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Rituximab for relapsing-remitting multiple sclerosis

  1. Dian He1,
  2. Rui Guo2,
  3. Fubo Zhang3,
  4. Chao Zhang4,
  5. Shuai Dong2,
  6. Hongyu Zhou5,*

Editorial Group: Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group

Published Online: 6 DEC 2013

Assessed as up-to-date: 9 AUG 2013

DOI: 10.1002/14651858.CD009130.pub3


How to Cite

He D, Guo R, Zhang F, Zhang C, Dong S, Zhou H. Rituximab for relapsing-remitting multiple sclerosis. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.: CD009130. DOI: 10.1002/14651858.CD009130.pub3.

Author Information

  1. 1

    Affiliated Hospital of Guiyang Medical College, Department of Neurology, Guiyang, Guizhou Province, China

  2. 2

    Jinan No. 6 People's Hospital, Department of Neurology, Jinan, Shandong Province, China

  3. 3

    Cangzhou City Cemtral Hospital, Department of Neurology, Cangzhou, Hebei Province, China

  4. 4

    Jinan No. 6 People's Hospital, Department of Internal Medicine, Jinan, Shandong Province, China

  5. 5

    West China Hospital, Sichuan University, Department of Neurology, Chengdu, Sichuan, China

*Hongyu Zhou, Department of Neurology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, Sichuan, 610041, China. Hyzhou98@yahoo.com.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 6 DEC 2013

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Characteristics of included studies [ordered by study ID]
Hauser 2008

MethodsThe trial was a phase 2, randomized, double-blind, placebo-controlled, 48-week trial conducted at 32 centres in the United States and Canada

Study start date: December 2004

Study completion date: December 2006

Follow-up period: 48 weeks


ParticipantsInclusion criteria: (1) patients 18 to 55 years of age with a diagnosis of RRMS; (2) at least one relapse during the preceding year; (3) an entry score of 0 to 5.0 on the EDSS

Exclusion criteria: (1) disease categorized as secondary progressive, primary progressive, or progressive relapsing disease; (2) relapse within 30 days; (3) cyclophosphamide or mitoxantrone treatment within 12 months; (4) systemic corticosteroid therapy within 30 days; (5) treatment with interferon-beta, glatiramer acetate, natalizumab, plasmapheresis, or intravenous immune globulin within 60 days; (6) or non-lymphocyte-depleting immunosuppressive therapies within 90 days

Baseline characteristics were generally balanced between the two groups except for the proportion of patients without gadolinium-enhancing lesions (higher in the placebo group than in the rituximab group, 85.7% versus 63.8%, P = 0.02)

Summary of patient characteristics at baseline (placebo: G1 (n = 35), rituximab: G2 (n = 69)):

Age: G1 = 41.5±8.5 years, G2 = 39.6±8.7 years

Sex: female G1 = 29 (82.9%), G2 = 52 (75.4%); male G1 = 6 (17.1%), G2 = 17 (24.6%)

Disease duration: since onset G1 = 9.6±7.1 years, G2 = 9.6±6.4 years; since diagnosis G1 = 6.9±6.2 years, G2 = 6.2±5.2 years

Relapses in past year: 0 relapse G1 = 2 (5.7%), G2 = 4 (5.8%); 1 relapse G1 = 27 (77.1%), G2 = 52 (75.4%); 2 relapse G1 = 5 (14.3%), G2 = 8 (11.6%); 3 relapse G1 = 0, G2 = 4 (5.8%); ≥4 relapse G1 = 1 (2.9%), G2 = 1 (1.4%); median (range) G1 = 1.0 (0-5), G2 = 1.0 (0-4)

EDSS score: 0 G1 = 1 (2.9%), G2 = 2 (2.9%); 1.0-1.5 G1 = 8 (22.9%), G2 = 9 (13.0%); 2.0-2.5 G1 = 10 (28.6%), G2 = 24 (34.8%); 3.0-3.5 G1 = 7 (20%), G2 = 20 (29.0%); 4.0-4.5 G1 = 7 (20%), G2 = 11 (15.9%); 5.0 G1 = 2 (5.7%), G2 = 3 (4.3%); median (range) G1 = 2.5 (0-5), G2 = 2.5 (0-5)

Previous treatment with interferon-beta or glatiramer acetate: none or discontinued >6 months before study entry G1 = 21 (60%), G2 = 44 (63.8%); treatment within 6 months before study entry G1 = 14 (40%), G2 = 25 (36.2%)

