Mycophenolate mofetil for relapsing-remitting multiple sclerosis

  • Review
  • Intervention

Authors


Abstract

Background

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system and a leading cause of disability in young and middle-aged adults. Mycophenolate mofetil (MMF) is an immunosuppressive agent that has been used for the prevention of allograft rejection after renal, cardiac, or liver transplant and in patients with autoimmune diseases such as active relapsing-remitting (RRMS) and progressive MS.

Objectives

To assess the efficacy and safety of MMF for preventing disease activity in patients with RRMS.

Search methods

We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (January 14, 2013). We searched three Chinese databases (January 2013) and checked reference lists of identified trials. We contacted authors and pharmaceutical companies to ask for additional information. We applied no language restrictions.

Selection criteria

We included randomized controlled trials with a follow-up of at least 12 months that compared MMF as monotherapy or in combination with other treatments versus placebo, another drug, or the same cointervention as the treated group.

Data collection and analysis

Two review authors independently selected the trials for inclusion, assessed trial quality, and extracted data.

Main results

One included study involving 26 participants with new-onset RRMS investigated the efficacy and safety of MMF (13 participants) versus placebo in interferon β-1a–treated participants. It was assessed to be at high risk of bias, and had a small numbers of participants receiving treatment with short-term duration. There was inadequate information provided by the study to determine the effect of MMF in reducing relapses, preventing disability progression, or developing new T2- or new gadolinium (Gd)-enhanced lesions on magnetic resonance imaging (MRI) after a 12-month follow-up period. No data were available at 24 months. No serious adverse effects were reported. All participants in the MMF-treated group suffered from gastrointestinal upset, but none of them discontinued therapy as a result.

Authors' conclusions

The evidence we found from one small study was insufficient to determine the effects of MMF as an add-on therapy for interferon β-1a in new-onset RRMS participants.

Résumé scientifique

Le mycophénolate mofétil pour la sclérose en plaques récurrente-rémittente

Contexte

La sclérose en plaques (SEP) est une maladie auto-immune du système nerveux central et une cause majeure d'invalidité chez les adultes jeunes et d'âge mûr. Le mycophénolate mofétil (MMF) est un agent immunosuppresseur qui a été utilisé pour prévenir le rejet de l'allogreffe rénale, cardiaque ou hépatique, et chez les patients atteints de maladies auto-immunes telles que la SEP récurrente-rémittente (SEP-RR) active et la SEP progressive.

Objectifs

Évaluer l'efficacité et l'innocuité du MMF pour la prévention de l'activité de la maladie chez les patients atteints de SEP-RR.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur la sclérose en plaques et les maladies rares du système nerveux central (le 14 janvier 2013). Nous avons effectué des recherches dans trois bases de données chinoises (en janvier 2013) et examiné les références bibliographiques des essais identifiés. Nous avons contacté les auteurs et sociétés pharmaceutiques concernés pour obtenir des informations supplémentaires. Nous n'avons appliqué aucune restriction concernant la langue.

Critères de sélection

Nous avons inclus les essais contrôlés randomisés avec un suivi d'au moins 12 mois qui comparaient le MMF en monothérapie ou en association avec d'autres traitements par rapport à un placebo, un autre médicament, ou la même co-intervention que le groupe traité.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment sélectionné les essais à inclure, évalué la qualité des essais et extrait les données.

Résultats principaux

Une étude incluse, portant sur 26 participants atteints de SEP-RR nouvellement diagnostiquée, examinait l'efficacité et l'innocuité du MMF (13 participants) par rapport à un placebo chez des patients traités par l'interféron β-1a. Elle a été évaluée comme étant à risque élevé de biais, et avait un petit nombre de participants ayant reçu un traitement de courte durée. Les informations fournies par l'étude étaient insuffisantes pour déterminer l'effet du MMF dans la réduction des rechutes, la prévention de la progression de l'invalidité, ou le développement de nouvelles lésions en T2 ou rehaussées par gadolinium (Gd) sur l'imagerie par résonance magnétique (IRM) après une période de suivi de 12 mois. Aucune donnée n'était disponible à 24 mois. Aucun effet indésirable grave n'a été rapporté. Tous les participants dans le groupe traité par le MMF ont souffert de troubles gastro-intestinaux, mais aucun d'entre eux n'a arrêté le traitement en conséquence.

