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 total amount of prednisone they had to take during the study. This was stated in the abstract’s “results” section:
The cumulative median prednisone dose over the 52-week period was 1862 mg in each tocilizumab group, as compared with 3296 mg in the placebo group that underwent the 26-week taper (P<0.001 for both comparisons) and 3818 mg in the placebo group that underwent the 52-week taper (P<0.001 for both comparisons).
Safety (adverse events). The authors reported no difference in serious adverse events (AE) between the groups receiving tocilizumab versus the groups receiving prednisone alone. From the abstract’s “results” section:
Serious adverse events occurred in 15% of the patients in the group that received tocilizumab weekly, 14% of those in the group that received tocilizumab every other week, 22% of those in the placebo group that underwent the 26-week taper, and 25% of those in the placebo group that underwent the 52-week taper. Anterior ischemic optic neuropathy developed in one patient in the group that received tocilizumab every other week.
The take-home message. Tocilizumab helped about half of patients get into remission over the 52 week trial. This was significantly better than the 14-18% of patients who went into remission from prednisone alone. Patients taking tocilizumab were also able to reduce the total amount of prednisone they had to take. Tocilizumab didn’t work for all patients. Only about half of the patients taking tocilizumab were able to achieve remission and stop taking their prednisone. More follow up will be needed to see if these patients are able to stay in remission beyond the 52 weeks they were followed during the trial.
My thoughts. Below is an breakdown of the patients in the study, the treatment course for each group of patients, which patients had flares during the trial, and whether they were in remission at the end of the trial.
Download a pdf of the image above here.
Tocilizumab plus prednisone is much better than prednisone alone for achieving remission in patients with giant cell arteritis. By the end of the trial, which lasted a year, 53-56% of patients in the tocilizumab groups were still in remission, which means that 44-47% of patients receiving tocilizumab were NOT in remission when they had stopped taking their prednisone at the end of the study. In comparison, only 14% of patients in the 26 week prednisone taper control group and 18% in the 52 week prednisone taper control group reached remission.
Giant cell arteritis patients being treated only with prednisone are likely to have symptoms return (flare) when they stop taking their prednisone. This was the a large and randomized controlled clinical trial for giant cell arteritis, meaning the patients were a carefully selected and well studied group of patients with similar clinical characteristics. The control group in this trial can tell us a lot about how well prednisone works for treating giant cell arteritis. Since only 14% of patients in the 26 week prednisone taper control group and 18% in the 52 week prednisone taper control group were in remission at 52 weeks, this means that 82-86% of patients taking prednisone alone are likely to flare once they taper their prednisone. What is different about the 14-18% of patients who were able to stop taking their prednisone and how can we predict which patients these are? If patients had remained on a small dose of prednisone, instead of tapering down to zero, would it have kept them in remission and helped to prevent these flares?
Tocilizumab reduced the number of flares during the trial. The authors also reported on the number of patients who had a flare during the trial, which is different than whether a patient had sustained remission (i.e. that they were in remission at the end of the trial). This was included as a secondary endpoint of the study. For the groups taking tocilizumab, 23% of patients receiving tocilizumab weekly had a flare and 26% of patients receiving tocilizumab every other week had a flare. Patients in the groups receiving only prednisone had flare rates of 68% in the 26 week taper group and 49% in the 52 week taper group. These results show that tocilizumab was better than prednisone alone in preventing flares and that 74-77% of patients had fewer flares. This suggests that tocilizumab has an added benefit in preventing flares in patients taking prednisone. From the results section of the paper:
The percentages of patients who had a flare were 23% in the group that received tocilizumab weekly, 26% in the group that received tocilizumab every other week, 68% in the placebo group that underwent the 26-week taper, and 49% in the placebo group that underwent the 52-week taper. As compared with the placebo group that underwent the 26-week taper, the hazard ratios for flare were 0.23 (99% confidence interval [CI], 0.11 to 0.46) in the group that received tocilizumab weekly and 0.28 (99% CI, 0.12 to 0.66) in the group that received tocilizumab every other week (P<0.001 for both comparisons).
More about adverse events. Patients who had adverse events serious enough to withdraw from the study were 6% in both of the tocilizumab groups versus 4% (26 week taper) and 0% (52 week taper). Serious adverse events included a few patients with low neutrophils (neutropenia) or high levels of liver enzymes. One patient taking tocilizumab every other week had a stroke that was believed to be caused by another medical problem unrelated to the trial or to their giant cell arteritis. One patient taking tocilizumab every other week had a flare with optic neuropathy and some vision loss. The patient took prednisone for the flare which helped resolve the vision loss. The authors concluded there were no differences in the number and severity of the adverse events between the two groups. It’s important to remember that new treatments may have unknown and unintended consequences and we are all risking the devil we know (prednisone!) versus the devil we don’t, so it’s good to proceed with caution.
Tocilizumab as an add-on treatment to reduce prednisone dose. Tocilizumab worked great in about half of the patients by helping them get into remission and get off prednisone, but what about the rest of the patients? In my opinion, an additional excitement of this study was its effect in reducing flares and reducing patients’ daily prednisone dose. This raises the possibility that even greater numbers of patients may achieve sustained remission with a reduced prednisone dose. Many giant cell arteritis patients will struggle to maintain remission and will have flares (relapses) when they try to reduce their prednisone. Tocilizumab could be a good add-on treatment to the prednisone that these patients are taking. Tocilizumab could help these patients go into remission, help reduce the number of flares, and could help them to reduce their total daily prednisone dose.
Other options? In addition to tocilizumab (Actemra), other anti-IL-6 inhibitors are in clinical trial or have been FDA approved for other diseases, including sarilumab (Kevzara) which targets the IL-6b receptor, and siltuximab (Sylvant), which directly targets IL-6.
Reference: Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, Brouwer E, Cid MC, Dasgupta B, Rech J, Salvarani C, Schett G, Schulze-Koops H, Spiera R, Unizony SH, Collinson N. Trial of Tocilizumab in Giant-Cell Arteritis. N Engl J Med. 2017 377(4):317-328.
Links. Below are some links to access the original article. Supplemental data and author disclosure forms can be found on the journal’s website at the links provided below.
PubMed PMID: 28745999 (link-free full text)
Journal website, supplemental data, video summary, disclosures: Go to the New England Journal of Medicine’s website to view the article, the supplemental data, the “Quick Takes” video summary, and author disclosure forms for this article (link-free full text)
Clinical trial number: NCT01791153. For more information about the clinical trial, visit the webpage for this clinical trial at http://www.clinicaltrials.gov (link-free full text)