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Leukemia & Lymphoma Sep 2016Randomized clinical trials that compared chlorambucil to different regimens, for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) do not... (Meta-Analysis)
Meta-Analysis Review
Randomized clinical trials that compared chlorambucil to different regimens, for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) do not support an overall survival (OS) benefit. To assess the efficacy and safety of chlorambucil as frontline treatment, we conducted a systematic review and meta-analysis of randomized controlled trials. OS was the primary outcome. Meta-analysis of 18 trials that compared purine analogs, alkylators, alemtuzumab and ibrutinib to chlorambucil demonstrated no OS benefit for therapy without chlorambucil over chlorambucil (pooled HR 0.99, 95% CI 0.91-1.08; 4133 patients). PFS was longer with purine analogs compared with chlorambucil with an increased risk of infection. The risk of secondary malignancies was not increased with chlorambucil. In conclusion, our study showed that chlorambucil is an acceptable chemotherapy backbone for unfit patients with CLL. Purine analogs should be preferred in fit younger patients because of longer PFS. Future trials should focus on unfit patients who are underrepresented in clinical trials.
Topics: Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Chlorambucil; Disease Progression; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms, Second Primary; Prognosis; Proportional Hazards Models; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 26980554
DOI: 10.3109/10428194.2016.1154956 -
The Cochrane Database of Systematic... Sep 2015Different 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 biologics. Although there is consensus that these therapies reduce the frequency of relapses, their relative benefit in delaying new relapses or disability worsening remains unclear due to the limited number of direct comparison trials.
OBJECTIVES
To compare the benefit and acceptability of interferon beta-1b, interferon beta-1a (Avonex, Rebif), glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine and immunoglobulins for the treatment of people with RRMS and to provide a ranking of these treatments according to their benefit and acceptability, defined as the proportion of participants who withdrew due to any adverse event.
SEARCH METHODS
We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register, which contains trials from CENTRAL (2014, Issue 9), MEDLINE (1966 to 2014), EMBASE (1974 to 2014), CINAHL (1981 to 2014), LILACS (1982 to 2014), clinicaltrials.gov and the WHO trials registry, and US Food and Drug Administration (FDA) reports. We ran the most recent search in September 2014.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that studied one or more of the 15 treatments as monotherapy, compared to placebo or to another active agent, for use in adults with RRMS.
DATA COLLECTION AND ANALYSIS
Two authors independently identified studies from the search results and performed data extraction. We performed data synthesis by pairwise meta-analysis and network meta-analysis. We assessed the quality of the body of evidence for outcomes within the network meta-analysis according to GRADE, as very low, low, moderate or high.
MAIN RESULTS
We included 39 studies in this review, in which 25,113 participants were randomised. The majority of the included trials were short-term studies, with a median duration of 24 months. Twenty-four (60%) were placebo-controlled and 15 (40%) were head-to-head studies.Network meta-analysis showed that, in terms of a protective effect against the recurrence of relapses in RRMS during the first 24 months of treatment, alemtuzumab, mitoxantrone, natalizumab, and fingolimod outperformed other drugs. The most effective drug was alemtuzumab (risk ratio (RR) versus placebo 0.46, 95% confidence interval (CI) 0.38 to 0.55; surface under the cumulative ranking curve (SUCRA) 96%; moderate quality evidence), followed by mitoxantrone (RR 0.47, 95% CI 0.27 to 0.81; SUCRA 92%; very low quality evidence), natalizumab (RR 0.56, 95% CI 0.47 to 0.66; SUCRA 88%; high quality evidence), and fingolimod (RR 0.72, 95% CI 0.64 to 0.81; SUCRA 71%; moderate quality evidence).Disability worsening was based on a surrogate marker, defined as irreversible worsening confirmed at three-month follow-up, measured during the first 24 months in the majority of included studies. Both direct and indirect comparisons revealed that the most effective treatments were mitoxantrone (RR versus placebo 0.20, 95% CI 0.05 to 0.84; SUCRA 96%; low quality evidence), alemtuzumab (RR 0.35, 95% CI 0.26 to 0.48; SUCRA 94%; low quality evidence), and natalizumab (RR 0.64, 95% CI 0.49 to 0.85; SUCRA 74%; moderate quality evidence).Almost all of the agents included in this review were associated with a higher proportion of participants who withdrew due to any adverse event compared to placebo. Based on the network meta-analysis methodology, the corresponding RR estimates versus placebo over the first 24 months of follow-up were: mitoxantrone 9.92 (95% CI 0.54 to 168.84), fingolimod 1.69 (95% CI 1.32 to 2.17), natalizumab 1.53 (95% CI 0.93 to 2.53), and alemtuzumab 0.72 (95% CI 0.32 to 1.61).Information on serious adverse events (SAEs) was scanty, characterised by heterogeneous results and based on a very low number of events observed during the short-term duration of the trials included in this review.
