1 |
| Recruitment arrangements (for publication) | K1_Recruitment_procedure_NL_20225026642100 | 1 |
| Subject information and informed consent form (for publication) | L1_Intrekkingsformulier Noisy Rebels 20225026642100 | 1 |
| Subject information and informed consent form (for publication) | L1_PIF Noisy Rebels Extensiefase 20225026642100 | 1.1 |
| Subject information and informed consent form (for publication) | L1_PIF Noisy Rebels VUmc 2022-502664-21-00 | 6.1 |
| Subject information and informed consent form (for publication) | L1_PIF_NoisyRebels VUmc_English_20225026642100 | 6.1 |
| Subject information and informed consent form (for publication) | L1_PIF_NoisyRebels_20225026642100 | 6.1 |
| Subject information and informed consent form (for publication) | L1_PIF_NoisyRebels_English_20225026642100 | 6.1 |
| Summary of Product Characteristics (SmPC) (for publication) | E1_SmPC_Mabthera_20225026642100 | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | E1_SmPC_Mabthera_20225026642100 | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | E1_SmPC_Ocrevus_20225026642100 | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | E1_SmPC_Rixathon_20225026642100 | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | E1_SmPC_Rixathon_20225026642100 | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | E1_SmPC_Ruxience_20225026642100 | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | E1_SmPC_Ruxience_20225026642100 | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | E1_SmPC_Truxima_20225026642100 | 1 |
| Summary of Product Characteristics (SmPC) (for publication) | E1_SmPC_Truxima_20225026642100 | 1 |
| Synopsis of the protocol (for publication) | D1_Protocol_synopsis_ENG_20225026642100 | 1 |
| Synopsis of the protocol (for publication) | D1_Protocol_synopsis_NL_20225026642100 | 1 |
Application history
8 submissions — initial application plus substantial / non-substantial modifications
| # | Type | Code | Submitted | Reference MS | Conclusion | Decision date |
|---|---|---|---|---|---|---|
| 1 | INITIAL | IN | 2022-11-18 | Netherlands | Acceptable 2023-02-27
|
2023-03-03 |
| 2 | SUBSTANTIAL MODIFICATION | SM-1 | 2023-06-22 | Netherlands | Acceptable 2023-07-28
|
2023-07-28 |
| 3 | SUBSTANTIAL MODIFICATION | SM-3 | 2024-01-18 | Netherlands | Acceptable 2024-02-27
|
2024-02-27 |
| 4 | SUBSTANTIAL MODIFICATION | SM-4 | 2024-07-02 | Netherlands | Acceptable 2024-08-15
|
2024-08-15 |
| 5 | SUBSTANTIAL MODIFICATION | SM-5 | 2024-10-29 | Netherlands | Acceptable | 2024-11-22 |
| 6 | SUBSTANTIAL MODIFICATION | SM-6 | 2025-01-03 | Netherlands | Acceptable | 2025-02-10 |
| 7 | SUBSTANTIAL MODIFICATION | SM-7 | 2025-09-08 | Netherlands | Acceptable 2025-10-14
|
2025-10-14 |
| 8 | SUBSTANTIAL MODIFICATION | SM-8 | 2026-02-11 | Netherlands | Acceptable 2026-04-07
|
2026-04-13 |