-
Journal of Comparative Effectiveness... Jul 2023To assess the relative efficacy of disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) including newer therapies (ozanimod, ponesimod,... (Meta-Analysis)
Meta-Analysis
To assess the relative efficacy of disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) including newer therapies (ozanimod, ponesimod, ublituximab) using network meta-analysis (NMA). Bayesian NMAs for annualised relapse rate (ARR) and time to 3-month and 6-month confirmed disability progression (3mCDP and 6mCDP) were conducted. For each outcome, the three most efficacious treatments versus placebo were monoclonal antibody (mAb) therapies: alemtuzumab, ofatumumab, and ublituximab for ARR; alemtuzumab, ocrelizumab, and ofatumumab for 3mCDP; and alemtuzumab, natalizumab, and either ocrelizumab or ofatumumab (depending on the CDP definition used for included ofatumumab trials) for 6mCDP. The most efficacious DMTs for RMS were mAb therapies. Of the newer therapies, only ublituximab ranked among the three most efficacious treatments (for ARR).
Topics: Humans; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Alemtuzumab; Network Meta-Analysis; Bayes Theorem; Recurrence
PubMed: 37265062
DOI: 10.57264/cer-2023-0016 -
The Cochrane Database of Systematic... Jan 2024Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015.
OBJECTIVES
To compare the efficacy and safety, through network meta-analysis, of interferon beta-1b, interferon beta-1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1-a and beta 1-b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS.
SEARCH METHODS
CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top-up search was conducted on 8 August 2022.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS.
DATA COLLECTION AND ANALYSIS
Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta-analysis. Certainty of the evidence was assessed by the GRADE approach.
MAIN RESULTS
We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo-controlled. Considering the risk of bias, the most frequent concern was related to the role of the sponsor in the authorship of the study report or in data management and analysis, for which we judged 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high-certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate-certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate-certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate-certainty evidence) probably result in a large reduction of people with relapses at 12 months. Relapses over 24 months: data were reported in 28 studies (19,869 participants). Cladribine (RR 0.53, 95% CI 0.44 to 0.64; high-certainty evidence), alemtuzumab (RR 0.57, 95% CI 0.47 to 0.68; high-certainty evidence) and natalizumab (RR 0.56, 95% CI 0.48 to 0.65; high-certainty evidence) result in a large decrease of people with relapses at 24 months. Fingolimod (RR 0.54, 95% CI 0.48 to 0.60; moderate-certainty evidence), dimethyl fumarate (RR 0.62, 95% CI 0.55 to 0.70; moderate-certainty evidence), and ponesimod (RR 0.58, 95% CI 0.48 to 0.70; moderate-certainty evidence) probably result in a large decrease of people with relapses at 24 months. Glatiramer acetate (RR 0.84, 95%, CI 0.76 to 0.93; moderate-certainty evidence) and interferon beta-1a (Avonex, Rebif) (RR 0.84, 95% CI 0.78 to 0.91; moderate-certainty evidence) probably moderately decrease people with relapses at 24 months. Relapses over 36 months findings were available from five studies (3087 participants). None of the treatments assessed showed moderate- or high-certainty evidence compared to placebo. Disability worsening over 24 months was assessed in 31 studies (24,303 participants). Natalizumab probably results in a large reduction of disability worsening (RR 0.59, 95% CI 0.46 to 0.75; moderate-certainty evidence) at 24 months. Disability worsening over 36 months was assessed in three studies (2684 participants) but none of the studies used placebo as the comparator. Treatment discontinuation due to adverse events data were available from 43 studies (35,410 participants). Alemtuzumab probably results in a slight reduction of treatment discontinuation due to adverse events (OR 0.39, 95% CI 0.19 to 0.79; moderate-certainty evidence). Daclizumab (OR 2.55, 95% CI 1.40 to 4.63; moderate-certainty evidence), fingolimod (OR 1.84, 95% CI 1.31 to 2.57; moderate-certainty evidence), teriflunomide (OR 1.82, 95% CI 1.19 to 2.79; moderate-certainty evidence), interferon beta-1a (OR 1.48, 95% CI 0.99 to 2.20; moderate-certainty evidence), laquinimod (OR 1.49, 95 % CI 1.00 to 2.15; moderate-certainty evidence), natalizumab (OR 1.57, 95% CI 0.81 to 3.05), and glatiramer acetate (OR 1.48, 95% CI 1.01 to 2.14; moderate-certainty evidence) probably result in a slight increase in the number of people who discontinue treatment due to adverse events. Serious adverse events (SAEs) were reported in 35 studies (33,998 participants). There was probably a trivial reduction in SAEs amongst people with RRMS treated with interferon beta-1b as compared to placebo (OR 0.92, 95% CI 0.55 to 1.54; moderate-certainty evidence).