AUTHORS' CONCLUSIONS
Conservative interpretation of these results is warranted, since most of the included treatments have been evaluated in few trials. The GRADE approach recommends providing implications for practice based on moderate to high quality evidence. Our review shows that alemtuzumab, natalizumab, and fingolimod are the best choices for preventing clinical relapses in people with RRMS, but this evidence is limited to the first 24 months of follow-up. For the prevention of disability worsening in the short term (24 months), only natalizumab shows a beneficial effect on the basis of moderate quality evidence (all of the other estimates were based on low to very low quality evidence). Currently, therefore, insufficient evidence is available to evaluate treatments for the prevention of irreversible disability worsening.There are two additional major concerns that have to be considered. First, the benefit of all of these treatments beyond two years is uncertain and this is a relevant issue for a disease with a duration of 30 to 40 years. Second, short-term trials provide scanty and poorly reported safety data and do not provide useful evidence in order to obtain a reliable risk profile of treatments. In order to provide long-term information on the safety of the treatments included in this review, it will be necessary also to evaluate non-randomised studies and post-marketing reports released from the regulatory agencies. Finally, more than 70% of the studies included in this review were sponsored by pharmaceutical companies and this may have influenced the results.There are three needs that the research agenda should address. First, randomised trials of direct comparisons between active agents would be useful, avoiding further placebo-controlled studies. Second, follow-up of the original trial cohorts should be mandatory. Third, more studies are needed to assess the medium and long-term benefit and safety of immunotherapies and the comparative safety of different agents.
Topics: Adult; Humans; Immunologic Factors; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Randomized Controlled Trials as Topic
PubMed: 26384035
DOI: 10.1002/14651858.CD011381.pub2 -
BioDrugs : Clinical Immunotherapeutics,... Aug 2015Monoclonal antibody (mAb)-based orphan drugs have led to advances in the treatment of diseases by selectively targeting molecule functions. However, their high treatment... (Review)
Review
BACKGROUND
Monoclonal antibody (mAb)-based orphan drugs have led to advances in the treatment of diseases by selectively targeting molecule functions. However, their high treatment costs impose a substantial cost burden on patients and society.
OBJECTIVES
The study aimed to systematically review cost-effectiveness evidence of mAb orphan drugs.
METHODS
Ovid MEDLINE(®), EMBASE(®), and PsycINFO(®) were searched in June 2014 and articles were selected if they conducted economic evaluations of the mAb orphan drugs that had received marketing approval in the USA. The quality of the selected studies was assessed using the Quality of Health Economic Studies (QHES) instrument.
RESULTS
We reviewed 16 articles that included 24 economic evaluations of nine mAb orphan drugs. Six of these nine drugs were included in cost-utility analysis studies, whereas three drugs were included in cost-effectiveness analysis studies. Previous cost-utility analysis studies revealed that four mAb orphan drugs (cetuximab, ipilimumab, rituximab, and trastuzumab) were found to be cost effective; one drug (bevacizumab) was not cost effective; and one drug (infliximab) was not consistent across the studies. Prior cost-effectiveness analysis studies which included three mAb orphan drugs (adalimumab, alemtuzumab, and basiliximab) showed that the incremental cost per effectiveness gained for these drugs ranged from $US4669 to $Can52,536 Canadian dollars. The quality of the included studies was good or fair with the exception of one study.
CONCLUSIONS
Some mAb orphan drugs were reported as cost effective under the current decision-making processes. Use of these expensive drugs, however, can raise an equity issue which concerns fairness in access to treatment. The issue of equal access to drugs needs to be considered alongside other societal values in making the final health policy decisions.
