Enbrel: Noruega inicia estudio complementario a Rituximab

[elipoarch]

Este post aparecido en un blog de Neuroinmunología noruego explica que Fluge y Mella, los mismos médicos que hicieron el estudio del Rituximab, van a iniciar un estudio preliminar con Enbrel, un inhibidor de TNF, incluyendo casos que no tuvieron respuesta con el Rituximab. En el estudio se incluyen casos de SFC/EM tanto moderados como graves. La idea es encontrar un tratamiento que sí funcione con ese tercio de casos que no obtuvieron respuesta con el Rituximab. Es un estudio pequeño, 15 casos, y parece ser que se publicará a principios de 2015. Es una traducción automática del noruego al inglés. Os pongo el enlace al final, para que podáis darle a la traducción en español, si quereis.

Norwegian research: [t]Treatment with TNF inhibitor Etanercept (Enbrel ®) for moderate and severe chronic fatigue syndrome (CFS / ME) - an open prestudie[/t]
MAY 3
Posted by memhj

This post gives an overview of the study protocol KTS-4-2011 for the treatment program at the trial of the drug Etanercept (Enbrel ®) for moderate and severe chronic fatigue syndrome (CFS / ME). Etanercept (Enbrel ®) for moderate and severe chronic fatigue syndrome (CFS / ME ), including for patients who have no response for B-lymphocyte depletion using a monoclonal anti-CD20 antibody Rituximab may be a therapeutic option for ME patients showed no response after treatment with Rituximab study.



The project description submitted REK December 13, 2011 are as follows:

Project Team:

Project Chief
Dr.med Øystein Fluge
Specialist in Oncology, Haukeland University Hospital Department of Oncology and Medical Physics

Research Manager
Prof. Dr. med. Olav Mella, division director at the Haukeland University Hospital

Researchers
Prof. Dr. Dr. med. Olav Dahl at Haukeland University Hospital.

Purpose:
Cause of chronic fatigue syndrome (CFS / ME) is unknown. Our studies show that a subgroup of CFS / ME patients have response for B-lymphocyte depletion using anti-CD20 antibody Rituximab. The hypothesis is that CFS / ME can be an autoimmune disease.

1/3 of CFS / ME patients had no response after B cell depletion. An alternative may be the use of TNF inhibitors such as etanercept (Enbrel). Enbrel is given by subcutaneous injection weekly, and binds to the cytokine TNF-alpha. There are no scientific studies that have evaluated Enbrel in CFS / ME. A contemporaneously referenced clear effect in six patients, and individual patient stories are unpublished.

Enbrel can reduce the risk of infections and paradoxes disorders of the immune system.

Drugs are still in widespread use as a treatment for rheumatoid arthritis, with acceptable side effect profile.

We want to give Enbrel for up to one year, for up to 15 patients with moderate and severe CFS / ME, including patients with no response after Rituximab treatment.

Project Framework:
Project Start 01/02/2012

Closing 31.12.2014

After project completion shall be de-identified data

Data from patients' self-reporting and physician reporting of symptom change in follow-up, along with other completed forms are kept for stud end, locked in Kreftavdeligen, Haukeland University Hospital, de-identified and separate from the link key. The information in the patient's electronic medical records remain a part of their usual medical information, according to hospital policy.

Publication

There are no restrictions with regard to the publication of the resultant from the project

The results will be published in reputable medical journals.

Research Methods
Both statistical and interpretive analysis

Intervention - Physical intervention

Treatment with etanercept (Enbrel ®), as weekly subcutaneous injections of Enbrel 50 mg, given up to one year (52 weeks).

Justification for the choice of data and method

The cancer department in cooperation with the Department of Neurology (Haukeland University Hospital) conducted clinical trials to evaluate the B-lymphocyte depletion using a monoclonal anti-CD20 antibody Rituximab against the symptoms of chronic fatigue syndrome (CFS / ME). We performed first a pilot study as a kasuistikkserie three patients (Fluge and Mella, BMC Neurology, 2009), and then a double-blind, placebo-controlled, randomized study with 30 patients (Fluge et al., PLoS ONE, 2011). These are described in the attached project description.

