Clinical Trials Register

Summary
EudraCT Number:	2020-002981-15
Sponsor's Protocol Code Number:	DanNORMS
National Competent Authority:	Denmark - DHMA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-07-13
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Denmark - DHMA

A.2

EudraCT number

2020-002981-15

A.3

Full title of the trial

Danish non-inferiority study of ocrelizumab and rituximab in MS (DanNORMS): A randomized study comparing the efficacy of ocrelizumab and rituximab in active multiple sclerosis.

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.3.2

Name or abbreviated title of the trial where available

DanNORMS

A.4.1

Sponsor's protocol code number

DanNORMS

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Danish Multiple Sclerosis Center, Rigshospitalet
B.1.3.4	Country	Denmark
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Danish Regions
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Danish Multiple Sclerosis Center, Rigshospitalet
B.5.2	Functional name of contact point	Danish Multiple Sclerosis Center
B.5.3	Address:
B.5.3.1	Street Address	Valdemar Hansens Vej 1- 23
B.5.3.2	Town/ city	Glostrup
B.5.3.3	Post code	2600
B.5.3.4	Country	Denmark
B.5.4	Telephone number	4538633045

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Ocrevus
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ocrelizumab
D.3.9.1	CAS number	637334-45-3
D.3.9.3	Other descriptive name	OCRELIZUMAB
D.3.9.4	EV Substance Code	SUB121707
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Ruxience
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
D.3.9.4	EV Substance Code	SUB12570MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Multiple sclerosis.

E.1.1.1

Medical condition in easily understood language

Multiple sclerosis.

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10063400
E.1.2	Term	Secondary progressive multiple sclerosis
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10063399
E.1.2	Term	Relapsing-remitting multiple sclerosis
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10063401
E.1.2	Term	Primary progressive multiple sclerosis
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

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.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Patients completing the core-study of 24 months treatment, will be asked to continue in the extension study of additional 36 months duration.

Substudies at local sites include additional MRI, clinical, optical coherence and cerebrospinal fluid biomarker endpoints.

E.3

Principal inclusion criteria

• 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 ≥1 new/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:

 CSF NFL level (measured with NF-Light® ELISA assay from Uman Diagnostics or Simoa):
o 18 to 40 years >560 ng/l
o 41 to 60 years >890 ng/l
o 61 to 65 years >1850 ng/l

 sNFL level (measured with Simoa™ NF-light® Advantage Kit)
o 18 to 20 years >7.4 ng/l
o 21 to 30 years >9.9 ng/l
o 31 to 40 years >13.1 ng/l
o 41 to 50 years >17.5 ng/l
o 51 to 60 years >23.3 ng/l
o 61 to 75 years >30.9 ng/l

• Signed written informed consent

E.4

Principal exclusion criteria

• Pregnancy or breast feeding
• Lack of effective contraception for women of child-bearing potential
Effective contraception includes:
 Oral contraception (combined and progestogen-only)
 Intrauterine devices and intrauterine hormone-releasing system
 Bilateral tubal occlusion
 Vasectomised partner (provided that partner is the sole sexual partner)
 Sexual abstinence (refraining from heterosexual intercourse during the study period; sexual abstinence should be evaluated in relation to the participants preferred and usual lifestyle)
 Other forms of contraception with failure rate <1%
• 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

E.5 End points

E.5.1

Primary end point(s)

• Percentage of patients with no new or enlarging T2 white matter lesions

E.5.1.1

Timepoint(s) of evaluation of this end point

From month 6 to month 24

E.5.2

Secondary end point(s)

• Percentage of patients with 6-month confirmed disease worsening (CDW) in EDSS from baseline to month 24
• ARR based on cumulative number of confirmed relapses from baseline to months 24
• Percentage of patients with 6-months CDW in T25FW from baseline to month 24
• Percentage of patients with 6-months CDW in 9HPT from baseline to month 24
• Percentage of patients with 6-months CDW in SDMT from baseline to month 24
• Change in MSIS-29 from baseline to month 24
• Change in FSMC from baseline to month 24
• EQ-5D (5-level version) from baseline to month 24
• Percentage of patients without GdEL on month 6 and month 24 scans
• Change in T2 white matter lesion volume from month 6 to month 24
• Change in T1 white matter lesion volume from month 6 to month 24
• PBVC from month 6 to month 24
• Difference in serum NFL level from baseline to month 24
• Blood levels of CD19+ B cells at month 6 and month 24

E.5.2.1

Timepoint(s) of evaluation of this end point

See definition above for each endpoint.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Primary endpoint with blinded evaluation

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

30 April 2028

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

584

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

594

F.4.2

For a multinational trial

F.4.2.1

In the EEA

594

F.4.2.2

In the whole clinical trial

594

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

When the subject leaves the study, further treatment will be accordingto local MS centre practice.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-08-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-12-15

P. End of Trial
P.	End of Trial Status	Ongoing

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