Topics: Antibodies, Monoclonal; Cost-Benefit Analysis; Decision Making; Drug Approval; Humans; Orphan Drug Production; Rare Diseases
PubMed: 26263903
DOI: 10.1007/s40259-015-0135-4 -
Seminars in Arthritis and Rheumatism Oct 2015To examine, separately, in children and adults with autoimmune chronic uveitis (ACU), the evidence regarding the effectiveness and the safety of switching to a... (Review)
Review
OBJECTIVE
To examine, separately, in children and adults with autoimmune chronic uveitis (ACU), the evidence regarding the effectiveness and the safety of switching to a non-anti-TNF biologic modifier immunosuppressant treatment (NTT) currently available in clinical practice.
METHODS
A systematic search between January 2000 and April 2014 was conducted using EMBASE, Ovid MEDLINE, Evidence Based Medicine Reviews-ACP Journal Club, Cochrane libraries, and EBM Reviews. Studies investigating the efficacy of NTT as a biologic modifier immunosuppressant medication for ACU, refractory to topical and/or systemic steroid therapy, were eligible for inclusion. The primary outcome measure was the improvement of intraocular inflammation, as defined by the SUN working group criteria. We determined a combined estimate of the proportion of subjects responding to NTT.
RESULTS
We initially identified 526 articles, of which 89 were potentially eligible. From the selection process, a total of 10 retrospective chart reviews and a randomized single-blind controlled study, providing a total of 12 children and 34 adults, were deemed eligible: 3 articles looked at rituximab, 3 at abatacept, 3 at tocilizumab, and the remaining 1 at alemtuzumab and the other at anakinra. Before the NTT treatment, all the eligible subjects received several combinations of one or more DMARDs and at least one anti-TNF strategy. With the exclusion of 7 adults enrolled in the RCT, 8 of 12 children and 18 of 27 adults responded to NTT treatment: 0.66 was the combined estimate of the proportion of subjects improving on NTT treatment in children (95% CI: 0.46-0.99) and in adults (95% CI: 0.49-0.84). Further statistical comparison between different NTT strategies was not possible due to the small sample size.
CONCLUSION
Although randomized controlled trials are needed, the available evidence suggests the clinical use of a NTT strategy in selected categories of ACU, refractory to previous course of immunosuppressive treatment, DMARDs, as well as anti-TNFα, in adults as well as children.
Topics: Abatacept; Alemtuzumab; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Biological Products; Humans; Interleukin 1 Receptor Antagonist Protein; Rituximab; Treatment Outcome; Uveitis
PubMed: 26164255
DOI: 10.1016/j.semarthrit.2015.05.006 -
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 -
Blood Mar 2015We analyzed cost-effectiveness studies related to hematologic malignancies from the Tufts Medical Center Cost-Effectiveness Analysis Registry (www.cearegistry.org),... (Review)
Review
We analyzed cost-effectiveness studies related to hematologic malignancies from the Tufts Medical Center Cost-Effectiveness Analysis Registry (www.cearegistry.org), focusing on studies of innovative therapies. Studies that met inclusion criteria were categorized by 4 cancer types (chronic myeloid leukemia, chronic lymphocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma) and 9 treatment agents (interferon-α, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide). We examined study characteristics and stratified cost-effectiveness ratios by type of cancer, treatment, funder, and year of study publication. Twenty-nine studies published in the years 1996-2012 (including 44 cost-effectiveness ratios) met inclusion criteria, 22 (76%) of which were industry funded. Most ratios fell below $50,000 per quality-adjusted life-years (QALY) (73%) and $100,000/QALY (86%). Industry-funded studies (n = 22) reported a lower median ratio ($26,000/QALY) than others (n = 7; $33,000/QALY), although the difference was not statistically significant. Published data suggest that innovative treatments for hematologic malignancies may provide reasonable value for money.