AUTHORS' CONCLUSIONS
We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate the efficacy and safety of DMTs in a longer term than two years, and this is a relevant issue for a chronic condition like MS that develops over decades. More than half of the included studies were sponsored by pharmaceutical companies and this may have influenced their results. Further studies should focus on direct comparison between active agents, with follow-up of at least three years, and assess other patient-relevant outcomes, such as quality of life and cognitive status, with particular focus on the impact of sex/gender on treatment effects.
Topics: Adult; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Glatiramer Acetate; Interferon beta-1a; Fingolimod Hydrochloride; Natalizumab; Interferon beta-1b; Cladribine; Alemtuzumab; Dimethyl Fumarate; Daclizumab; Network Meta-Analysis; Immunologic Factors; Recurrence
PubMed: 38174776
DOI: 10.1002/14651858.CD011381.pub3 -
The Cochrane Database of Systematic... Jun 2023Multiple sclerosis (MS) is an autoimmune, T-cell-dependent, inflammatory, demyelinating disease of the central nervous system, with an unpredictable course. Current MS... (Review)
Review
BACKGROUND
Multiple sclerosis (MS) is an autoimmune, T-cell-dependent, inflammatory, demyelinating disease of the central nervous system, with an unpredictable course. Current MS therapies focus on treating and preventing exacerbations, and avoiding the progression of disability. At present, there is no treatment that is capable of safely and effectively reaching these objectives. Clinical trials suggest that alemtuzumab, a humanized monoclonal antibody, could be a promising option for MS.
OBJECTIVES
To evaluate the benefits and harms of alemtuzumab alone or associated with other treatments in people with any form of MS.
SEARCH METHODS
We used standard, extensive Cochrane search methods. The latest search date was 21 June 2022.
SELECTION CRITERIA
We included randomized controlled trials (RCTs) in adults with any subtype of MS comparing alemtuzumab alone or associated with other medications versus placebo; another active drug; or alemtuzumab in another dose, regimen, or duration.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. Our co-primary outcomes were 1. relapse-free survival, 2. sustained disease progression, and 3. number of participants experiencing at least one adverse event. Our secondary outcomes were 4. participants free of clinical disability, 5. quality of life, 6. change in disability, 7. fatigue, 8. new or enlarging lesions on resonance imaging, and 9. dropouts. We used GRADE to assess certainty of evidence for each outcome.
MAIN RESULTS
We included three RCTs (1713 participants) comparing intravenous alemtuzumab versus subcutaneous interferon beta-1a for relapsing-remitting MS. Participants were treatment-naive (two studies) or had experienced at least one relapse after interferon or glatiramer (one study). Alemtuzumab was given at doses of 12 mg/day or 24 mg/day for five days at months 0 and 12, or 24 mg/day for three days at months 12 and 24. Participants in the interferon beta-1a group received 44 μg three times weekly. Alemtuzumab 12 mg: 1. may improve relapse-free survival at 36 months (hazard ratio [HR] 0.31, 95% confidence interval [CI] 0.18 to 0.53; 1 study, 221 participants; low-certainty evidence); 2. may improve sustained disease progression-free survival at 36 months (HR 0.25, 95% CI 0.11 to 0.56; 1 study, 223 participants; low-certainty evidence); 3. may make little to no difference on the proportion of participants with at least one adverse event at 36 months (risk ratio [RR] 1.00, 95% CI 0.98 to 1.02; 1 study, 224 participants; low-certainty evidence), although the proportion of participants with at least one adverse event was high with both drugs; 4. may slightly reduce disability at 36 months (mean difference [MD] -0.70, 95% CI -1.04 to -0.36; 1 study, 223 participants; low-certainty evidence). The evidence is very uncertain regarding the risk of dropouts at 36 months (RR 0.81, 95% CI 0.57 to 1.14; 1 study, 224 participants; very low-certainty evidence). Alemtuzumab 24 mg: 1. may improve relapse-free survival at 36 months (HR 0.21, 95% CI 0.11 to 0.40; 1 study, 221 participants; low-certainty evidence); 2. may improve sustained disease progression-free survival at 36 months (HR 0.33, 95% CI 0.16 to 0.69; 1 study, 221 participants; low-certainty evidence); 3. may make little to no difference on the proportion of participants with at least one adverse event at 36 months (RR 0.99, 95% CI 0.97 to 1.02; 1 study, 215 participants; low-certainty evidence), although the proportion of participants with at least one adverse event was high with both drugs; 4. may slightly reduce disability at 36 months (MD -0.83, 95% CI -1.16 to -0.50; 1 study, 221 participants; low-certainty evidence); 5. may reduce the risk of dropouts at 36 months (RR 0.08, 95% CI 0.01 to 0.57; 1 study, 215 participants; low-certainty evidence). For quality of life, fatigue, and participants free of clinical disease activity, the studies either did not consider these outcomes or they used different measuring tools to those planned in this review.