Any key therapy for MS in previous 2 years: glatiramer acetate G1 = 8 (22.9%), G2 = 18 (26.1%); interferon beta-1a G1 = 16 (45.7%), G2 = 24 (34.8%); interferon beta-1b G1 = 5 (14.3%), G2 = 13 (18.8%); methylprednisolone or methylprednisolone sodium succinate G1 = 8 (22.9%), G2 = 19 (27.5%); natalizumab G1 = 2 (5.7%), G2 = 5 (7.2%)

Any key therapy for MS: G1 = 27 (77.1%), G2 = 54 (78.3%)

Gadolinium-enhancing lesions: 0 lesions G1 = 30 (85.7%), G2 = 44 (63.8%); 1 lesion G1 = 2 (5.7%), G2 = 7 (10.1%); 2 lesions G1 = 2 (5.7%), G2 = 4 (5.8%); 3 lesions G1 = 0, G2 = 2 (2.9%); ≥4 lesions G1 = 1 (2.9%), G2 = 11 (15.9%); mean lesions G1 = 0.3±0.8, G2 = 2.1±5.6; median lesions (range) G1 = 0 (0-4), G2 = 0 (0-36)

Volume of lesions detected on MRI: on gadolinium-enhanced MRI, mean G1 = 29.2±127.5 mm3, G2 = 211.6±702.2 mm3; median G1 = 0, G2 = 0; on T2-weighted MRI, mean G1 = 5723.1±5514.8 mm3, G2 = 6452.2±8022.2 mm3; median G1 = 4032.0, G2 = 2878.5; on T1-weighted MRI, mean G1 = 717.6±1025.0 mm3, G2 = 784.2±1206.4 mm3; median G1 = 369.0, G2 = 211.0


InterventionsExperimental group: 1000 mg intravenous infusions of rituximab on study days 1 and 15, before each infusion, acetaminophen (at a dose of 1 g) and diphenhydramine hydrochloride (at a dose of 50 mg) were administered orally 30 to 60 minutes beforehand as premedication

Control group: 1000 mg intravenous infusions of placebo on study days 1 and 15, before each infusion, acetaminophen (at a dose of 1 g) and diphenhydramine hydrochloride (at a dose of 50 mg) were administered orally 30 to 60 minutes beforehand as premedication


OutcomesThe primary outcome measures: the sum of the number of gadolinium-enhancing lesions on serial T1-weighted MRI brain scans at weeks 12, 16, 20, and 24. Lesions that persisted for more than 4 weeks were counted more than once.

Secondary outcome measures: (1) the total number of new gadolinium-enhancing lesions observed on serial T1-weighted MRI brain scans at weeks 12, 16, 20, and 24 (lesions persisting for more than 4 weeks were counted only once); (2) the change from the baseline lesion volume on T2-weighted MRI scans; (3) the proportion of patients with relapses at week 24 and week 48; (4) the annualised rate of relapse from week 0 to week 24 and week 0 to week 48; (5) safety. Relapse was defined as new or recurrent neurologic symptoms that were consistent with MS, lasted for at least 48 hours, and were preceded by a relatively stable or improving neurologic state for at least 30 days.


NotesThe study was originally designed to enroll 280 patients but before the primary endpoint at week 24, the sample-size target was reduced to 99 patients. With such a sample size the study would have 70% power at a two-sided significance level of 0.05.

The study was designed jointly by Genentech and the investigators and supported by Biogen Idec and Genentech. Data were collected by the investigators and held and analysed by Genentech. ClinicalTrials.gov Identifier: NCT00097188.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomly assigned in a 2:1 ratio to receive rituximab or placebo, and they were hierarchically stratified according to study site, status with respect to previous treatment with interferon beta or glatiramer acetate (either no treatment or discontinuation of medication ≥6 months previously versus treatment within the previous 6 months), and baseline disease severity according to the Expanded Disability Status Scale (EDSS) score (≤2.5 versus >2.5)".

Comment: the authors did not mention the specific method of random sequence generation. We wrote to the principal author (hausers@neurology.ucsf.edu) for the methodological information, but we got no reply. The risk of selection bias was unclear.

Allocation concealment (selection bias)Unclear riskThe authors did not mention the specific method of allocation concealment. We wrote to the principal author but we got no reply. The risk of selection bias was unclear.

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "This trial was double-blinded. Each site had both a treating investigator and an examining investigator. The treating investigator was the safety assessor, and the examining investigator was the efficacy assessor. Staff members from a central MRI reading center who were unaware of the data evaluated all scans. Data were collected by the investigators and held and analyzed by Genentech."