Topics: Antineoplastic Agents; Cost-Benefit Analysis; Decision Making; Diffusion of Innovation; Economics, Medical; Hematologic Neoplasms; Humans; Models, Economic; Quality of Life; Quality-Adjusted Life Years; Registries; Treatment Outcome
PubMed: 25655601
DOI: 10.1182/blood-2014-07-592832 -
Human Vaccines & Immunotherapeutics 2014Cancer immunotherapy is a rapidly growing field in oncology. One attractive feature of cancer immunotherapy is the purported combination of minimal toxicity and durable... (Review)
Review
Cancer immunotherapy is a rapidly growing field in oncology. One attractive feature of cancer immunotherapy is the purported combination of minimal toxicity and durable responses. However such treatments are often very expensive. Given the wide-spread concern over rising health care costs, it is important for all stakeholders to be well-informed on the cost and cost-effectiveness of cancer immunotherapies. We performed a comprehensive literature review of cost and cost-effectiveness research on therapeutic cancer vaccines and monoclonal antibodies, to better understand the economic impacts of these treatments. We summarized our literature searches into three tables by types of papers: systematic review of economic studies of a specific agent, cost and cost-effectiveness analysis. Our review showed that out of the sixteen immunotherapy agents approved, nine had relevant published economic studies. Five out of the nine studied immunotherapy agents had been covered in systematic reviews. Among those, only one (rituximab for non-Hodgkin lymphoma) was found to be cost-effective. Of the four immunotherapy drugs not covered in systematic reviews (alemtuzumab, ipilimumab, sipuleucel-T, ofatumumab), high incremental cost-effectiveness ratio (ICER) was reported for each. Many immunotherapies have not had economic evaluations, and those that have been studied show high ICERs or frank lack of cost-effectiveness. One major hurdle in improving the cost-effectiveness of cancer immunotherapies is to identify predictive biomarkers for selecting appropriate patients as recipients of these expensive therapies. We discuss the implications surrounding the economic factors involved in cancer immunotherapies and suggest that further research on cost and cost-effectiveness of newer cancer vaccines and immunotherapies are warranted as this is a rapidly growing field with many new drugs on the horizon.
Topics: Antibodies, Monoclonal; Cancer Vaccines; Cost-Benefit Analysis; Cytokines; Humans; Immunotherapy; Neoplasms
PubMed: 25483656
DOI: 10.4161/hv.29407 -
The Cochrane Database of Systematic... Nov 2014Most people who receive a kidney transplant die from either cardiovascular disease or cancer before their transplant fails. The most common reason for someone with a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Most people who receive a kidney transplant die from either cardiovascular disease or cancer before their transplant fails. The most common reason for someone with a kidney transplant to lose the function of their transplanted kidney necessitating return to dialysis is chronic kidney transplant scarring. Immunosuppressant drugs have side effects that increase risks of cardiovascular disease, cancer and chronic kidney transplant scarring. Belatacept may provide sufficient immunosuppression while avoiding unwanted side effects of other immunosuppressant drugs. However, high rates of post-transplant lymphoproliferative disease (PTLD) have been reported when belatacept is used in particular kidney transplant recipients at high dosage.
OBJECTIVES
1) Compare the relative efficacy of belatacept versus any other primary immunosuppression regimen for preventing acute rejection, maintaining kidney transplant function, and preventing death. 2) Compare the incidence of several adverse events: PTLD; other malignancies; chronic transplant kidney scarring (IF/TA); infections; change in blood pressure, lipid and blood sugar control. 3) Assess any variation in effects by study, intervention and recipient characteristics, including: differences in pre-transplant Epstein Barr virus serostatus; belatacept dosage; and donor-category (living, standard criteria deceased, or extended criteria deceased).
SEARCH METHODS
We searched the Cochrane Renal Group's Specialised Register to 1 September 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.
SELECTION CRITERIA
Randomised controlled trials (RCT) that compared belatacept versus any other immunosuppression regimen in kidney transplant recipients were eligible for inclusion.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data for study quality and transplant outcomes and synthesized results using random effects meta-analysis, expressed as risk ratios (RR) and mean differences (MD), both with 95% confidence intervals (CI). Subgroup analyses and univariate meta-regression were used to investigate potential heterogeneity.
