Clinical Trial Results:
RItuximab versus FUmarate in Newly Diagnosed Multiple Sclerosis – RIFUND-MS A randomized phase 3 study comparing Rituximab with Dimethyl Fumarate in early Relapsing-Remitting Multiple Sclerosis Objective: To compare the efficacy of rituximab on the ability to prevent relapses in early RRMS and CIS compared with dimethyl fumarate (DMF), which is an approved first-line medication for RRMS today, using a phase 3 design. Population: Patients with newly diagnosed RRMS or CIS with no more than 10 years disease duration (since diagnosis), 18 – 50 years of age and previously not treated with immunomodulating drugs OR treated with first-line injectables. Patients should display protocol-defined clinical or radiological disease activity during the preceding year before screening for inclusion. Intervention: Treatment with rituximab (Mabthera®) with an initial dose of 1000 mg intravenously (iv) followed by 500 mg iv every six months. Control: Treatment with DMF (Tecfidera®) 240 mg twice daily. The two treatments are randomised in a 1:1 proportion. Outcome: Primary outcome is the relative risk of experiencing a relapse during the two–year period for either compound. As secondary endpoints worsening on neurological disability, magnetic-resonance imaging-defined disease activity and effect on cerebrospinal fluid biomarkers will be analysed. In addition, health-economic evaluations of using rituximab as first-line treatment for RRMS will be performed.

Trial information Top of page
Trial identification
Sponsor protocol code	RIFUND-MS
Additional study identifiers
ISRCTN number	-
US NCT number	-
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Karolinska Institutet
Sponsor organisation address	Nobels väg 6, Solna, Sweden, 17177
Public contact	Department of Clinical Sciences, KI, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, 46 8123 555 33, anders.svenningsson@ki.se
Scientific contact	Department of Clinical Sciences, KI, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, 46 8123 555 33, anders.svenningsson@ki.se
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	08 Oct 2021
Is this the analysis of the primary completion data?	Yes
Primary completion date	21 Apr 2021
Global end of trial reached?	Yes
Global end of trial date	21 Apr 2021
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	The primary objective of this study is • To compare clinical efficacy between rituximab administered according to a Swed-ish treatment schedule and dimethyl fumarate administered according to label
Protection of trial subjects	All participants provided written informed consent at enrolment. The study protocol was approved by the ethical review board in Stockholm (reference number 2016/473-32) and the Swedish Medical Products Agency. The trial was monitored for compliance with Good Clinical Practice standards by an external monitor (Karolinska Trial Alliance) and was conducted in accordance with the Declaration of Helsinki.
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	01 Jul 2016
Long term follow-up planned	Yes
Long term follow-up rationale	Safety, Efficacy, Scientific research
Long term follow-up duration	10 Years
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Sweden: 200
Worldwide total number of subjects	200
EEA total number of subjects	200
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	0
Children (2-11 years)	0
Adolescents (12-17 years)	0
Adults (18-64 years)	200
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	Trial performed at 17 Swedish university and community hospitals. Eligible participants were aged 18–50 years with a diagnosis of relapsing-remitting multiple sclerosis, according to the prevailing McDonald criteria or with a demyelinating episode in conjunction with at least one asymptomatic lesion compatible with multiple sclerosis.
Pre-assignment
Screening details	Key inclusion criteria for participants were: age 18–50 years; relapsing-remitting multiple sclerosis or clinically isolated syndrome according to prevailing McDonald criteria; 10 years or less since diagnosis; untreated or only exposed to interferons or glatiramer acetate; and with clinical or neuroradiological disease activity in the past year.
Period 1
Period 1 title	Overall trial (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Single blind [1]
Roles blinded	Data analyst, Assessor, Investigator [2]
Arms
Are arms mutually exclusive	Yes
Arm title	Dimethyl Fumarate (DMF)
Arm description	oral dimethyl fumarate 240 mg twice daily
Arm type	Active comparator
Investigational medicinal product name	DIMETHYL FUMARATE
Investigational medicinal product code
Other name
Pharmaceutical forms	Capsule, hard
Routes of administration	Oral use
Dosage and administration details	240 mg twice daily
Arm title	Rituximab
Arm description	intravenous rituximab 1000 mg followed by 500 mg every 6 months
Arm type	Experimental
Investigational medicinal product name	RITUXIMAB
Investigational medicinal product code
Other name
Pharmaceutical forms	Infusion
Routes of administration	Intravenous use
Dosage and administration details	intravenous rituximab 1000 mg followed by 500 mg every 6 months
Notes [1] - The number of roles blinded appears inconsistent with a single blinded trial. It is expected that there will be one role blinded in a single blind trial. Justification: All roles selected as blinded (investigator, data analyst, and assessor) are part of the researcher/staff group, which is in line with a single-blinded trial. [2] - The roles blinded appear inconsistent with a simple blinded trial. Justification: This was a rater-blinded study where the investigator, data analyst, and assessor roles were blinded. Participants were not blinded because we were unable to obtain placebo capsules identical to dimethyl fumarate.
Number of subjects in period 1 Dimethyl Fumarate (DMF) Rituximab Started 100 100 Completed 97 98 Not completed 3 2      Consent withdrawn by subject 1 1      Lost to follow-up 1 1      Protocol deviation 1 -