AUTHORS' CONCLUSIONS
Compared with interferon beta-1a, alemtuzumab may improve relapse-free survival and sustained disease progression-free survival, and make little to no difference on the proportion of participants with at least one adverse event for people with relapsing-remitting MS at 36 months. The certainty of the evidence for these results was very low to low.
Topics: Adult; Humans; Alemtuzumab; Interferon beta-1a; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Neoplasm Recurrence, Local
PubMed: 37272540
DOI: 10.1002/14651858.CD011203.pub3 -
The Cochrane Database of Systematic... Apr 2016Multiple sclerosis (MS) is an autoimmune, T-cell-dependent, inflammatory, demyelinating disease of the central nervous system, with an unpredictable course. Current MS... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Multiple sclerosis (MS) is an autoimmune, T-cell-dependent, inflammatory, demyelinating disease of the central nervous system, with an unpredictable course. Current MS therapies focus on treating exacerbations, preventing new exacerbations and avoiding the progression of disability. However, at present there is no effective treatment that is capable of safely and effectively reaching these objectives. This has led to the development and investigation of new drugs. Recent clinical trials suggest that alemtuzumab, a humanised monoclonal antibody against cell surface CD52, could be a promising option for MS.
OBJECTIVES
To assess the safety and effectiveness of alemtuzumab used alone or associated with other treatments to decrease disease activity in patients with any form of MS.
SEARCH METHODS
We searched the Trials Register of the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group (30 April 2015), which contains trials from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, LILACS and the trial registry databases ClinicalTrials.gov and WHO International Clinical Trials Registry Platform. There was no restriction on the source, publication date or language.
SELECTION CRITERIA
All randomised clinical trials (RCTs) involving adults diagnosed with any form of MS according to the McDonald criteria, comparing alemtuzumab alone or associated with other medications, at any dose and for any duration, versus placebo or any other active drug therapy or alemtuzumab in other dose, regimen or duration. The co-primary outcomes were relapse-free survival, sustained disease progression and number of participants with at least one of any adverse events, including serious adverse events.
DATA COLLECTION AND ANALYSIS
Two independent review authors performed study selection, data extraction and 'Risk of bias' assessment. A third review author checked the process for accuracy. We used the Cochrane 'Risk of bias' tool to assess the risk of bias of the studies included in the review. We used the GRADE system to assess the quality of the body of evidence. To measure the treatment effect on dichotomous outcomes we used the risk ratio (RR); for the treatment effect on continuous outcomes, we used the mean difference (MD) and for time-to-event outcomes we used hazard ratio (HR). We calculated 95% confidence intervals (CI) for these measures. When there was no heterogeneity, we used a fixed-effect model to pool data.