Our hypothesis is that CFS / ME, which is often preceded by infection, can be a form of autoimmune disease. The assumption is based on the sequence of response and relapse after B cell depletion. While B-cells is reduced to very low levels in peripheral blood within a few weeks, the "delay" from 2 up to 7 months before the onset of clinical response, which may be consistent with the gradual elimination of autoantibodies. Response Rate and timing of response and relapse is consistent with what can be seen after Rituximab treatment, for example rheumatoid arthritis. Overweight women, a proven genetic predisposition and the occurrence of other autoimmune diseases in the family are other factors that suggest a possible autoimmune pathogenesis.

We have not yet proven this, and laboratory work is ongoing to elucidate disease etiology and pathogenesis. B-cell depletion is a fundamental intervention in the immune system and several possible interpretations for our treatment results than fall in autoantibody titer is, as stated in the project description.

In the randomized study was the third of those treated with Rituximab who had no signs of clinical response. Given our assumption that CFS / ME can be a form of autoimmune disease is correct, there are several possibilities for mechanisms of non-response. For some patients it may be very high level of presumptive autoantibody initially, so the patient does not "reach" to eliminate them (half-life of 3-5 weeks) after prolonged (12 months) B-cell depletion.

For other patients it may be that the presumptive autoantibody produced by fully mature plasma cells that is seldom affected by anti-CD20 antibody, whereas such treatment is more effective where autoantibody production of more "early" plasma blasts. Other mechanisms for non-response may be that some patients are other facets of an autoimmune process (other than B-cell functions) that are most important to symptom maintenance.

Such processes can be T-cell activation, and effects of abberante cytokines such as tumor necrosis factor alpha (TNF-) which is an important pro-inflammatory mediator and has regulatory properties of the immune system to other cells such as regulatory T cells.

Finally, some patients with CFS / ME diagnosis have other conditions that are not immune-mediated, such as primary psychiatric conditions associated with fatigue.

An alternative for patients with typical CFS / ME illness strict diagnostic criteria, but no response after Rituximab, the use of a TNF inhibitor Enbrel.

In autoimmune diseases like arthritis seen the effects of illness often after a few weeks, as this is mediated via the elimination of the cytokine directly.

Enbrel will thus not be able to cure an autoimmune condition, but often effective as symptomatic treatment. Enbrel is given by subcutaneous injection once weekly (see project description). Etanercept acts by binding to TNF-, and thus inhibits binding of TNF to receptors on the cell surface, with subsequent inhibition TNF-mediated cellular response.

In addition, affected a number of biological responses associated with such cytokines and adhesion molecules that are induced or regulated by TNF-. Injection of proinflammatory cytokines such as IL-1, IL-6 and TNF-, directly into the brains of experimental animals, can provide a clinical picture reminiscent of CFS / ME, with impaired motor activity, sleep problems, altered fluid and food intake and signs of cognitive issues. Systemically administered IL-6 and TNF-in humans can cause inflammatory symptoms, including severe fatigue.

There are no published scientific published study that evaluated the use of Enbrel in CFS / ME. However, there is a contemporaneously where six CFS / ME patients had been treated with etanercept with good clinical effect, but these results have not been published later (Lamprecht K. American Association of Chronic Fatigue Syndrome, Seattle 2001). In addition, individual patient unpublished stories available.

The Cancer Department, we have had contact with a 35-year-old woman who has had severe CFS / ME with a typical clinical picture of 16-years of age who for years was significantly isolated and disabled by the condition.

She had a moderate rheumatoid arthritis 27-year-old, and started as a 31-year-old with Enbrel administered subcutaneously every week and have used the drug last 5 years. She explains how Enbrel during the 2-3 weeks resulted in a significant clinical effect on all symptoms related to her CFS / ME. She describes clearly how the ME disease is still present, and that she must be aware of in terms of load factor, but that she still has a significant change of quality of life. Such a description is consistent with our idea that CFS / ME can be a form of autoimmune disease.

Enbrel may have more side effects than Rituximab, and is somewhat more associated with risk of infections and paradoxes disorders of the immune system. Drugs are still in widespread use in the treatment of rheumatoid arthritis with good results and acceptable safety profile. Toxicity profile of Enbrel in CFS / ME is unknown.