Conclusions des auteurs

Les preuves issues d'une étude de petite taille sont insuffisantes pour déterminer les effets du MMF en traitement complémentaire à l'interféron β-1a chez les participants atteints de SEP-RR nouvellement diagnostiquée.

Plain language summary

Mycophenolate mofetil for relapsing-remitting multiple sclerosis

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system. Preliminary data show that mycophenolate mofetil (MMF), an immunosuppressive agent, might be beneficial for MS patients. The authors of this review evaluated the efficacy and safety of MMF in patients with relapsing-remitting MS. Only one small study met the inclusion criteria, and it compared MMF versus placebo in 26 interferon β-1a–treated patients. The results showed no evidence favoring MMF in reducing relapses or preventing disability progression after a 12-month follow-up period. No data were available at 24 months. All patients receiving MMF suffered from gastrointestinal upset, and one had a transient diarrhea, but no serious adverse effects were reported.

Résumé simplifié

Le mycophénolate mofétil pour la sclérose en plaques récurrente-rémittente

La sclérose en plaques (SEP) est une maladie auto-immune du système nerveux central. Les données préliminaires montrent que le mycophénolate mofétil (MMF), un agent immunosuppresseur, pourrait être bénéfique pour les patients atteints de SEP. Les auteurs de cette revue ont évalué l'efficacité et l'innocuité du MMF chez les patients atteints de SEP récurrente-rémittente. Une seule petite étude répondait aux critères d'inclusion, et il comparait le MMF par rapport à un placebo chez 26 patients traités par l'interféron β-1a. Les résultats n'ont montré aucune preuve en faveur du MMF dans la réduction des rechutes ou dans la prévention de la progression de l'invalidité après une période de suivi de 12 mois. Aucune donnée n'était disponible à 24 mois. Tous les patients recevant le MMF ont souffert de troubles gastro-intestinaux, dont un de diarrhée transitoire, mais aucun effet indésirable grave n'a été rapporté.

Notes de traduction

Traduit par: French Cochrane Centre 15th June, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Laički sažetak

Mikofenolat mofetil za relapsirajuće-remitirajuću multiplu sklerozu

Multipla skleroza je imunološki posredovana bolest središnjeg živčanog sustava. Preliminarni podatci pokazuju da mikofenolat mofetil (MMF), lijek koji potiskuje imunološki sustav, može biti koristan za oboljele od multiple skleroze. Autori Cochrane sustavnog pregleda procijenili su učinkovitost i sigurnost MMF-a u oboljelih od relapsirajuće-remitirajuće multiple skleroze. Pronađena je samo jedna malena klinička studija koja je odgovarala kriterijima uključenja. U tu je studiju bilo uključeno svega 26 pacijenata s novonastalom remitirajuće-relapsirajućom multiplom sklerozom liječenih interferonom-beta-1a koji su podijeljeni u skupinu koja je primala MMF (13 ispitanika) i skupinu koja je primala placebo (13 ispitanika). Rezultati nisu pokazali koristan učinak MMF-a za smanjenje relapsa ili sprječavanje napredovanja onesposobljenosti nakon 12-mjesečnog razdoblja praćenja. Podatci za razdoblje od 24 mjeseca nakon početka terapije nisu bili dostupni. Svi pacijenti koji su primali MMF razvili su probavne tegobe, a jedan je imao prolazni proljev, ali nisu prijavljene ozbiljne nuspojave.

Bilješke prijevoda

Hrvatski Cochrane ogranak.
Prevela: Livia Puljak

Background

Description of the condition

Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system and a leading cause of disability in young and middle-aged adults (Koch-Henriksen 2010). It affects approximately 400,000 Americans and 2.5 million people worldwide (Vollmer 2007), with an overall incidence rate of 3.6 cases per 100,000 person-years in women and 2.0 in men (Alonso 2008). Different clinical types of MS are distinguishable. About 80% of patients have a disease course characterized by relapses and remissions (relapsing-remitting MS [RRMS]), and the remaining patients have primary or transitional progressive MS (PPMS) and experience a progressive decline in neurological function from the onset. People with MS and their families are affected by their disabling condition, and society carries a substantial economic burden. In the United States, annual costs of drugs and other medical care per patient are estimated to average USD 47,215 (Kobelt 2006).

