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The MIRRA trial: Mepolizumab (Nucala) or placebo for the treatment of EGPA/Churg-Strauss Syndrome

Wechsler et al. Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis. N. Engl. J. Med. 2017 376(20):1921-1932. Disclosure:  I was a patient in this clinical trial from March 2015 to May 2016 and I am still taking mepolizumab to treat my EGPA. For more details and a full list of my disclosures, please see the Disclaimer page. Game changer:  Why is this study important? This clinical trial was the first randomized controlled trial ever conducted for EGPA. It is also one of the largest clinical trials conducted for EGPA, requiring the participation of 31 trial sites to enroll enough patients with this rare disease.  Mepolizumab is the first medication to be approved by the FDA for the treatment of EGPA.  The results from this clinical trial supported the application for FDA approval which was granted in December 2017. Trial sponsorship.  The trial was sponsored by a collaboration between GlaxoSmithKline and the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health. NIAID funded an investigator initiated clinical trial application, which provided support for five of eight clinical trial sites in the United States.  Disclosures related to the MIRRA trial and the published manuscript can be found in the supplemental data on the manuscript publisher’s website at the links provided at the bottom of this post. The big picture.  This Phase III double blinded clinical trial tested mepolizumab (Nucala), a monoclonal antibody which targets IL-5, an important regulator of eosinophils, for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA).  The study focused on patients with EGPA who had relapsing disease (flares) or difficult to control symptoms (refractory disease). Purpose of the study and study endpoints.  Patients with EGPA have high levels of eosinophils. Mepolizumab is a monoclonal antibody which targets IL-5, an important regulator of eosinophils, and reduces eosinophil levels in the blood, so it may be useful to help control symptoms related to EGPA.  The purpose of the study was to measure whether mepolizumab could lead to better remission in patients with EGPA compared to controls. The end points of the study were the number of weeks patients were in remission (no evidence of disease activity) and the number of patients in remission at weeks 36 and 48 of the trial. Patient population.  Patients diagnosed with EGPA who had relapsed (had a flare) or were unable to go into remission (refractory disease) and were at least 18 years of age were eligible to be enrolled in the study.  136 patients were enrolled at 31 sites across nine countries between February 2014 and September 2016. Outline of the study.  This was a Phase III clinical trial studying patients diagnosed with EGPA who were receiving typical treatment for their EGPA and who had relapsed (had a flare) or were unable to go into remission (refractory disease).  136 adult EGPA patients were randomized into two groups of 68 patients per group.  One group received their regular treatments with prednisone and other drugs like methotrexate or azathioprine (standard of care), plus monthly injections of mepolizumab (300 mg subcutaneously). The second group received their regular treatments plus a monthly subcutaneous injection of saline (placebo control).  Treatments were given monthly for one year (52 weeks).  The study was double-blinded, meaning that neither the patients nor their doctors knew whether they were receiving injections of the placebo or the drug.  Patients were monitored monthly and their EGPA symptoms were measured and scored.  Patients began a controlled taper of their daily prednisone dose one month after their first injection and continued tapering their prednisone doses according to a defined schedule.  The level of the symptoms and the number of weeks in remission (i.e. no major relapses or worsening symptoms) were compared between the mepolizumab and placebo control groups. Mepolizumab led to more patients in remission than placebo.  Patients who received mepolizumab had more weeks with no EGPA symptoms (remission) than the patients who received the placebo, which allowed the patients to reduce the amount of prednisone they were taking.  However, only about half of the patients who received mepolizumab had their symptoms reduced enough to go into remission.  This means that mepolizumab could control symptoms and lead to remission in about half of the patients, but mepolizumab did not completely control symptoms in the other half of the patients.  Here is a quote from the abstract’s “conclusions” which summarized these results: mepolizumab resulted in significantly more weeks in remission and a higher proportion of participants in remission than did placebo, thus allowing for reduced glucocorticoid use. Even so, only approximately half the participants treated with mepolizumab had protocol-defined remission Mepolizumab helped patients remain in remission compared to patients in the placebo group. Patients taking mepolizumab had more weeks in remission than patients on placebo (28% vs. 3%).  The patients taking mepolizumab were also more likely to be in remission at the end of the trial than patients in the placebo group (32% in remission for the mepolizumab group vs. 3% for the placebo group at week 48 of the trial). As stated in the abstract’s “results” section: mepolizumab treatment led to significantly more accrued weeks of remission than placebo (28% vs. 3% of the participants had ≥24 weeks of accrued remission; odds ratio, 5.91; 95% confidence interval [CI], 2.68 to 13.03; P<0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32% vs. 3%; odds ratio, 16.74; 95% CI, 3.61 to 77.56; P<0.001) Mepolizumab also helped patients reduce the total dose of prednisone they were taking.  About half of the patients receiving mepolizumab were able to reduce their daily dose of prednisone to 4 mg or less per day by the end of the study, while only 7% of patients in the control group reached 4 mg or less of prednisone per day. This was stated in the abstract’s “results” section: a total of 44% of the participants in the mepolizumab group, as compared with 7% of those in the placebo group, had an average daily dose of prednisolone or prednisone of 4.0

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The GiACTA trial: Tocilizumab in Giant Cell Arteritis

