Limits of add-on trials: antirheumatic drugs

Ottolenghi, L; Bertelè, Vittorio

doi:10.1007/s00228-008-0545-z

Cited by 8 publications

(9 citation statements)

References 26 publications

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“…Rituximab is a chimeric monoclonal anti-CD20 antibody developed for the treatment of B-cell malignancies. It has been approved for B cell non-Hodgkin lymphoma resistant to other chemotherapy regimens and also in combination with methotrexate in adult patients with moderate to severe active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies [104,127]. Efficacy of rituximab has also been shown in autoimmune disorders such as systemic lupus erythematosus and pemphigus vulgaris [128][129][130].…”

Section: Targeting Cd20 Cd23mentioning

confidence: 98%

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Monoclonal Antibodies in Allergy; Current Applications and Promising Trials

Özdemir¹

2009

IAD

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Allergic disorders, including asthma, allergic rhinoconjunctivitis, atopic dermatitis, food allergies, urticaria and anaphylaxis have significant impacts on our daily lives. Innovation of novel treatment modalities targeting effector cells, cytokines, receptors or signaling pathways may bring new alternatives in the management of diseases, including allergic disorders. Understanding the mechanisms of allergic immune response is a requisite to plan or switch to a new or an adjunctive treatment course instead of or in addition to current conventional therapies, which are almost effective and safe in most of the cases. Monoclonal antibodies are major candidates that may act on the specific targets of allergic immune response in the treatment of these disorders. As monoclonal antibodies may contribute to our designing of new treatment options within the next years, specific concerns have to be considered such as efficacy, safety, long-term tolerability of these molecules as well as identifying associations with the mechanisms of disease pathogenesis. Hereby, it is aimed to review most of the currently published clinical studies in which some monoclonal antibodies were trialed for the management of allergic disorders. This review also addressed some recently patented monoclonal antibodies and their uses.

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Section: Targeting Cd20 Cd23mentioning

confidence: 98%

“…Monoclonal antibodies targeting TNFare mostly approved for selected autoimmune inflammatory disorders [102][103][104]. Experimental and clinical studies also suggest that TNF-may play a role in the pathogenesis of asthma [105,106].…”

Section: Targeting Tnf-; Adalimumab Certolizu-mab Pegol Etanerceptmentioning

confidence: 99%

Monoclonal Antibodies in Allergy; Current Applications and Promising Trials

Özdemir¹

2009

IAD

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“…Corticosteroids are major active medications used in systemic diseases. However, as a cointervention, their potential effect on the results of parallel-group randomized trials has not been extensively evaluated (2,3,18,19). Our study showed that the between-arm difference in corticosteroid dose may have a clinical impact and may lead to biased interpretation of the results.…”

Section: Discussionmentioning

confidence: 81%

“…Whether the combined prescription of another therapeutic agent (e.g., an immunosuppressant) can further improve patient outcome is evaluated by conducting clinical trials, whereby the treatments being compared are prescribed in addition to corticosteroids (1)(2)(3)(4). Randomization aims to equally balance prior corticosteroid use in each arm at baseline, but corticosteroid dose is highly likely to be modified by physicians throughout the trial, depending on the course of the disease, the effect of the tested intervention, and adverse events (5).…”

Section: Introductionmentioning

confidence: 99%

Reporting of corticosteroid use in systemic disease trials: Evidence from a systematic review of the potential impact on treatment effect

Pagnoux¹,

Dechartres

Giraudeau

et al. 2010

Arthritis Care & Research

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Objective. To study how corticosteroid therapy is planned and described in reports of systemic disease trials and estimate the impact of the between-arm difference in corticosteroid dose on treatment effect. Methods. We performed a systematic review of PubMed and Cochrane databases on all reports of randomized systemic disease trials with corticosteroids as a cointervention. Data were extracted on the trial characteristics and results, planning of corticosteroid use, and dose. Success rates were adjusted for corticosteroid use for studies with available data and a binary outcome. Because the exact impact of between-arm differences in corticosteroid dose on success rates is unknown, we tested different values for the impact of a difference of 1 unit (1 mg for daily dosage or 250 mg for cumulative dose at the end of the trial). Results. A total of 139 trials were identified, including 79 investigating lupus and 30 investigating vasculitis. Planned management of corticosteroid use was specified in 101 reports (72.7%), with a fully described tapering scheme in 33 (23.7%). Corticosteroid consumption for each arm was given in 60 reports (43.2%), with a comparison of daily or cumulative dosage at the end of the trial in 32 (23.0%). An attempt to adjust for corticosteroid use was described in 2 (1.5%). With a value of 2.5% for the impact of a 1-unit difference in corticosteroid dose, adjustment yielded changes in success rate differences exceeding 10% in 11 (46%) of the 24 reports analyzed. Conclusion. For systemic disease trials, use of corticosteroids as a cointervention is often inadequately planned and reported and could affect treatment effect.

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“…For instance in trials with an add-on design one of the two arms receives the new drug and the other a placebo, while both are given an effective drug that is already available which, as such, cannot be omitted; this is acceptable if there is no previous study showing that another drug has already shown a beneficial effect for the same indication with the same design. The RCTs of new anti-TNFa or other so-called disease modifying anti-rheumatic drugs (DMARD) is paradigmatic: they are added to methotrexate in comparison with placebo even though other drugs are already known to act synergistically with methotrexate [2]. Another example is in diabetes.…”

Section: The Excessive Use Of Placebomentioning

confidence: 99%

Ethics in clinical research

Garattini

Bertelè

2009

Journal of Hepatology

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R&D of new drugs is driven by pharmaceutical companies that invest considerable amounts of money for this purpose. This may introduce bias, to emphasize the clinical value of drugs to be allowed onto the market. Bias is caused by methodological flaws including the population under study, the choice of inadequate comparators or of their dosage, the adoption of surrogate or composite endpoints, the decision to publish mainly positive findings or to overlook some safety concerns, etc. All this happens in a legal context that requires no added value for new drugs to be approved for the market. This encourages the use of placebo even when active comparators are available, or the search for non-inferiority of new products in comparison with active comparators. Superiority over placebo and non-inferiority to active comparators may allow drugs onto the market that are in fact less active (or safe, tolerable, convenient, etc.) than those already available, usually with consolidated properties and lower costs. In addition, they do not meet patients' or physicians' needs of defining the place in therapy and respective roles of new and available treatments. The current legislative and regulatory setting seems designed to meet commercial interests rather than public health needs.

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Limits of add-on trials: antirheumatic drugs

Abstract: International audienc

Cited by 8 publications

References 26 publications

Monoclonal Antibodies in Allergy; Current Applications and Promising Trials

Monoclonal Antibodies in Allergy; Current Applications and Promising Trials

Reporting of corticosteroid use in systemic disease trials: Evidence from a systematic review of the potential impact on treatment effect

Ethics in clinical research

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