MAIN RESULTS
Three RCTs (1713 participants) fulfilled the selection criteria and we included them in the review. All three trials compared alemtuzumab versus subcutaneous interferon beta-1a for patients with relapsing-remitting MS. Patients were treatment-naive in the CARE-MS and CAMMS223 studies. The CARE-MS II study included patients with at least one relapse while being treated with interferon beta or glatiramer acetate. Alemtuzumab was given for 12 or 24 months; for some outcomes, the follow-up period reached 36 months. The regimens were (a) 12 mg or 24 mg per day administered intravenously, once a day for five consecutive days at month 0 and 12 or (b) 24 mg per day, intravenously, once a day for three consecutive days at month 12 and 24. The patients in the other arm of the trials received interferon beta-1a 44 μg subcutaneously three times weekly after dose titration.At 24 months, alemtuzumab 12 mg was associated with: (a) higher relapse-free survival (hazard ratio (HR) 0.50, 95% CI 0.41 to 0.60; 1248 participants, two studies, moderate quality evidence); (b) higher sustained disease progression-free survival (HR 0.62, 95% CI 0.44 to 0.87; 1191 participants; two studies; moderate quality evidence); (c) a slightly higher number of participants with at least one adverse event (RR 1.04, 95% CI 1.01 to 1.06; 1248 participants; two studies; moderate quality evidence); (d) a lower number of participants with new or enlarging T2-hyperintense lesions on magnetic resonance imaging (MRI) (RR 0.74, 95% CI 0.59 to 0.91; 1238 participants; two studies; I(2) = 80%); and (e) a lower number of dropouts (RR 0.31, 95% CI 0.23 to 0.41; 1248 participants; two studies, I(2) = 29%; low quality evidence).At 36 months, alemtuzumab 24 mg was associated with: (a) higher relapse-free survival (45 versus 17; HR 0.21, 95% CI 0.11 to 0.40; one study; 221 participants); (b) a higher sustained disease progression-free survival (HR 0.33, 95% CI 0.16 to 0.69; one study; 221 participants); and (c) no statistical difference in the rate of participants with at least one adverse event. We did not find any study that reported any of the following outcomes: rate of participants free of clinical disease activity, quality of life, fatigue or change in the numbers of MRI T2- and T1-weighted lesions after treatment. It was not possible to perform subgroup analyses according to disease type and disability at baseline due to lack of data.
AUTHORS' CONCLUSIONS
In patients with relapsing-remitting MS, alemtuzumab 12 mg was better than subcutaneous interferon beta-1a for the following outcomes assessed at 24 months: relapse-free survival, sustained disease progression-free survival, number of participants with at least one adverse event and number of participants with new or enlarging T2-hyperintense lesions on MRI. The quality of the evidence for these results was low to moderate. Alemtuzumab 24 mg seemed to be better than subcutaneous interferon beta-1a for relapse-free survival and sustained disease progression-free survival, at 36 months.More randomised clinical trials are needed to evaluate the effects of alemtuzumab on other forms of MS and compared with other therapeutic options. These new studies should assess additional relevant outcomes such as the rate of participants free of clinical disease activity, quality of life, fatigue and adverse events (individual rates, serious adverse events and long-term adverse events). Moreover, these new studies should evaluate other doses and durations of alemtuzumab course.
Topics: Adult; Alemtuzumab; Antibodies, Monoclonal, Humanized; Disease-Free Survival; Humans; Interferon beta-1a; Multiple Sclerosis, Relapsing-Remitting; Randomized Controlled Trials as Topic
PubMed: 27082500
DOI: 10.1002/14651858.CD011203.pub2 -
Experimental and Clinical... Aug 2016Kidney transplant remains the best type of renal replacement therapy in most patients with end-stage kidney disease, even in those with high immunologic risk.... (Review)
Review
Kidney transplant remains the best type of renal replacement therapy in most patients with end-stage kidney disease, even in those with high immunologic risk. Immunosuppression in these patients is regarded as more complex, owing to the higher risk of both acute and chronic rejection. The advent of induction immunosuppression has resulted in a lower incidence of acute rejection and consequently improved short-term patient and allograft outcomes. Indeed, the use of these agents, especially in high-risk recipients, has become standard of care at most transplant centers. Transplant physicians are constantly faced with the challenge of estimating the recipients' immunologic risk and tailoring their immunosuppression accordingly. This review article aims to provide an up-to-date evaluation of the various studies available, which investigated the use of induction agents in kidney transplant, specifically in high-risk recipients. It evaluates the use of the most frequently used polyclonal antibody (rabbit antithymocyte globulin) versus the less commonly used monoclonal antibody alemtuzumab, superseded agents such as muromonab-CD3, and potentially emerging agents such as rituximab, bortezomib, and eculizumab. With this systematic review, we hope to inform the scientific community and facilitate this controversial decision through the implementation of robust scientific evidence.