Description of the intervention

Mycophenolate mofetil (MMF) is an expensive immunosuppressive agent that has been used in the past few years for the prevention of allograft rejection after renal, cardiac, or liver transplant (Villarroel 2009). It is increasingly used in the treatment of autoimmune diseases such as MS because of its potential efficacy and safety (Etemadifar 2011; Frohman 2010; Remington 2010; Vermersch 2007). MMF, a prodrug of mycophenolic acid (MPA), is a compound that was synthesized to improve the bioavailability of MPA. After oral or intravenous administration, MMF is rapidly converted to MPA in the plasma, resulting in a bioavailability of MPA of 94% (Lipsky 1996). MPA is rapidly conjugated to a glucuronide that is excreted in the urine; its plasma elimination half-life is approximately 17.9 hours (Zwerner 2007). Generally, MMF is well tolerated; the most frequently reported adverse effects have been gastrointestinal (abdominal pain, vomiting, diarrhea) or related to the hematopoietic system (anemia and leukopenia) (Hood 1997; Kulkarni 2004; Lipsky 1996). Hematopoietic adverse effects have been reported in about 10% of study participants (Kulkarni 2004). In addition, MMF has been reported on occasion to increase the risk of certain malignancies (Hood 1997; Kulkarni 2004). The recommended oral dose of MMF ranges from 1.0 to 1.5 g/d twice daily.

How the intervention might work

MMF is a selective inhibitor of inosine 5'-monophosphate dehydrogenase type II, an important enzyme that is responsible for the de novo synthesis of the purine nucleotide guanine within activated T and B lymphocytes and macrophages (Allison 2000; Frohman 2004; Zwerner 2007). Therefore, it exerts its immunomodulatory activities through inhibition of both T and B lymphocyte proliferation, reducing the synthesis of antibodies. MPA, the active metabolite of MMF, has been shown to prevent the production of interferon-gamma (IFN-γ), lipopolysaccharide (LPS)-induced interleukin-6 (IL-6), and nitric oxide (NO) (Frohman 2004; Miljkovic 2002), which may lead to decreased inflammation and cytotoxic effects to the central nervous system. Hence, MMF may be useful in the treatment of patients with MS.

Why it is important to do this review

MMF has been increasingly used for the treatment of patients with RRMS and has shown some promising therapeutic effects (Etemadifar 2011; Frohman 2004; Frohman 2010; Remington 2010; Vermersch 2007), but it has not been systematically reviewed. The aim of this review was to investigate efficacy and safety in randomized trials evaluating MMF for patients with RRMS,

Objectives

To assess the efficacy and safety of MMF for preventing disease activity in patients with RRMS.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCTs) and randomized cross-over trials were included. RCTs with follow-up less than or equal to six months were excluded.

Types of participants

Patients of all age groups and genders with clinically definite RRMS according to Poser criteria (Poser 1983) or original or revised McDonald criteria (McDonald 2001; Polman 2005; Polman 2011) were eligible for inclusion.

Types of interventions

MMF as monotherapy or in combination with other treatment versus placebo or another active agent, or the same cointervention as was used in the the MMF group.

Types of outcome measures

Primary outcomes
  1. Proportions of participants who had relapses at 12 and 24 months after randomization.

  2. Proportions of participants who experienced disease progression, as measured by the Expanded Disability Status Scale (EDSS) (Kurtzke 1983), at 12 and 24 months after randomization. Progression is defined as an increase of 0.5 point of disability for participants with baseline EDSS greater than or equal to 5.5, and 1.0 point of disability for those with basal EDSS less than or equal to 5.0, sustained for six months.

Secondary outcomes
  1. Proportions of participants who developed new T2- or new Gd-enhanced lesions (GELs) on magnetic resonance imaging (MRI) at 12 and 24 months after randomization.

  2. Numbers of new T2-enhanced lesions or GELs on MRI at 12 and 24 months after randomization.

  3. Proportions of participants who experienced any of the following side effects were evaluated: abdominal pain, vomiting, diarrhea, anemia, leukopenia, and infection, or other severe adverse effects. 