MAIN RESULTS
We included five studies that compared belatacept and calcineurin inhibitors (CNI) that reported data from a total of 1535 kidney transplant recipients. Of the five studies, three (478 participants) compared belatacept and cyclosporin and two (43 recipients) compared belatacept and tacrolimus. Co-interventions included basiliximab (4 studies, 1434 recipients); anti-thymocyte globulin (1 study, 89 recipients); alemtuzumab (1 study, 12 recipients); mycophenolate mofetil (MMF, 5 studies, 1509 recipients); sirolimus (1 study, 26 recipients) and prednisone (5 studies, 1535 recipients).Up to three years following transplant, belatacept and CNI-treated recipients were at similar risk of dying (4 studies, 1516 recipients: RR 0.75, 95% CI 0.39 to 1.44), losing their kidney transplant and returning to dialysis (4 studies, 1516 recipients: RR 0.91, 95% CI 0.61 to 1.38), and having an episode of acute rejection (4 studies, 1516 recipients: RR 1.56, 95% CI 0.85 to 2.86). Belatacept-treated kidney transplant recipients were 28% less likely to have chronic kidney scarring (3 studies, 1360 recipients: RR 0.72, 95% CI 0.55 to 0.94) and also had better graft function (measured glomerular filtration rate (GFR) (3 studies 1083 recipients): 10.89 mL/min/1.73 m², 95% CI 4.01 to 17.77; estimated GFR (4 studies, 1083 recipients): MD 9.96 mL/min/1.73 m², 95% CI 3.28 to 16.64) than CNI-treated recipients. Blood pressure was lower (systolic (2 studies, 658 recipients): MD -7.51 mm Hg, 95% CI -10.57 to -4.46; diastolic (2 studies, 658 recipients): MD -3.07 mm Hg, 95% CI -4.83 to -1.31, lipid profile was better (non-HDL (3 studies 1101 recipients): MD -12.25 mg/dL, 95% CI -17.93 to -6.57; triglycerides (3 studies 1101 recipients): MD -24.09 mg/dL, 95% CI -44.55 to -3.64), and incidence of new-onset diabetes after transplant was reduced by 39% (4 studies (1049 recipients): RR 0.61, 95% CI 0.40 to 0.93) among belatacept-treated versus CNI-treated recipients.Risk of PTLD was similar in belatacept and CNI-treated recipients (4 studies, 1516 recipients: RR 2.79, 95% CI 0.61 to 12.66) and was no different among recipients who received different belatacept dosages (high versus low dosage: ratio of risk ratios (RRR) 1.06, 95% CI 0.11 to 9.80, test of difference = 0.96) or among those who were Epstein Barr virus seronegative compared with those who were seropositive before their kidney transplant (seronegative versus seropositive; RRR 1.49, 95% CI 0.15 to 14.76, test for difference = 0.73).The belatacept dose used (high versus low), type of donor kidney the recipient received (extended versus standard criteria) and whether the kidney transplant recipient received tacrolimus or cyclosporin made no difference to kidney transplant survival, incidence of acute rejection or estimated GFR. Selective outcome reporting meant that data for some key subgroup comparisons were sparse and that estimates of the effect of treatment in these groups of recipients remain imprecise.
AUTHORS' CONCLUSIONS
There is no evidence of any difference in the effectiveness of belatacept and CNI in preventing acute rejection, graft loss and death, but treatment with belatacept is associated with less chronic kidney scarring and better kidney transplant function. Treatment with belatacept is also associated with better blood pressure and lipid profile and a lower incidence of diabetes versus treatment with a CNI. Important side effects (particularly PTLD) remain poorly reported and so the relative benefits and harms of using belatacept remain unclear. Whether short-term advantages of treatment with belatacept are maintained over the medium- to long-term or translate into better cardiovascular outcomes or longer kidney transplant survival with function remains unclear. Longer-term, fully reported and published studies comparing belatacept versus tacrolimus are needed to help clinicians decide which patients might benefit most from using belatacept.
Topics: Abatacept; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Basiliximab; Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunoconjugates; Immunosuppressive Agents; Kidney Transplantation; Lymphoproliferative Disorders; Mycophenolic Acid; Prednisone; Randomized Controlled Trials as Topic; Recombinant Fusion Proteins; Sirolimus; Tacrolimus
PubMed: 25416857
DOI: 10.1002/14651858.CD010699.pub2 -
The Cochrane Database of Systematic... Jun 2014Liver transplantation is an established treatment option for end-stage liver failure. To date, no consensus has been reached on the use of immunosuppressive T-cell... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Liver transplantation is an established treatment option for end-stage liver failure. To date, no consensus has been reached on the use of immunosuppressive T-cell antibody induction for preventing rejection after liver transplantation.
OBJECTIVES
To assess the benefits and harms of immunosuppressive T-cell specific antibody induction compared with placebo, no induction, or another type of T-cell specific antibody induction for prevention of acute rejection in liver transplant recipients.
SEARCH METHODS
We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) until September 2013.
SELECTION CRITERIA
Randomised clinical trials assessing immunosuppression with T-cell specific antibody induction compared with placebo, no induction, or another type of antibody induction in liver transplant recipients. Our inclusion criteria stated that participants within each included trial should have received the same maintenance immunosuppressive therapy. We planned to include trials with all of the different types of T-cell specific antibodies that are or have been used for induction (ie., polyclonal antibodies (rabbit of horse antithymocyte globulin (ATG), or antilymphocyte globulin (ALG)), monoclonal antibodies (muromonab-CD3, anti-CD2, or alemtuzumab), and interleukin-2 receptor antagonists (daclizumab, basiliximab, BT563, or Lo-Tact-1)).