Stone et al. Trial of Tocilizumab in Giant-Cell Arteritis. N. Engl. J. Med. 2017 377(4):317-328. NEJM Quick Take:  Click on the following link from the New England Journal of Medicine to view a 2 minute video summarizing the study results: video. Game changer:  Why is this study important? Tocilizumab is the first treatment, other than corticosteroids, shown to be effective for giant cell arteritis.  Giant cell arteritis can cause very serious problems including blindness and aortic aneurysms. Corticosteroids like prednisone cause lots of side effects, especially when used long term, so it is important to limit the amount of prednisone. This clinical trial was the first large scale randomized controlled trial to test tocilizumab for the treatment of giant cell arteritis.  Tocilizumab was approved by the FDA for the treatment of giant cell arteritis in May of 2017 based on the results of this trial. Trial sponsorship.  The trial was sponsored by Hoffman-La Roche (Roche), which provided the study drug and support for the clinical trial sites.  Disclosures related to the GiACTA trial and the published manuscript can be found in the supplemental data on the manuscript publisher’s website at the links provided at the bottom of this post. The big picture.  The Giant Cell Arteritis Actemra (GiACTA) trial was a Phase III double blinded clinical trial testing tocilizumab (Actemra) for giant cell arteritis.  Tocilizumab is a monoclonal antibody which binds to the IL-6 receptor alpha and blocks the cytokine IL-6 from binding to its receptor.  IL-6 is a pro-inflammatory cytokine that is elevated in several inflammatory diseases including giant cell arteritis.  The study focused on patients with giant cell arteritis who were newly diagnosed with giant cell arteritis or who had relapsing disease (flares) when tapering prednisone. Purpose of the study and study endpoints.  Patients with giant cell arteritis have high levels of inflammation markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP).  They also have high levels of some specific cytokines including IL-6, which is a cytokine that is known to cause inflammation (pro-inflammatory cytokine) and can induce CRP. Patients with giant cell arteritis are usually treated with prednisone to control the inflammation, but often have relapses or flares when they try to taper their prednisone levels.  Tocilizumab is a monoclonal antibody which blocks the function of IL-6 by binding to its receptor (IL-6 receptor alpha) so it may be useful to help control symptoms related to IL-6 induced inflammation.  The purpose of the study was to measure whether tocilizumab could lead to better remission in patients with giant cell arteritis compared to patients receiving prednisone alone. The end points of the study were the number of patients who were in remission in each study group at the end of the 52 week trial. Remission was defined as a normal CRP and the absence of a flare (a flare was defined as a return of signs and symptoms and an elevated ESR). Patient population.  Patients who were newly diagnosed with giant cell arteritis or who had relapsed (had a flare) and were 50 years or older were eligible to be enrolled in the study.  251 patients were enrolled at sites in fourteen countries starting in July 2013 and the study was completed in April 2016. Outline of the study.  This was a Phase III clinical trial studying patients diagnosed with giant cell arteritis who were newly diagnosed or who were treated with prednisone and had relapsed (had a flare) when they tried to taper their prednisone.  The study was scheduled to last 52 weeks.  251 adult patients with giant cell arteritis were randomized into four groups.  The first group (100 patients) received weekly subcutaneous injections of tocilizumab (TCZ) plus high dose daily prednisone and began a controlled taper of their daily prednisone dose down to 0 according to a defined schedule over 26 weeks.  The second group received subcutaneous injections of tocilizumab every two weeks while tapering their prednisone over 26 weeks.  The third group (50 patients) received prednisone but no tocilizumab while tapering their prednisone over 26 weeks, and the fourth group of patients (51 patients) received prednisone but no tocilizumab and tapered their prednisone over 52 weeks. Patients were followed for one year (52 weeks).  Patients in the second, third, and fourth groups received subcutaneous injection of saline (placebo control) on weeks they were not scheduled to receive tocilizumab.  The study was double-blinded, meaning that neither the patients nor their doctors knew whether they were receiving injections of the placebo or the drug.  Patients were monitored monthly and their prednisone doses and giant cell arteritis symptoms were measured and scored.  The number of patients in remission (i.e. no major relapses or worsening symptoms) and the cumulative prednisone dose were compared between the two tocilizumab groups and the two placebo control groups. Tocilizumab led to more patients in remission than prednisone alone.  More patients who received tocilizumab were in remission at 52 weeks than the patients who only received prednisone.  A little more than half (53-56%) of the patients who received tocilizumab had their symptoms reduced enough that they were in remission without prednisone at the end of the study, while only 14-18% of patients taking prednisone alone were in remission at the end of the study.  This means that tocilizumab alone could not control symptoms enough to keep the other half of the patients (44-47%) in remission at the end of the study.  Here is a quote from the abstract’s “results” which summarized these results: Sustained remission at week 52 occurred in 56% of the patients treated with tocilizumab weekly and in 53% of those treated with tocilizumab every other week, as compared with 14% of those in the placebo group that underwent the 26-week prednisone taper and 18% of those in the placebo group that underwent the 52-week prednisone taper (P<0.001 for the comparisons of either active treatment with placebo). Tocilizumab also helped patients reduce the total dose of prednisone they were taking.  The patients receiving tocilizumab who went into remission were able to reduce the

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