We want to try treatment with Enbrel for up to 15 patients with moderate and severe CFS / ME, including patients who have not had a response after treatment with Rituximab-maintenance (5 infusion and 12 month follow-up), with weekly subcutaneous injections for up to one year.

Patients / participants
Up to 15 evaluable patients with chronic fatigue syndrome (CFS / ME) with moderate and severe illness, according to revised criteria from 1994 (Fukuda criteria).

Age 18-66 years. Signed informed consent.

Patients who have participated in either the KTS-1-2008, KTS-2-2010, or KTS-3-2010 with a typical CFS / ME symptom picture, but where there have been signs of clinical response after 12 months follow-up after start of intervention with Rituximab can be included (non-responders to Rituximab).

The purpose of this study is to investigate the effect on the symptom picture in moderate and severe CFS / ME, after treatment with etanercept (Enbrel) that weekly subcutaneous injections of 50 mg up to 52 weeks.

Remote (s) or historical (e) control group (s)

In our published, double-blind, placebo-controlled and randomized study of Rituximab or placebo in CFS / ME (Fluge et al, PLoS ONE, 2011), we have a historical control group who signed symptom change every other week for 12 months follow-up, corresponding to that outlined in this study.

Cut-off for what is ready response, and data from symptom variation in a placebo group is therefore. We also have data from responders and non-responders after the intervention with Rituximab, which will be a relevant basis for comparison. This study will be exploratory and should be considered a pilot study, to obtain evidence for activity of etanercept in CFS / ME, with an impression of the response rate and possible toxicity.

Research Ethical challenges of the project
Benefits:

Each project participant

Each project participant will have the opportunity for clinical improvement of symptoms from the disease, which is often significant and debilitating for the patient with regard to social and familiar life, study / work / school and with regard to quality of life.

Groups of people

Patients with moderate and severe CFS / ME.

There are no established and proven drug therapy that is effective in CFS / ME. The estimated prevalence of CFS / ME will vary, but most often reported to be around 0.2 to 0.4%. There is also a large group of patients, often with younger people who often are out of work or studies, and significant problems.

If the study confirms that TNF-inhibitor etanercept is associated with a clear response in CFS / ME, this could be very important for many patients. If non-responders after the intervention with Rituximab getting ready response by the use of etanercept, the treatment with etanercept may be a useful alternative for these patients.

Community

There are large economic costs of CFS / ME. There is no approved drug therapy for now. If the study can confirm that etanercept is associated with a clear response in a proportion of CFS / ME patients, this could mean that patients can be attributed to a more active life, participating in studies, education, job and familiar and social life.

Science

The study will provide data on possible pathogenetic mechanisms in CFS / ME. Our hypothesis is that CFS / ME is a form of autoimmune disease, often triggered by an infection, in which B-cells have a central role in a subgroup of patients.

For non-responders by Rituximab treatment and when such treatment can not be used, TNF-alpha inhibitors such as Etanercept is a useful therapeutic option. We use the biobank for research designed to elucidate pathogenetic mechanisms of disease.

Disadvantages:

Each project participant

Therapeutic use of TNF-inhibitor etanercept in autoimmune diseases like rheumatoid arthritis is considered a safe treatment. There are serious side effects, but very rarely. The treatment is associated with increased risk of infections such as respiratory infections and urinary tract infections. The use of etanercept is a risk of reactivation of latent tuberculosis.

Patients will be carefully informed about the precautions during ongoing treatment with etanercept. If patients have symptoms such as infection. fever, sore throat, cough, or urinary tract infection symptoms, they do not take etanercept before symptoms are over.

If they are short of breath or recent neurological symptoms, they do not take etanercept and call your doctor, to rule out interstitial lung disease or neurological disease.

Progressive multifocal leukoencephalopati (PML) is very rare but can be fatal. PML, which is the reactivation of JC virus infection of the central nervous system, is described by most of the newer, so-called "biological agents" that interferes with the immune system.

Other side effects are skin discomfort at the injection site (normal) and less frequently allergic reactions to the drug. In the recently published review article it is stated that any increased incidence of cancer or lymphoma, it seems more associated to the disease extent of the underlying immunological condition, than to the use of etanercept per se (see project description).

The experience from the widespread use of etanercept in autoimmune diseases such as. rheumatoid arthritis.