Comment: the participants, personnel and the outcomes assessors in this study were blinded to the allocated interventions. The risks of performance bias and detection bias were low.

Incomplete outcome data (attrition bias)
All outcomes
High riskAccording to the table showing study sample and reasons for study discontinuation, of the 104 patients 96 (92.3%) completed 24 weeks, and 79 patients (76.0%) completed 48 weeks; 66 (95.7%) in the rituximab group and 30 (85.7%) in the placebo group completed 24 weeks; 58 (84.1%) in the rituximab group and 21 (60.0%) in the placebo group completed 48 weeks; 11 patients (15.9%) in the rituximab group and 14 patients (40.0%) in the placebo group discontinued before week 48. Reasons for discontinuation (placebo: G1, rituximab: G2): death G1 0, G2 1 (1.4%); adverse events G1 = 0, G2 = 1 (1.4%); pregnancy G1 = 1 (2.9%), G2 0; lost to follow-up G1 = 2 (5.7%), 2 (2.9%); patient's decision G1 = 4 (11.4%), G2 = 0; physician's decision G1 = 3 (8.6%), G2 = 3 (4.3%); relapse G1 = 2 (5.7%), G2 = 2 (2.9%); initiation of excluded therapy G1 = 2 (5.7%), G2 = 2 (2.9%). A last observation carried forward imputation strategy was used for the missing data. The intention-to-treat principle was used for analyses.

Comment: a risk of attrition bias could have resulted from the high rate of dropouts (24%) over the period of 48 weeks and the imbalance in the reasons for discontinuation between the two groups. Although a last observation carried forward imputation strategy was used for the missing data and the intention-to-treat principle was used for analyses, the high rate of dropouts had a potential impact on the results. Generally, the higher the ratio of participants with missing data to participants with events, the greater potential there is for bias, especially for the high frequency of events. The potential impact of missing continuous outcomes increases with the proportion of participants with missing data. Both MS relapse and the occurrence of gadolinium-enhancing T1-weighted lesions are common events. The risk of attrition bias was high.

Selective reporting (reporting bias)Low riskAll listed outcomes were reported adequately. The risk of reporting bias was low

Other biasUnclear riskQuote: "The study was designed jointly by Genentech and the investigators"

Comment: conflict of interests may exist

Quote: "At baseline the proportion of patients without gadolinium-enhancing lesions was greater in the placebo group than in the rituximab group (85.7% versus 63.8%, P = 0.02)"

Comment: this may have led to biased results

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Bar-Or 2008An open-label trial

Naismith 2010An uncontrolled trial

 
Characteristics of ongoing studies [ordered by study ID]
NCT01569451

Trial name or titleA Double Blinded, Placebo Controlled, Randomized Study Comparing Rituximab Induction Therapy Followed by Glatiramer Acetate Therapy to Glatiramer Acetate Monotherapy in Patients With Relapsing Forms of Multiple Sclerosis

MethodsNot yet assessed

ParticipantsInclusion criteria:

(1) 18 through 55 years of age

(2) Patients with CIS demonstrating one unifocal neurological event and at least 2 T2-weighted brain lesions measuring a minimum of 6 mm in diameter by MRI analysis; or a definite diagnosis of RMS, as defined by the 2005 revised McDonald criteria, and have had at least one clinically defined relapse within the past year or one GEL on an MRI within the past year

(3) Women of child-bearing potential must agree to practice an acceptable method of birth control

(4) No evidence of progressive multifocal leukoencephalopathy (PML) or primary central nervous system (PCNS) lymphoma

(5) Neurologically stable with no evidence of relapse or corticosteroid treatment within 30 days prior to randomisation

Exclusion criteria:

(1) ≥ 15 GELs on baseline MRI

(2) Treatment with interferon-β, natalizumab, or fingolimod within three months of randomisation; or treatment with mitoxantrone, cyclophosphamide, or any other chemotherapeutic agent for MS or malignancy within 12 months of randomisation; or any prior treatment with alemtuzumab or cladribine

(3) Attenuated live virus vaccination within 4 weeks of randomisation; or positive urine and serum pregnancy test at screening or baseline visit

(4) Unable to tolerate GA; or inability to undergo MRI scans or history of hypersensitivity to gadolinium- diethylenetriamine penta-acetic acid (DTPA)

(5) History of cardiac arrhythmias, angina or any other significant cardiac abnormalities; or history of clinically significant chronic disease of the immune system or a known immunodeficiency syndrome (HIV) other than MS; or history or presence of malignancy (except basal cell carcinoma); or positive for any evidence of past, or current, hepatitis B or C infection