DATA COLLECTION AND ANALYSIS
We used RevMan analysis for statistical analysis of dichotomous data with risk ratio (RR) and of continuous data with mean difference (MD), both with 95% confidence intervals (CIs). We assessed the risk of systematic errors (bias) using bias risk domains with definitions. We used trial sequential analysis to control for random errors (play of chance). We presented outcome results in a summary of findings table.
MAIN RESULTS
We included 19 randomised clinical trials with a total of 2067 liver transplant recipients. All 19 trials were with high risk of bias. Of the 19 trials, 16 trials were two-arm trials, and three trials were three-arm trials. Hence, we found 25 trial comparisons with antibody induction agents: interleukin-2 receptor antagonist (IL-2 RA) versus no induction (10 trials with 1454 participants); monoclonal antibody versus no induction (five trials with 398 participants); polyclonal antibody versus no induction (three trials with 145 participants); IL-2 RA versus monoclonal antibody (one trial with 87 participants); and IL-2 RA versus polyclonal antibody (two trials with 112 participants). Thus, we were able to compare T-cell specific antibody induction versus no induction (17 trials with a total of 1955 participants). Overall, no difference in mortality (RR 0.91; 95% CI 0.64 to 1.28; low-quality of evidence), graft loss including death (RR 0.92; 95% CI 0.71 to 1.19; low-quality of evidence), and adverse events ((RR 0.97; 95% CI 0.93 to 1.02; low-quality evidence) outcomes was observed between any kind of T-cell specific antibody induction compared with no induction when the T-cell specific antibody induction agents were analysed together or separately. Acute rejection seemed to be reduced when any kind of T-cell specific antibody induction was compared with no induction (RR 0.85, 95% CI 0.75 to 0.96; moderate-quality evidence), and when trial sequential analysis was applied, the trial sequential monitoring boundary for benefit was crossed before the required information size was obtained. Furthermore, serum creatinine was statistically significantly higher when T-cell specific antibody induction was compared with no induction (MD 3.77 μmol/L, 95% CI 0.33 to 7.21; low-quality evidence), as well as when polyclonal T-cell specific antibody induction was compared with no induction, but this small difference was not clinically significant. We found no statistically significant differences for any of the remaining predefined outcomes - infection, cytomegalovirus infection, hepatitis C recurrence, malignancy, post-transplant lymphoproliferative disease, renal failure requiring dialysis, hyperlipidaemia, diabetes mellitus, and hypertension - when the T-cell specific antibody induction agents were analysed together or separately. Limited data were available for meta-analysis on drug-specific adverse events such as haematological adverse events for antithymocyte globulin. No data were found on quality of life.When T-cell specific antibody induction agents were compared with another type of antibody induction, no statistically significant differences were found for mortality, graft loss, and acute rejection for the separate analyses. When interleukin-2 receptor antagonists were compared with polyclonal T-cell specific antibody induction, drug-related adverse events were less common among participants treated with interleukin-2 receptor antagonists (RR 0.23, 95% CI 0.09 to 0.63; low-quality evidence), but this was caused by the results from one trial, and trial sequential analysis could not exclude random errors. We found no statistically significant differences for any of the remaining predefined outcomes: infection, cytomegalovirus infection, hepatitis C recurrence, malignancy, post-transplant lymphoproliferative disease, renal failure requiring dialysis, hyperlipidaemia, diabetes mellitus, and hypertension. No data were found on quality of life.
AUTHORS' CONCLUSIONS
The effects of T-cell antibody induction remain uncertain because of the high risk of bias of the randomised clinical trials, the small number of randomised clinical trials reported, and the limited numbers of participants and outcomes in the trials. T-cell specific antibody induction seems to reduce acute rejection when compared with no induction. No other clear benefits or harms were associated with the use of any kind of T-cell specific antibody induction compared with no induction, or when compared with another type of T-cell specific antibody. Hence, more randomised clinical trials are needed to assess the benefits and harms of T-cell specific antibody induction compared with placebo, and compared with another type of antibody, for prevention of rejection in liver transplant recipients. Such trials ought to be conducted with low risks of systematic error (bias) and low risk of random error (play of chance).