Search methods for identification of studies

Electronic searches

The Review Group's Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register (January 14, 2013), which, among other sources, contains the following.

  1. The Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 1).

  2. MEDLINE (PubMed) (1966 to January 14, 2013).

  3. EMBASE (EMBASE.com) (1974 to January 14, 2013).

  4. CINAHL (EBSCO host) (1981 to January 14, 2013).

  5. LILACS (Bireme) (1982 to January 14, 2013).

  6. PEDro (1990 to January 14, 2013).

  7. Clinical trial registries (http://clinicaltrials.gov).

Information on the Review Group's Trials Register and details of search strategies used to identify trials can be found in the "Specialised register" section within the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group's module.

The keywords used in the search strategy are listed in Appendix 1.

Additional databases were searched by the review authors.

The following three Chinese databases were searched using the search terms (duofaxingyinghua) AND ((matimaikaofenzhi) OR (maikaofensuan)).

  1. China Biological Medicine Database (CBM-disc) (1979 to January 20, 2013).

  2. Chinese National Knowledge Infrastructure Database (CNKI) at www.cnki.net (1979 to January 20, 2013).

  3. VIP Chinese Science and Technique Journals Database (1979 to January 20, 2013).

Searching other resources

To identify other relevant study data, we:

  1. contacted authors of published studies when data reported were incomplete;

  2. screened reference lists of review articles and primary studies identified; and

  3. contacted the pharmaceutical company (Roche Pharmaceutical Co., Ltd.) that produces MMF to identify further published or unpublished trials.

Data collection and analysis

Selection of studies

Two review authors (XY and HJ) independently read titles and abstracts of all references identified by the search and excluded irrelevant references. The full texts of the remaining studies were obtained, and the same two review authors independently evaluated each trial for inclusion. Disagreements were resolved by discussion among all review authors.

Data extraction and management

Two review authors (XY and HJ) independently extracted the following data using a predefined data extraction form.

  1. Participants: diagnostic criteria, number in each group, age, gender, baseline clinical characteristics, and withdrawals or losses to follow-up.

  2. Methods: study design, randomization, allocation concealment, blinding, and intention-to-treat analysis.

  3. Interventions: details of MMF and control intervention, such as dosage and duration, treatment period, and cointerventions.

  4. Outcomes: primary and secondary outcomes and adverse effects.

  5. Other: country and setting, publication year, and sources of funding.

Disagreements were resolved by discussion among all review authors.

Assessment of risk of bias in included studies

Two review authors (XY and HJ) independently assessed the risk of bias (RoB) of included studies using the Q Cochrane Collaboration criteria (Higgins 2011). These included random sequence generation, allocation concealment, blinding of participants and outcome assessors, incomplete outcome data, selective outcome reporting, and other bias. The RoB of each study was explicitly judged on each criterion, and each study was classified as having "low," "high," or "unclear" risk of bias. Disagreements were resolved by discussion among all review authors.

Measures of treatment effect

We did not perform a meta-analysis because only one study was included in this review. If new data become available in the future, we will present the results for dichotomous outcomes using risk ratios (RRs) with 95% confidence intervals (CIs), and for continuous outcomes, mean differences (MDs) with 95% CIs.

Unit of analysis issues

The unit of data extraction, evaluation, and analysis was the primary randomized trial.

Dealing with missing data

Review authors contacted study authors to request additional data not reported in the included study; however, we received no response.

Assessment of heterogeneity

As only one study was included in this review, we did not assess heterogeneity. If further studies will be available in future updates, we will assess statistical heterogeneity by calculating the Chi² test and the I² statistic. If the I² statistic will be greater than 50%, which indicates substantial heterogeneity (Higgins 2011), potential sources of heterogeneity will include different baseline characteristics of participants (diagnostic criteria, age, gender, disease duration), interventions (administration method, dosage and duration, control intervention, cointerventions), and study designs (allocation concealment, blinding methods, incomplete outcome data). We will investigate the distribution of these characteristics and will carry out a subgroup analysis for efficacy outcomes at each time point.