(6) White blood cell count of less than 2.5x109/L or lymphocyte count below 0.4x109/L

(7) Clinically significant alcohol or drug abuse within past two years; or any medical, psychiatric or other condition that could result in a subject not being able to give fully informed consent or to comply with the protocol requirements

(8) Participation in any clinical study evaluating another investigational drug or therapy within three months prior to randomisation

InterventionsIntervention group:

(1) Intravenous (IV) infusion of 1000 mg of rituximab on study days 1 (baseline visit) and 15

(2) Glatiramer acetate 20 mg injected subcutaneously daily

Active comparator:

(1) intravenous (IV) infusion of placebo (normal saline) on study days 1 (baseline visit) and 15

(2) Glatiramer acetate 20 mg injected subcutaneously daily

OutcomesPrimary outcome measures: number of disease-free patients. Defined as patients without new lesions on brain MRI using the combined unique lesion approach (CUL), without sustained change in EDSS score over any 3-month period and without relapse

Secondary outcome measures:

(1)Time to treatment failure

(2) Percentage of subjects that fail treatment

(3) Proportion of relapse-free subjects

(4) Frequency of corticosteroid use

(5) Percentage of subjects who experience multiple relapses

(6) Number of patients that develop sustained accumulation of disability

(7) Change from baseline to the end of study on the Multiple Sclerosis Functional Composite (MSFC) z-score

(8) Percentage of subjects worsening one point or more on the Patient Determined Disease Steps (PDDS) questionnaire

(9) Change in mean score on performance scales

Starting dateFebruary 2012

Contact informationMimi Burch: University of Colorado Hospital, Aurora, Colorado, United States, 80045. Phone: 303-724-6632; Email address: Mimi.Burch@ucdenver.edu

Nicole Gendelman: Phone: 303-724-2197; Email address: Nicole.Gendelman@ucdenver.edu

Principal investigator: Timothy Vollmer, MD. University of Colorado, Denver

NotesOther Study ID Numbers: 10-1143

http://clinicaltrials.gov/ct2/show/NCT01569451

 
Summary of findings for the main comparison. Rituximab for relapsing-remitting multiple sclerosis

Rituximab for relapsing-remitting multiple sclerosis

Patient or population: patients with relapsing-remitting multiple sclerosis
Settings: this trial was performed in the United States and Canada
Intervention: rituximab

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlRituximab

The annualised rate of relapse
Scale from: 0 to infinity.
Follow-up: mean 48 weeks
The mean the annualised rate of relapse in the control groups was
0.72
The mean the annualised rate of relapse in the intervention groups was 0.35 lower
(0.75 to 0.05 lower)
104
(1 study)
⊕⊕⊝⊝
low1,2

The sum of the number of gadolinium-enhancing T1-weighted lesions
Scale from: 0 to infinity.
Follow-up: mean 24 weeks
The mean the sum of the number of gadolinium-enhancing t1-weighted lesions in the control groups was
5.5
The mean the sum of the number of gadolinium-enhancing t1-weighted lesions in the intervention groups was
5 lower
(0.75 to 0.01 lower)
104
(1 study)
⊕⊕⊝⊝
low1,2

The number of patients with adverse effects
Follow-up: mean 48 weeks
HighRR 0.99
(0.94 to 1.05)
104
(1 study)
⊕⊕⊝⊝
low1,2

100 per 10099 per 100
(94 to 100)

The number of patients with serious adverse events
Follow-up: mean 48 weeks
LowRR 0.91
(0.33 to 2.52)
104
(1 study)
⊕⊕⊝⊝
low1,2

143 per 1000130 per 1000
(47 to 360)

The number of patients who withdrew or dropped out from the study because of AEs
Follow-up: mean 48 weeks
LowRR 0.76
(0.13 to 4.35)
104
(1 study)
⊕⊕⊝⊝
low1,2

57 per 100043 per 1000
(7 to 248)

The number of patients with disability progressionStudy populationNot estimable0
(0)
See commentThis outcome was not included as an endpoint in the trial.

See commentSee comment



The time to confirmed disease progressionStudy populationNot estimable0
(0)
See commentThis outcome was not included as an endpoint in the trial.

See commentSee comment



*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 This study had a high rate of dropouts (24.0%), and the methodology for random sequence generation and allocation concealment was unclear.
2 This study had a small sample size and would only have 70% power for the primary endpoint.