The use of Etanercept in CFS / ME should still side effect profile is said to be unknown.

Sound

CFS / ME is a very serious disease with significant problems for the patient and the great burden for their relatives. There is no established pharmacological treatment. The disease affects many young people, with an estimated prevalence of approximately 0.2 to 0.4% of the population.

Intervention with B-cell depletion using Rituximab is a promising but still experimental.

Use of TNF-inhibitor etanercept may be a useful therapeutic option for this patient group.

The risk of treatment with etanercept is low and considered in our opinion acceptable considering the possible health benefits for patients.

Summary:
Haukeland hospital project Øystein Fluge has initiated a clinical trial with the use of TNF inhibitors Enbrel for 15 patients who meet the CDC 1994 Fakuda criteria. Patients who have moderate to severe symptoms.

Patients were recruited from previous studies and Rituximab trial is expected to be completed in 2014.

Enbrel inhibits the receptor on cells that secrete the cytokine TNF-alpha and thus has immunosuppressive properties. The drug requires special requirements for surveillance for adverse effects.

Enbrel is in this study with injections once a week subcutaneously (such as diabetes, syringes) for 52 weeks.

Basis for the study are:

Patients who did not respond to Rituximab study, that non-responders.

Hypothesis for non-responders:

If the hypothesis of an autoimmune disease can be proved, it is conceivable that the amount of auto-antibodies are too high and Enbrel may be an alternative treatment approach for these patients.

The second hypothesis is activated T cells constitute a major component of symptom maintenance. Thus, other facets of autoimmunity that are not related to B-lymphocytes.

The third explanation is that patients meet the criteria for the diagnosis of ME / CFS, but that does not have an immune-mediated profile. So have a mental condition including fatigue.

Main objective of the study is to investigate whether the use of TNF-inhibitor etanercept may be a useful therapeutic option for this patient group. Side effect profile is unknown to the patient group.

Sources:

Study Protocol KTS-4-2011: KTS_4_2011_Protokoll_TNF alpha inhibitor

Decision Letter from the IEC: KTS_4_2011_vedtak REK_Enbrel_TNF inhibitor

Information on Enbrel: KTS_4_2011_medisinsk kompendium_Enbrel_TNF inhibitor

Request for participation in information: KTS_4_2011_forespørsel on deltagelse_Enbrel_TNF inhibitor

Application clincal trials - registration of clinical research study abroad: KTS_4_2011_Clinical trial application abroad

Appendix:

PDR: drug Enbrel
_______________________________________
Comment:
After reviewing the study protocol and assessment of adverse aspect of the drug via a common directory, there are several aspects that are not entirely consistent with the symptom picture of ME patients. To clarify this further to exclusion / precautions for exclusion of many patients with ME.

I stand therefore critical to the use of Enbrel in ME patients, but obviously can not exclude the possibility that some may have the effect of the drug as TNF-alpha is found elevated in ME patients.

The next element that is reprehensible in this study protocol is the use of Fakuda criteria, which may include patients who have fatigue for reasons other than illness ME.

The disease ME has a characteristic and distinct pattern of disease, whether acute or gradual onset in such a way that the clinical disease signs for subjective and objective manifestations are present. Together with the use of medical history, genetic predominans and the use of stringent criteria that Canada-criteria or the new ICC criteria to exclude patients who do not have the disease ME.

Cf hypotheses of this study protocol as it may seem that there is some confusion about the diagnosis and the illness ME.

Now this is a clinical drug trials on ME patients so that the answers we get about two years. One year of drug use and one year of follow-up of participants.
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[Náufrago]

Y no se publicará hasta 2015? No es mucho tiempo para un estudio tan pequeño?

[elipoarch]

El estudio acaba en diciembre de 2014, así que hasta 2015... nasti de plasti.

No sé si es mucho tiempo... son dos años de seguimiento... supongo que en inmunología se han de asegurar muy mucho antes de afirmar según qué cosas. Yo prefiero que lo hagan bien. Yo soy de las de la antigua escuela: "poco a poco y buena letra..." Para que publiquen un churro a toda prisa o hagan un estudio de 20 personas sobre la q10... prefiero un estudio que tenga cara y ojos, para variar...

A veces es preferible un "vísteme despacio, que tengo prisa".