Longitudinal Dose–Response Models
John O’Quigley, Alexia Iasonos, Björn Bornkamp in Handbook of Methods for Designing, Monitoring, and Analyzing Dose-Finding Trials, 2017
We consider here the analysis of a dose-finding clinical trial for the monoclonal antibody canakinumab in patients with acute gouty arthritis, a painful inflammatory disease. The phase II trial lasted 24 weeks, and the participating patients were randomized to one of seven treatment groups [1]. More precisely, five groups received a single subcutaneous injection of canakinumab (25, 50, 100, 200, or 300 mg, respectively), and one group received multiple injections of canakinumab (50 mg at baseline and at week 4, and then 25 mg at weeks 8 and 12). The last group received an active comparator on a daily basis; we will ignore this treatment arm in the following. About 50 patients were randomized to each of the six canakinumab groups. An important endpoint in the study was the C-reactive protein (CRP) level, which can be considered as an indicator of the severity of the disease. Measurements of CRP were taken at baseline, week 2, week 4, and then every 4 weeks. For the analysis, the logarithm of CRP values was used.
COVID-19 and MIS-C
Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide in Clinical Innovation in Rheumatology, 2023
Targeted immunomodulators have also played an important role in the treatment of acute COVID-19. Initial promising results for high-dose anakinra (anti-IL-1) were not replicated in a more recent trial, though the later study included more mildly ill patients, and anakinra was previously shown to have greater benefit in patients with more profound systemic inflammation (Pontali, Kyriazopoulou, CORIMUNO ANA-1). Canakinumab, an IL-1β monoclonal antibody, also failed to show a survival benefit (Carricchio). Tocilizumab, an anti-IL-6 monoclonal antibody, has also been widely used, and randomized studies have shown benefit in hospitalized adults (Rosas, REMAP-CAP, Strohbehn). More recently, JAK inhibitors have been used more broadly after studies showing benefit. Tofacitinib reduced risk of respiratory failure or death among hospitalized adults, and baricitinib, while not meeting primary disease progression end point, was associated with reduced mortality (Guimarães, Marconi). A study assessing baricitinib plus remdesivir found benefit from the combination therapy compared to remdesivir alone, especially among those patients receiving high-flow oxygen or noninvasive ventilation (Kalil).
Oxidative Stress, Inflammation, Immune System and Hypertension
Giuseppe Mancia, Guido Grassi, Konstantinos P. Tsioufis, Anna F. Dominiczak, Enrico Agabiti Rosei in Manual of Hypertension of the European Society of Hypertension, 2019
An important study recently highlighted the significance of inflammation, immunity and atherosclerotic vascular disease in clinical medicine. A randomized double-blind trial in over 10,000 patients investigated the effects of canakinumab, a therapeutic monoclonal antibody targeting IL-1β, on nonfatal myocardial infarction, nonfatal stroke or cardiovascular death (CANTOS study). Results demonstrated that anti-inflammatory therapy targeting IL-1β, at a dose of 150 mg every 3 months, resulted in a lower recurrent cardiovascular event versus placebo, independent of lipid lowering. This was associated with reduced levels of proinflammatory markers, IL-6 and C-reactive protein. This large clinical trial provides important evidence that innate immunity can be modulated to reduce cardiovascular risk. Targeting inflammation may be a potentially interesting strategy to reduce atherosclerotic disease. However, whether this approach would also influence blood pressure reduction in hypertension is unknown.
KRAS G12C inhibition and innate immune targeting
Published in Expert Opinion on Therapeutic Targets, 2021
Tetsuo Tani, Shunsuke Kitajima, Ella B. Conway, Erik H. Knelson, David A. Barbie
Constitutive generation of IL-1β by activation of inflammasomes in the lung can promote chronic inflammation and tumorigenesis. Indeed, depletion of GATA2, a regulator of IL-1β, has been reported to inhibit tumor growth in a mouse model of KRAS-mutant NSCLC [20]. The inhibition of the NLRP3 pathway, a mediator of the inflammasome and IL-1 release, has also been reported to inhibit cell proliferation and migration in KRAS-mutant lung cancer cell lines [18]. Canakinumab is a humanized anti-IL-1β monoclonal antibody which antagonizes its activity. In a serendipitous observation, canakinumab treatment strongly reduced the incidence of lung cancer in patients treated for atherosclerosis on the CANTOS trial [21]. KRAS mutations were not specifically studied in the CANTOS trial; however, the frequency of a smoking history in a population with atherosclerosis was high and it is presumed that these patients have a high frequency of KRAS mutations. These protective effects were dose-dependent, strongly supporting that IL-1β is involved in lung cancer carcinogenesis in humans and highlighting the therapeutic potential of its blockade.
Current and emerging drugs for the treatment of atherosclerosis: the evidence to date
Published in Expert Review of Cardiovascular Therapy, 2022
Ali A. Rizvi, Djordje S. Popovic, Nikolaos Papanas, Anca Pantea Stoian, Wael Al mahmeed, Amirhossein Sahebkar, Andrej Janez, Manfredi Rizzo
Canakinumab is a human anti-interleukin-1β monoclonal antibody [71]. Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) was a randomized, double-blind, placebo-controlled trial [72]. It has involved 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein (hsCRP) level of ≥2 mg/l. The CANTOS atrial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every three months) with the placebo group. The primary efficacy endpoint was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. Unlike the other two doses, the canakinumab dose of 150 mg met the prespecified multiplicity-adjusted threshold for statistical significance for the primary endpoint. In addition, Canakinumab was associated with a higher incidence of fatal infection than placebo [71].
Canakinumab and cardiovascular outcomes: results of the CANTOS trial
Published in Journal of Community Hospital Internal Medicine Perspectives, 2018
Syed Raza Shah, Zainab Abbasi, Mazia Fatima, Rohan Kumar Ochani, Waqas Shahnawaz, Muhammad Asim Khan, Syed Arbab Shah
Recently, monoclonal antibodies to IL-1β have been successful in controlling inflammatory markers. In addition to their approved indications so far, these drugs are currently being tested and used in preclinical and clinical trials to assess their widespread applicability and relevance in other pathological conditions in which IL-1β has a key role to play. These very trials led to additional investigation into exploring the role of canakinumab in suppressing the effects of inflammatory markers. One such trial was the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) trial where promising results were seen [9]. During the trial, 10,061 patients with previously diagnosed myocardial infarction were targeted [9]. Three doses of canakinumab (50, 150, and 300 mg, administered subcutaneously every 3 months) in addition to a placebo were compared with the primary efficacy point being nonfatal myocardial infarction or cardiovascular death. Inflammatory markers including high-sensitivity C-reactive protein level was measured during the study. At 4 years, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26, 37, and 41 percentage points greater in the group than in the placebo group that received 50-, 150- and 300-mg, respectively. Furthermore, the incidence rate for primary end point was 4.50 events per 100 person-years in the placebo group as compared to 4.11, 3.86, and 3.90 in the 50-, 150- and the 300-mg group, respectively [9]. The results with the 150-mg dose, but not with the other doses, met the statistical significance for the primary end point. However, no significant difference was noted in all-cause mortality [9].
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