Assessment of reporting biases

If sufficient studies will be identified in the future, potential biases of reporting will be assessed by using funnel plots and visual inspection for asymmetry according to the approach outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Data synthesis

Review Manager 5.2 software (RevMan 2013) will be used to synthesize the results. If sufficient studies are identified in future updates of the review, the selection of a fixed-effect model or a random-effects model will be based on results of the Chi² test and the I² statistic for heterogeneity (Higgins 2011). If the I² statistic indicates substantial statistical heterogeneity, we will explore potential causes of heterogeneity first, to determine whether a subgroup analyses is needed. If the substantial heterogeneity still cannot be explained, we will adopt a random-effects model. If the I² statistic indicates no significant statistical heterogeneity, we will use a fixed-effect model.

Subgroup analysis and investigation of heterogeneity

If we identify a sufficient number of studies in future updates, the following subgroup analyses will be performed.

  1. Treatment dose and duration.

  2. Cointerventions.

  3. Types of control groups.  

Sensitivity analysis

The RoB ("low," "high," or "unclear" risk of bias) of included studies will be taken into account in the interpretation of evidence.

Results

Description of studies

See Characteristics of included studies and Characteristics of excluded studies.

Results of the search

A flow chart describes the results of the electronic search (Figure 1). Twenty-seven references were identified. After screening titles and abstracts, we excluded 19 references, as they were not relevant. Of the remaining eight references, we excluded five studies (seven references) (Frohman 2004; Frohman 2010; NCT00618527; Remington 2010; Vermersch 2007); the reasons for exclusion were carefully recorded in the Characteristics of excluded studies table. One study (NCT00324506) was completed in June 2013, but only partial short-term results were published (Frohman 2010). One study (Etemadifar 2011) was included in the review.

Figure 1.

Study flow diagram.

Included studies

A randomized, blinded, placebo-controlled study (Etemadifar 2011) enrolled a total of 26 participants with RRMS. This study investigated the efficacy and safety of oral MMF 2000 mg daily versus placebo in IFN-β-1a–treated participants. All 26 participants completed the 12-month follow-up period and were included in the final analysis. The primary outcome was the number of new T2 lesions and new GELs noted on MRI evaluation; secondary outcomes included relapse rates, changes in EDSS score, and adverse effects. Details of the study are outlined in the Characteristics of included studies table.

Excluded studies

Five studies were excluded for the following reasons: Frohman 2004 was a retrospective review; Vermersch 2007 was a case series without a control group; Remington 2010 enrolled both participants with early RRMS and those with clinically isolated syndrome (CIS), and no separate data were available; Frohman 2010 had a short-term (six out of 12 months as planned) follow-up study of MMF compared with IFN-β in participants with RRMS; NCT00618527 was an experimental study that evaluated mRNA for levels of the MxA gene, a marker of IFN bioactivity, as measured after treatment.

One study awaiting classification (NCT00324506) was completed in June 2013, but only partial short-term results were published (Frohman 2010). In the second-phase evaluation (12 months after the beginning of the study), MRIs and clinical examinations are planned for participants treated with active combination therapy consisting of both MMF and IFN-β-1a.

Risk of bias in included studies

See overall results of risk of bias (RoB) assessments as summarized in Characteristics of included studies, Figure 2, and Figure 3.

Figure 2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

The method of allocation concealment was not described. It is unclear whether all potentially eligible patients were approached for participation, and whether the results reflect a continuous series of participants or a selected series.

Blinding

This study did not blind clinical outcome assessors or treating personnel to the study arm allocation. In addition, no description was provided of whether MMF and placebo with identical appearance and packaging were provided.

Incomplete outcome data

All participants completed the 12-month follow-up period and were included in the final analysis. We judged this study to be at low risk of attrition bias.

Selective reporting

All specified primary and secondary outcomes were reported. However, the interval of confirmation used to assess sustained disability progression was not reported. Poor reporting of adverse effects was another major limitation of the study.

Other potential sources of bias

Sample size calculation was not clearly reported. Small sample size led to an inadequately powered trial. No description was provided of the source of the MMF and placebo (eg, sponsored by a pharmaceutical company or other).

Effects of interventions

MMF plus IFN versus placebo plus IFN

Primary outcomes

In light of the fact that only a single trial was suitable for inclusion, no meta-analysis was performed; instead, outcome measures reported in the trial were described.