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Dimethyl Fumarate (DMF)
Reporting group description	oral dimethyl fumarate 240 mg twice daily
Reporting group title	Rituximab
Reporting group description	intravenous rituximab 1000 mg followed by 500 mg every 6 months
Reporting group values Dimethyl Fumarate (DMF) Rituximab Total Number of subjects 100 100 200 Age categorical Units: Subjects     In utero 0 0 0     Preterm newborn infants (gestational age < 37 wks) 0 0 0     Newborns (0-27 days) 0 0 0     Infants and toddlers (28 days-23 months) 0 0 0     Children (2-11 years) 0 0 0     Adolescents (12-17 years) 0 0 0     Adults (18-64 years) 100 100 200     From 65-84 years 0 0 0     85 years and over 0 0 0 Age continuous Units: years     arithmetic mean (standard deviation) 33.7 ( 7.9 ) 34.1 ( 7.8 ) - Gender categorical Units: Subjects     Female 64 68 132     Male 36 32 68 number of treatment naïve patients Units: Subjects     Treatment naive 95 98 193     Not treatment naive 5 2 7 Multiple sclerosis duration Units: years     arithmetic mean (standard deviation) 1.7 ( 2.5 ) 1.8 ( 3.4 ) - EDSS score Units: score     arithmetic mean (standard deviation) 1.7 ( 1.0 ) 1.6 ( 1.2 ) -

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Dimethyl Fumarate (DMF)
Reporting group description	oral dimethyl fumarate 240 mg twice daily
Reporting group title	Rituximab
Reporting group description	intravenous rituximab 1000 mg followed by 500 mg every 6 months

End points Top of page

Primary: Patients with any protocol-defined relapse Top of page
End point title	Patients with any protocol-defined relapse
End point description
End point type	Primary
End point timeframe	Start of study until 24 months
End point values Dimethyl Fumarate (DMF) Rituximab Number of subjects analysed 97 98 Units: participant number     number (n) 16 3     percentage (%) 16 3
Statistical analysis title	Risk Ratio
Comparison groups	Rituximab v Dimethyl Fumarate (DMF)
Number of subjects included in analysis	195
Analysis specification	Pre-specified
Analysis type	superiority [1]
P-value	= 0.006
Method	Log-binomial regression analysis
Parameter type	Risk ratio (RR)
Point estimate	0.19
Confidence interval
level	95%
sides	2-sided
lower limit	0.06
upper limit	0.62
Notes [1] - Log-binomial regression analysis

Primary: Patients with any protocol-defined relapse Top of page

Secondary: Patients with any new T2 lesion or contrast-enhancing lesion Top of page
End point title	Patients with any new T2 lesion or contrast-enhancing lesion
End point description
End point type	Secondary
End point timeframe	between baseline and month 24
End point values Dimethyl Fumarate (DMF) Rituximab Number of subjects analysed 97 98 Units: participant number     number (n) 36 21     percentage (%) 37 21
Statistical analysis title	Risk Ratio
Comparison groups	Dimethyl Fumarate (DMF) v Rituximab
Number of subjects included in analysis	195
Analysis specification	Pre-specified
Analysis type	superiority [2]
P-value	= 0.019
Method	Log-binomial regression analysis
Parameter type	Risk ratio (RR)
Point estimate	0.58
Confidence interval
level	95%
sides	2-sided
lower limit	0.36
upper limit	0.91
Notes [2] - Log-binomial regression analysis