Topics: Drug Therapy, Combination; Evidence-Based Medicine; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome
PubMed: 27041548
DOI: 10.6002/ect.2015.0328 -
Vaccines Jul 2021Understanding the risks of COVID-19 in patients with Multiple Sclerosis (MS) receiving disease-modifying therapies (DMTs) and their immune reactions is vital to analyze... (Review)
Review
Understanding the risks of COVID-19 in patients with Multiple Sclerosis (MS) receiving disease-modifying therapies (DMTs) and their immune reactions is vital to analyze vaccine response dynamics. A systematic review on COVID-19 course and outcomes in patients receiving different DMTs was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Emerging data on SARS-CoV-2 vaccines was used to elaborate recommendations. Data from 4417 patients suggest that MS per se do not portend a higher risk of severe COVID-19. As for the general population, advanced age, comorbidities, and higher disability significantly impact COVID-19 outcomes. Most DMTs have a negligible influence on COVID-19 incidence and outcome, while for those causing severe lymphopenia and hypogammaglobulinemia, such as anti-CD20 therapies, there might be a tendency of increased hospitalization, worse outcomes and a higher risk of re-infection. Blunted immune responses have been reported for many DMTs, with vaccination implications. Clinical evidence does not support an increased risk of MS relapse or vaccination failure, but vaccination timing needs to be individually tailored. For cladribine and alemtuzumab, it is recommended to wait 3-6 months after the last cycle until vaccination. For the general anti-CD20 therapies, vaccination must be deferred toward the end of the cycle and the next dose administered at least 4-6 weeks after completing vaccination. Serological status after vaccination is highly encouraged. Growing clinical evidence and continuous surveillance are extremely important to continue guiding future treatment strategies and vaccination protocols.
PubMed: 34358189
DOI: 10.3390/vaccines9070773 -
The Cochrane Database of Systematic... Apr 2015Multiple sclerosis (MS) often leads to severe neurological disability and a serious decline in quality of life. The ideal target of disease-modifying therapy for MS is... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Multiple sclerosis (MS) often leads to severe neurological disability and a serious decline in quality of life. The ideal target of disease-modifying therapy for MS is to prevent disability worsening and improve quality of life. Dimethyl fumarate is considered to have an immunomodulatory activity and neuroprotective effect. It has been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency as a first-line therapy for adult patients with relapsing-remitting MS (RMSS).
OBJECTIVES
To assess the benefit and safety of dimethyl fumarate as monotherapy or combination therapy versus placebo or other approved disease-modifying drugs (interferon beta, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, alemtuzumab) for patients with MS.
SEARCH METHODS
The Trials Search Co-ordinator searched the Trials Specialised Register of the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group (4 June 2014). We checked reference lists of published reviews and retrieved articles and searched reports (2004 to June 2014) from the MS societies in Europe and America. We also communicated with investigators participating in trials of dimethyl fumarate and the Biogen Idec Medical Information.
SELECTION CRITERIA
We included randomised, controlled, parallel-group clinical trials (RCTs) with a length of follow-up equal to or greater than one year evaluating dimethyl fumarate, as monotherapy or combination therapy, versus placebo or other approved disease-modifying drugs for patients with MS without restrictions regarding dosage, administration frequency and duration of treatment.
DATA COLLECTION AND ANALYSIS
We used the standard methodological procedures of The Cochrane Collaboration. Two review authors independently assessed trial quality and extracted data. Disagreements were discussed and resolved by consensus among the review authors. We contacted the principal investigators of included studies for additional data or confirmation of data.
MAIN RESULTS
Two RCTs were included, involving 2667 adult patients with RRMS to evaluate the efficacy and safety of two dosages of dimethyl fumarate (240 mg orally three times daily or twice daily) by direct comparison with placebo for two years. Among them, a subsample of 1221 (45.8%) patients were selected to participate in MRI evaluations by each study site with MRI capabilities itself. No powered head-to-head study with an active treatment comparator has been found. Meta-analyses showed that dimethyl fumarate both three times daily and twice daily reduced the number of patients with a relapse (risk ratio (RR) 0.57, 95% confidence interval (CI) 0.50 to 0.66, P < 0.00001 and 0.64, 95% CI 0.54 to 0.77, P < 0.00001, respectively) or disability worsening (RR 0.70, 95% CI 0.57 to 0.87, P = 0.0009 and 0.65, 95% CI 0.53 to 0.81, P = 0.0001, respectively) over two years, compared to placebo. The treatment effects were decreased in the likely-case scenario analyses taking the effect of dropouts into consideration. Both dosages also reduced the annualised relapse rate. Data of active lesions on MRI scans were not combined because there was a high risk of selection bias for MRI outcomes and imprecision of MRI data in both studies, as well as an obvious heterogeneity between the studies. In terms of safety profile, both dosages increased the risk for adverse events and the risk for drug discontinuation due to adverse events. The most common adverse events included flushing and gastrointestinal events (upper abdominal pain, nausea and diarrhoea). Uncommon adverse events included lymphopenia and leukopenia, but they were more likely to happen with dimethyl fumarate than with placebo (high dosage: RR 5.25, 95% CI 2.20 to 12.51, P = 0.0002 and 5.23, 95% CI 2.47 to 11.07, P < 0.0001, respectively; low dosage: RR 5.69, 95% CI 2.40 to 13.46, P < 0.0001 and 6.53, 95% CI 3.13 to 13.64, P < 0.00001, respectively). Both studies had a high attrition bias resulting from the unbalanced reasons for dropouts among groups. Quality of evidence for relapse outcome was moderate, but for disability worsening was low.