1. Proportions of participants who had relapses at 12-month and 24 months after randomization.

One participant in the placebo group had a relapse compared with no participants in the MMF group. No data were available at 24 months.

2. Proportions of participants who experienced disease progression at 12-month and 24 months after randomization.

Three participants in each group experienced more than one-point progression in EDSS at 12-month follow-up. The study authors reported no significant differences between groups in EDSS scores at 12-month follow-up. No data were available at 24 months.

Secondary outcomes

1. Proportions of participants who developed new T2- or new Gd-enhancing lesions at 12-month and 24 months after randomization.

No significant differences between groups were noted in the proportion of participants developing new T2- or new Gd-enhanced lesions at 12-month follow-up (Etemadifar 2011). No data were available at 24 months.

2. Numbers of new T2- or new Gd-enhanced lesions at 12-month and 24 months after randomization.

Differences between the two groups in the number of new T2 lesions seen on MRI were not statistically significant. Two participants in the placebo group had Gd enhancement, but no participants in the MMF group experienced this finding (Etemadifar 2011). No data were available at 24 months.

3. Proportions of participants who experienced any of the following side effects: abdominal pain, vomiting, diarrhea, anemia, leukopenia, and infection, or other severe adverse effects.

Adverse effects were briefly reported. In the MMF-treated group, all participants suffered from gastrointestinal upset of varying degrees, and one participant had a transient diarrhea; however, no participants needed to discontinue the drug (Etemadifar 2011).

Discussion

Summary of main results

This systematic review assessed the efficacy and safety of MMF in participants with RRMS. Only one study (Etemadifar 2011) comparing oral MMF 2000 mg daily versus placebo in IFN-β-1a–treated participants with RRMS was eligible for inclusion.There was inadequate information provided by the study to determine the effect of MMF in reducing relapses, preventing disability progression, or developing new T2- or new gadolinium (Gd)-enhanced lesions on magnetic resonance imaging (MRI) after a 12-month follow-up period. No data were available at 24 months.

It is worth noting that both MMF plus IFN and placebo plus IFN groups reported a very low risk of relapse at the end of the 12-month follow-up, and only one participant in the placebo group had a relapse. A reasonable explanation for the low relapse rate might be that the investigators included participants with new-onset RRMS with a short disease duration (mean of five months in the MMF group and 3.6 months in the placebo group) and few relapses (one of 13 participants in the MMF group and two of 13 in the placebo group had relapses in the two years before enrollment) (Etemadifar 2011).

Overall completeness and applicability of evidence

The findings presented in this review originated from a single high risk study with a small number of participants with RRMS in short-term treatment. Moreover, another important limitation involved the characteristics of the enrolled participants, whose condition was new-onset and almost without relapse in the previous two years. For this reason, the validity of this review is limited. Furthermore, no evidence is available on MMF monotherapy for RRMS, and evidence about the long-term efficacy of MMF is still lacking.

Quality of the evidence

The included study (Etemadifar 2011) was a randomized controlled trial with serious limitations that deserve consideration. The sample size was small, leading to an inadequately powered trial. Treating personnel and likely the assessor of clinical outcomes were unblinded, leading to performance and detection biases. The interval of confirmation used to assess sustained disability progression was not reported. Poor reporting of adverse effects was another major limitation of the study. No information was provided on the source of the investigated drugs, and conflicts of interest could not be excluded. All of the above mentioned limitations make the results unconvincing.

Potential biases in the review process

No potential biases were reported by the review authors in the review process.

Agreements and disagreements with other studies or reviews

The efficacy and safety of MMF for the treatment of patients with RRMS have never been systematically reviewed.

Authors' conclusions

Implications for practice

The evidence we found from one small study was insufficient to determine the effects of MMF as an add-on therapy for interferon β-1a in new-onset RRMS participants. The study had serious methodological limitations; therefore, no definitive conclusions can be drawn.

Implications for research

High-quality, large-scale RCTs are needed to assess the efficacy and safety of MMF monotherapy or as add-on treatment for patients with RRMS. Future studies should carefully select participants and outcome measures and should have a follow-up duration of at least two years.