Secondary: Patients with any new T2 lesion or contrast-enhancing lesion Top of page

Post-hoc: Patients who discontinued drug Top of page
End point title	Patients who discontinued drug
End point description
End point type	Post-hoc
End point timeframe	between baseline and 24 months
End point values Dimethyl Fumarate (DMF) Rituximab Number of subjects analysed 97 98 Units: participant number     number (n) 48 3     percentage (%) 49 3
Statistical analysis title	Risk Ratio
Comparison groups	Dimethyl Fumarate (DMF) v Rituximab
Number of subjects included in analysis	195
Analysis specification	Pre-specified
Analysis type	superiority [3]
P-value	< 0.0001
Method	Log-binomial regression analysis
Parameter type	Risk ratio (RR)
Point estimate	0.06
Confidence interval
level	95%
sides	2-sided
lower limit	0.02
upper limit	0.19
Notes [3] - Log-binomial regression analysis

Post-hoc: Patients who discontinued drug Top of page

Adverse events Top of page
Adverse events information [1]
Timeframe for reporting adverse events	01/07/16 – 21/04/21
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	CTCAE (27/11/17)
Dictionary version	5
Reporting groups
Reporting group title	Rituximab
Reporting group description	-
Reporting group title	Dimethyl Fumarate (DMF)
Reporting group description	-
Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Data is not available. See article (https://pubmed.ncbi.nlm.nih.gov/35841908/) for info about occurrences för non-serious adverse events.
Serious adverse events Rituximab Dimethyl Fumarate (DMF) Total subjects affected by serious adverse events      subjects affected / exposed 8 / 100 (8.00%) 5 / 100 (5.00%)      number of deaths (all causes) 0 0      number of deaths resulting from adverse events 0 0 Injury, poisoning and procedural complications accident      subjects affected / exposed 1 / 100 (1.00%) 0 / 100 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Cardiac disorders sinus tachycardia      subjects affected / exposed 1 / 100 (1.00%) 0 / 100 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Pregnancy, puerperium and perinatal conditions extrauterine pregnancy      subjects affected / exposed 0 / 100 (0.00%) 1 / 100 (1.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Blood and lymphatic system disorders neutropenia      subjects affected / exposed 1 / 100 (1.00%) 0 / 100 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Gastrointestinal disorders bleeding ulcer      subjects affected / exposed 2 / 100 (2.00%) 0 / 100 (0.00%)      occurrences causally related to treatment / all 2 / 2 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Respiratory, thoracic and mediastinal disorders bronchiectasis      subjects affected / exposed 1 / 100 (1.00%) 0 / 100 (0.00%)      occurrences causally related to treatment / all 1 / 1 0 / 0      deaths causally related to treatment / all 0 / 0 0 / 0 Hepatobiliary disorders cholecystitis      subjects affected / exposed 0 / 100 (0.00%) 1 / 100 (1.00%)      occurrences causally related to treatment / all 0 / 0 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0 Psychiatric disorders suicide attempt or depression      subjects affected / exposed 0 / 100 (0.00%) 2 / 100 (2.00%)      occurrences causally related to treatment / all 0 / 0 2 / 2      deaths causally related to treatment / all 0 / 0 0 / 0 Infections and infestations pneumonia, pyelonephritis, or SARS-CoV-2      subjects affected / exposed 2 / 100 (2.00%) 1 / 100 (1.00%)      occurrences causally related to treatment / all 2 / 2 1 / 1      deaths causally related to treatment / all 0 / 0 0 / 0
Frequency threshold for reporting non-serious adverse events: 0%
Non-serious adverse events Rituximab Dimethyl Fumarate (DMF) Total subjects affected by non serious adverse events      subjects affected / exposed 0 / 100 (0.00%) 0 / 100 (0.00%)

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
13 Apr 2017	- Extended inclusion age from 18 – 40 years of age (YOA) to 18 – 50 YOA; - Extended inclusion from 5 years disease duration to 10 years disease duration
30 Mar 2020	- The protocol was adapted to the emerging COVID-19 pandemic allowing longer infusion intervals in the rituximab arm and consequently prolongation of the study
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported
Online references
http://www.ncbi.nlm.nih.gov/pubmed/35841908

More information Top of page