AUTHORS' CONCLUSIONS
There is moderate-quality evidence to support that dimethyl fumarate at a dose of 240 mg orally three times daily or twice daily reduces both the number of patients with a relapse and the annualised relapse rate over two years of treatment in comparison with placebo. However, the quality of the evidence to support the benefit in reducing the number of patients with disability worsening is low. There is no high-quality data available to evaluate the benefit on MRI outcomes. The common adverse effects such as flushing and gastrointestinal events are mild-to-moderate for most patients. Lymphopenia and leukopenia are uncommon adverse events but significantly associated with dimethyl fumarate. Both dosages of dimethyl fumarate have similar benefit and safety profile, which supports the option of low-dose administration. New studies of high quality and long-term follow-up are needed to evaluate the benefit of dimethyl fumarate on prevention of disability worsening and to observe the long-term adverse effects including progressive multifocal leukoencephalopathy.
Topics: Administration, Oral; Adult; Dimethyl Fumarate; Drug Administration Schedule; Fumarates; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Randomized Controlled Trials as Topic
PubMed: 25900414
DOI: 10.1002/14651858.CD011076.pub2 -
Neurology and Therapy Dec 2020Since 2010, 27 mixed-treatment comparisons (MTCs) of disease-modifying therapies (DMTs) for multiple sclerosis have been published. However, there has been continued... (Review)
Review
BACKGROUND
Since 2010, 27 mixed-treatment comparisons (MTCs) of disease-modifying therapies (DMTs) for multiple sclerosis have been published. However, there has been continued evolution in the field of MTCs. Additionally, limitations in methodological approach and reporting transparency, even in the most recent publications, makes interpretation and comparison of existing studies difficult.
OBJECTIVES
The objectives of this study are twofold: (1) to estimate the efficacy and safety of DMTs at European Commission-approved doses compared with placebo in adults with relapsing-remitting multiple sclerosis (RRMS) using MTC, and (2) to identify and address methodological challenges when performing MTC in RRMS, thereby creating a baseline for comparisons with future treatments.
METHODS
Searches were completed in 14 databases, including MEDLINE, Embase, CENTRAL, CDSR and DARE, from inception to June 2018 to identify published or unpublished prospective, randomised controlled trials of all European Union-approved DMTs or DMTs expected to be approved in the near future in RRMS or rapidly-evolving severe RRMS. No language or date restrictions were applied. Studies were included in the MTC if they were judged to have sufficiently similar characteristics, based on the following: patient age; proportion of male participants; Expanded Disability Status Scale (EDSS) score; duration of disease; number of relapses prior to enrolment and proportion of previously treated patients. Background information from the included studies, as well as effect size and confidence intervals (where relevant) of defined outcomes were extracted. Reporting of the MTC was consistent with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) network meta-analysis guidelines.
RESULTS
In total, 33 studies were included in the MTC. Annualised relapse rate (ARR 28 trials) was significantly reduced in all treatments compared with placebo. Alemtuzumab had the highest probability (63%) of being the most effective treatment in terms of ARR compared with placebo (rate ratio [RR] 0.28, 95% credible interval [CrI] 0.21-0.38), followed by natalizumab (30% probability; RR 0.32, 95% CrI 0.23-0.43). The risk of 3- and 6-month confirmed disability progression (CDP3M, 13 trials; CDP6M, 14 trials) were similar; CDP6M was significantly reduced for alemtuzumab (hazard ratio [HR] 0.365; 95% CrI 0.165-0.725), ocrelizumab (HR 0.405, 95% CrI 0.188-0.853) and natalizumab (HR 0.459, 95% CrI 0.252-0.840) relative to placebo. There were no significant differences in the odds of serious adverse events (SAEs, 6 trials) between any treatment and placebo. The results of the MTC were limited by the lack of studies reporting direct comparisons between the included treatments and by heterogeneous reporting of key outcome data.