Topics: Acute Disease; Antibodies, Monoclonal; Antibody Formation; Graft Rejection; Humans; Immunity, Cellular; Immunosuppression Therapy; Liver Transplantation; Randomized Controlled Trials as Topic; T-Lymphocytes
PubMed: 24901467
DOI: 10.1002/14651858.CD010253.pub2 -
The Cochrane Database of Systematic... Dec 2013This is an update of the Cochrane review "Rituximab for relapsing-remitting multiple sclerosis" (first published in The Cochrane Library 2011, Issue 12).More than 80% of... (Review)
Review
BACKGROUND
This is an update of the Cochrane review "Rituximab for relapsing-remitting multiple sclerosis" (first published in The Cochrane Library 2011, Issue 12).More than 80% of individuals with multiple sclerosis (MS) experience a relapsing-remitting disease course. Approximately 10 years after disease onset, an estimated 50% of individuals with relapsing-remitting MS (RRMS) convert to secondary progressive MS. MS causes a major socioeconomic burden for the individual patient and for society. Effective treatment that reduces relapse frequency and prevents progression could impact both costs and quality of life and help to reduce the socioeconomic burden of MS. Alternative and more effective MS treatments with new modes of action and good safety are needed to expand the current treatment repertoire. It has been shown that B lymphocytes are involved in the pathophysiology of MS and rituximab lyses B-cells via complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Current clinical trials are evaluating the role of rituximab as a B-cell depletion therapy in the treatment of RRMS.
OBJECTIVES
The safety and effectiveness of rituximab, as monotherapy or combination therapy, versus placebo or approved disease-modifying drugs (DMDs) (interferon-β (IFN-β), glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab) to reduce disease activity for people with RRMS were assessed.
SEARCH METHODS
The Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (9 August 2013). We checked the references in identified trials and manually searched the reports (2004 to August 2013) from neurological associations and MS societies in Europe and America. We also communicated with researchers who were participating in trials on rituximab and contacted Genentech, BiogenIdec and Roche.
SELECTION CRITERIA
All randomised, double-blind, controlled parallel group clinical trials with a length of follow-up equal to or greater than one year evaluating rituximab, as monotherapy or combination therapy, versus placebo or approved DMDs for patients with RRMS 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. Principal investigators of included studies were contacted for additional data or confirmation of data.
MAIN RESULTS
One trial involving 104 adult RRMS patients with an entry score ≤ 5.0 on the Expanded Disability Status Scale (EDSS) and at least one relapse during the preceding year was included. This trial evaluated rituximab as monotherapy versus placebo, with a single course of 1000 mg intravenous rituximab (on day 1 and day 15). A significant attrition bias was found at week 48 (24.0%). Patients receiving rituximab had a significant reduction in total number of gadolinium-enhancing lesions at week 24 (mean number 0.5 versus 5.5; relative reduction 91%) and in annualised rate of relapse at week 24 (0.37 versus 0.84) but not at week 48 (0.37 versus 0.72). Disability progression was not included as an outcome in this trial. More patients in the rituximab group had adverse events within the 24 hours after the first infusion (78.3% versus 40.0%), such as chills, headache, nausea, pyrexia, pruritus, fatigue, throat irritation, pharyngolaryngeal pain, and most were mild-to-moderate events (92.6%). The most common infection-associated adverse events (> 10% in the rituximab group) were nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis. Among them, only urinary tract infections (14.5% versus 8.6%) and sinusitis (13.0% versus 8.6%) were more common in the rituximab group. One ongoing trial was identified.
AUTHORS' CONCLUSIONS
There is not sufficient evidence to support the use of rituximab as a disease-modifying therapy for RRMS because only one RCT was included. The quality of the study was limited due to high attrition bias, the small number of participants, and short follow-up. The beneficial effects of rituximab for RRMS remain inconclusive. However, short-term treatment with a single course of rituximab was safe for most patients with RRMS. Mild-to-moderate infusion-associated adverse events were common, as well as nasopharyngitis, upper respiratory tract infections, urinary tract infections and sinusitis. The potential benefits of rituximab for treating RRMS need to be evaluated in large-scale studies that are of high quality along with long-term safety.
Topics: Adult; Antibodies, Monoclonal, Murine-Derived; Humans; Immunologic Factors; Multiple Sclerosis, Relapsing-Remitting; Randomized Controlled Trials as Topic; Rituximab
PubMed: 24310855
DOI: 10.1002/14651858.CD009130.pub3