Acknowledgements

We would like to thank the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group and the peer reviewers for their help in developing this review.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. Keywords

{mycophenolic acid morpholinoethylester } OR {mycophenolate mofetil hydrochloride} OR {sodium mycophenolate} OR {myfortic} OR {rs 61443} OR {RS-61443} OR {cellcept} OR {mycophenolate sodium} OR {mycophenolate mofetil} OR {Mycophenolate-mofetil}

Contributions of authors

All the authors listed contributed to this review.

Declarations of interest

None known.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Etemadifar 2011

MethodsRandomized, blinded, placebo-controlled design was mentioned in the report. Random list generated was using a random number table. We could obtain no additional information through correspondence with the study authors
Participants

Setting: Isfahan MS Society, Iran

N = 26; MMF group = 13, F/M = 8/5, mean age = 31.3 ± 8.1 years, disease duration = 5.0 ± 4.5 months; placebo group = 13, F/M = 9/4, mean age = 29.6 ± 6.7 years, disease duration = 3.6 ± 3.2 months

Inclusion criteria: clinically definite RRMS, age 18 to 55 years, disease duration < two years, baseline EDSS < 6.0

Exclusion criteria: use of immunomodulatory or immunosuppressive drugs, relapse within two months, pregnant, abnormal blood tests, other major medical illnesses (eg, cancer, significant gastrointestinal disease, immunodeficiency, other autoimmune diseases)
Characteristics of participants at baseline: similar

InterventionsIntervention group: IFN-β-1a and oral MMF started at 500 mg daily for one week, then increased by 500 mg per week until a target dose of 2000 mg daily; after this, dose was continued for 12 months
Control group: IFN-β-1a and placebo; same dose and administration method as in the intervention group for 12 months
Outcomes
  1. Numbers of new T2- and new Gd-enhanced lesions on MRI evaluation after 12-month follow-up

  2. Relapse rate

  3. Changes in EDSS score. EDSS assessment was performed at baseline and then after one year of therapy

  4. Adverse effects

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table generated by software
Allocation concealment (selection bias)Unclear riskNot described
Blinding of participants and personnel (performance bias)
All outcomes
High riskTreating personnel were not blinded. No description on whether MMF and placebo with identical appearance and packaging were provided
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskOutcome assessors were blinded. Blinding is reported only for "Two radiologists, blinded to the treatment arms, [who] were responsible for MRI evaluations" but is not reported for assessors of clinical outcome
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants completed the study
Selective reporting (reporting bias)High riskAll specified primary and secondary outcomes were reported. The interval of confirmation to assess sustained disability progression was not reported. Poor reporting of adverse effects was another major limitation of the study
Other biasHigh risk

Sample size calculation was not clearly reported. Small sample size led to an inadequately powered trial

No description of the source of MMF and placebo (eg, sponsored by a pharmaceutical company or other)

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Frohman 2004Retrospective review
Frohman 2010Six-month follow-up study without our specified 12-month follow-up outcome measures
NCT00618527Experimental study that was "completed" in May 2012 (as reported on clinicaltrials.gov). Outcome measures did not fulfil our inclusion criteria
Remington 2010Study authors enrolled both participants with early RRMS and those with clinically isolated syndrome (CIS). Details of RRMS and CIS were not available
Vermersch 2007Case series study of 30 participants with RRMS treated with MMF in combination with IFN without a control group

Characteristics of studies awaiting assessment [ordered by study ID]

NCT00324506

MethodsRandomized, open-label, parallel-group multicenter study to determine the safety/efficacy of mycophenolate mofetil in mono and combination therapy with interferon-β-1a in patients with relapsing remitting multiple sclerosis
ParticipantsSixty participants (20 participants at each recruiting center) with RRMS
InterventionsMycophenolate mofetil in mono and combination therapy with interferon-β-1a
OutcomesPrimary objective of this safety/mechanistic study is to determine the safety and tolerability of oral mycophenolate when compared with weekly intramuscular interferon-β-1a in RRMS. Safety will be assessed by virtue of changes on MRI. Secondary outcome measures included
changes in exacerbation frequency, incidence of exacerbation in treated groups, changes in level of sustained disability, and changes in quality of life measures and in assessment of fatigue
NotesPrimary completion date: June 2009 (final data collection date for primary outcome measure). This study has been completed. Last updated: June 17, 2013