CONCLUSIONS
Meta-analyses confirmed the benefit of all DMTs in terms of relapse rate compared with placebo with a comparable rate of SAEs for the DMTs that could be included in the network. The rigor and transparency of reporting in this study provide a benchmark for comparisons with future new agents.
PubMed: 32989721
DOI: 10.1007/s40120-020-00212-5 -
The Cochrane Database of Systematic... Mar 2016This is an update of the Cochrane review "Teriflunomide for multiple sclerosis" (first published in The Cochrane Library 2012, Issue 12).Multiple sclerosis (MS) is a... (Review)
Review
BACKGROUND
This is an update of the Cochrane review "Teriflunomide for multiple sclerosis" (first published in The Cochrane Library 2012, Issue 12).Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system. It is clinically characterized by recurrent relapses or progression, or both, often leading to severe neurological disability and a serious decline in quality of life. Disease-modifying therapies (DMTs) for MS aim to prevent occurrence of relapses and disability progression. Teriflunomide is a pyrimidine synthesis inhibitor approved by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as a DMT for adults with relapsing-remitting MS (RRMS).
OBJECTIVES
To assess the absolute and comparative effectiveness and safety of teriflunomide as monotherapy or combination therapy versus placebo or other disease-modifying drugs (DMDs) (interferon beta (IFNβ), glatiramer acetate, natalizumab, mitoxantrone, fingolimod, dimethyl fumarate, alemtuzumab) for modifying the disease course in people with MS.
SEARCH METHODS
We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Specialised Trials Register (30 September 2015). We checked reference lists of published reviews and retrieved articles and searched reports (2004 to September 2015) from the MS societies in Europe and America. We also communicated with investigators participating in trials of teriflunomide and the pharmaceutical company, Sanofi-Aventis.
SELECTION CRITERIA
We included randomized, controlled, parallel-group clinical trials with a length of follow-up of one year or greater evaluating teriflunomide, as monotherapy or combination therapy, versus placebo or other approved DMDs for people with MS without restrictions regarding dose, administration frequency and duration of treatment.
DATA COLLECTION AND ANALYSIS
We used the standard methodological procedures of Cochrane. Two review authors independently assessed trial quality and extracted data. Disagreements were discussed and resolved by consensus among the review authors. We contacted the principal investigators of included studies for additional data or confirmation of data.
MAIN RESULTS
Five studies involving 3231 people evaluated the efficacy and safety of teriflunomide 7 mg and 14 mg, alone or with add-on IFNβ, versus placebo or IFNβ-1a for adults with relapsing forms of MS and an entry Expanded Disability Status Scale score of less than 5.5.Overall, there were obvious clinical heterogeneities due to diversities in study designs or interventions and methodological heterogeneities across studies. All studies had a high risk of detection bias for relapse assessment and a high risk of bias due to conflicts of interest. Among them, three studies additionally had a high risk of attrition bias due to a high dropout rate and two studies had an unclear risk of attrition bias. The studies of combination therapy with IFNβ (650 participants) and the study with IFNβ-1a as controls (324 participants) also had a high risk for performance bias and a lack of power due to the limited sample.Two studies evaluated the benefit and the safety of teriflunomide as monotherapy versus placebo over a period of one year (1169 participants) or two years (1088 participants). A meta-analysis was not conducted. Compared to placebo, administration of teriflunomide at a dose of 7 mg/day or 14 mg/day as monotherapy reduced the number of participants with at least one relapse over one year (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.59 to 0.87, P value = 0.001 with 7 mg/day and RR 0.60, 95% CI 0.48 to 0.75, P value < 0.00001 with 14 mg/day) or two years (RR 0.85, 95% CI 0.74 to 0.98, P value = 0.03 with 7 mg/day and RR 0.80, 95% CI 0.69 to 0.93, P value = 0.004 with 14 days). Only teriflunomide at a dose of 14 mg/day reduced the number of participants with disability progression over one year (RR 0.55, 95% CI 0.36 to 0.84, P value = 0.006) or two years (RR 0.74, 95% CI 0.56 to 0.96, P value = 0.02). When taking the effect of drop-outs into consideration, the likely-case scenario analyses still showed a benefit in reducing the number of participants with at least one relapse, but not for the number of participants with disability progression. Both doses also reduced the annualized relapse rate and the number of gadolinium-enhancing T1-weighted lesions over two years. Quality of evidence for relapse outcomes at one year or at two years was low, while for disability progression at one year or at two years was very low.When compared to IFNβ-1a, teriflunomide at a dose of 14 mg/day had a similar efficacy to IFNβ-1a in reducing the proportion of participants with at least one relapse over one year, while teriflunomide at a dose of 7 mg/day was inferior to IFNβ-1a (RR 1.52, 95% CI 0.87 to 2.67, P value = 0.14; 215 participants with 14 mg/day and RR 2.74, 95% CI 1.66 to 4.53, P value < 0.0001; 213 participants with 7 mg/day). However, the quality of evidence was very low.In terms of safety profile, the most common adverse events associated with teriflunomide were diarrhoea, nausea, hair thinning, elevated alanine aminotransferase, neutropenia and lymphopenia. These adverse events had a dose-related effects and rarely led to treatment discontinuation.
AUTHORS' CONCLUSIONS
There was low-quality evidence to support that teriflunomide at a dose of 7 mg/day or 14 mg/day as monotherapy reduces both the number of participants with at least one relapse and the annualized relapse rate over one year or two years of treatment in comparison with placebo. Only teriflunomide at a dose of 14 mg/day reduced the number of participants with disability progression and delayed the progression of disability over one year or two years, but the quality of the evidence was very low. The quality of available data was too low to evaluate the benefit teriflunomide as monotherapy versus IFNβ-1a or as combination therapy with IFNβ. The common adverse effects were diarrhoea, nausea, hair thinning, elevated alanine aminotransferase, neutropenia and lymphopenia. These adverse effects were mostly mild-to-moderate in severity, but had a dose-related effect. New studies of high quality and longer follow-up are needed to evaluate the comparative benefit of teriflunomide on these outcomes and the safety in comparison with other DMTs.
Topics: Adult; Crotonates; Humans; Hydroxybutyrates; Immunologic Factors; Immunosuppressive Agents; Interferon-beta; Middle Aged; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Nitriles; Randomized Controlled Trials as Topic; Toluidines; Young Adult
PubMed: 27003123
DOI: 10.1002/14651858.CD009882.pub3 -
Experimental and Clinical... May 2021Induction immunosuppression for simultaneous pancreas-kidney transplant has helped reduce graft loss due to early rejection. Both thymoglobulin and interleukin 2... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
Induction immunosuppression for simultaneous pancreas-kidney transplant has helped reduce graft loss due to early rejection. Both thymoglobulin and interleukin 2 receptor antagonists are the most commonly used induction agents; however, some high-volume centers prefer alemtuzumab.Thisnetwork meta-analysis aimedto compare differentinductionregimens for simultaneouspancreaskidney transplantin terms ofbothpancreas and patient graft survival, as well to assess acute rejection.
MATERIALS AND METHODS
A systematic review was conducted to identify randomized clinical trials up to October 31, 2019, that examined induction regimens for simultaneous pancreas-kidney transplant. Study characteristics, postoperative data (patient, pancreas, and kidney graft survival), complications (eg, bleeding), infection rates, and malignancy rates were extracted. We compared all regimens using randomeffects network meta-analyses to maintain randomization within trials.
RESULTS
This study identified 7 randomized clinical trials that involved 536 patients, which reported 5 induction regimens. These regimens included antithymocyte globulin (97 patients), alemtuzumab (42 patients), 2 doses (113 patients) or 5 doses (164 patients) of daclizumab, and no induction therapy (120 patients). In the network meta-analysis, a regimen with 2 doses of daclizumab was consistently ranked first for patient survival and kidney and pancreas graft survival. In contrast, alemtuzumab was ranked best for acute rejection (both pancreas and kidney). Rates of majorinfection (ie, cytomegalovirus) and malignancy were reported in 3 studies, precluding a reliable analysis.
CONCLUSIONS
Daclizumab with 2 doses, given before simultaneous pancreas-kidney transplant, was associated with the best rates of patient and graft survival. Despite the recent withdrawal of daclizumab, an alternative anti-interleukin 2 induction regimen (basiliximab) has demonstrated promising results in nonrandomized series, warranting that further highquality large-scale randomized clinical trials are still needed.
Topics: Alemtuzumab; Daclizumab; Humans; Immunosuppression Therapy; Kidney Transplantation; Neoplasms; Network Meta-Analysis; Pancreas Transplantation; Randomized Controlled Trials as Topic
PubMed: 34053419
DOI: 10.6002/ect.2020.0231