Browsing by Author "Feelders, Richard A."

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    Corrigendum: Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study
    (Frontiers Media, 2022-04-27) Pivonello, Rosario; Bancos, Irina; Feelders, Richard A.; Kargi, Atil Y.; Kerr, Janice M.; Gordon, Murray B.; Mariash, Cary N.; Terzolo, Massimo; Ellison, Noel; Moraitis, Andreas G.; Medicine, School of Medicine
    [This corrects the article DOI: 10.3389/fendo.2021.662865.].
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    Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study
    (Frontiers Media, 2021-07) Pivonello, Rosario; Bancos, Irina; Feelders, Richard A.; Kargi, Atil Y.; Kerr, Janice M.; Gordon, Murray B.; Mariash, Cary N.; Terzolo, Massimo; Ellison, Noel; Moraitis, Andreas G.; Medicine, School of Medicine
    Introduction/purpose: Relacorilant is a selective glucocorticoid receptor modulator (SGRM) with no progesterone receptor activity. We evaluated the efficacy and safety of relacorilant in patients with endogenous Cushing syndrome (CS). Materials and methods: A single-arm, open-label, phase 2, dose-finding study with 2 dose groups (NCT02804750, https://clinicaltrials.gov/ct2/show/NCT02804750) was conducted at 19 sites in the U.S. and Europe. Low-dose relacorilant (100-200 mg/d; n = 17) was administered for 12 weeks or high-dose relacorilant (250-400 mg/d; n = 18) for 16 weeks; doses were up-titrated by 50 mg every 4 weeks. Outcome measures included proportion of patients with clinically meaningful changes in hypertension and/or hyperglycemia from baseline to last observed visit. For patients with hypertension, clinical response was defined as a ≥5-mmHg decrease in mean systolic or diastolic blood pressure, measured by a standardized and validated 24-h ABPM. For patients with hyperglycemia, clinical response was defined ad-hoc as ≥0.5% decrease in HbA1c, normalization or ≥50-mg/dL decrease in 2-h plasma glucose value on oral glucose tolerance test, or decrease in daily insulin (≥25%) or sulfonylurea dose (≥50%). Results: 35 adults with CS and hypertension and/or hyperglycemia (impaired glucose tolerance or type 2 diabetes mellitus) were enrolled, of which 34 (24 women/10 men) received treatment and had postbaseline data. In the low-dose group, 5/12 patients (41.7%) with hypertension and 2/13 patients (15.4%) with hyperglycemia achieved response. In the high-dose group, 7/11 patients (63.6%) with hypertension and 6/12 patients (50%) with hyperglycemia achieved response. Common (≥20%) adverse events included back pain, headache, peripheral edema, nausea, pain at extremities, diarrhea, and dizziness. No drug-induced vaginal bleeding or hypokalemia occurred. Conclusions: The SGRM relacorilant provided clinical benefit to patients with CS without undesirable antiprogesterone effects or drug-induced hypokalemia.
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    THU035 Impact Of Surgery Or Medical Treatment With The Selective Glucocorticoid Receptor Modulator Relacorilant On Hypercoagulopathy In Patients With Cushing Syndrome
    (The Endocrine Society, 2023-10-05) Simeoli, Chiara; Di Paola, Nicola; Stigliano, Antonio; Lardo, Pina; Kearney, Tara; Mezosi, Emese; Ghigo, Ezio; Giordano, Roberta; Mariash, Cary N.; Donegan, Diane; Feelders, Richard A.; Hand, Austin L.; Moraitis, Andreas G.; Pivonello, Rosario; Medicine, School of Medicine
    In patients with Cushing syndrome (CS), hypercoagulability represents a significant concern, leading to an elevated risk for thrombotic events. Hypercoagulability persists for several months (mos) after curative surgery, and current CS treatment guidelines recommend anticoagulation therapy for up to 3 mos after surgery. In patients with Cushing disease, hemostatic parameters may even worsen after surgery, independent of surgical outcome, with improvements beginning about 3 mos after successful surgery (Casonato et al. Blood Coagul Fibrinolysis 1999). This transient worsening may be due to increased inflammation as cortisol levels, and hence cortisol’s anti-inflammatory effects, are reduced after successful surgery, leading to increased activity in the coagulation cascade, which normalizes over time. Here, we evaluate the impact of surgery or treatment with the selective glucocorticoid receptor modulator relacorilant (RELA) on the coagulation state in patients with CS, reporting findings from a retrospective, longitudinal, monocentric, surgical cohort study and an open-label phase 2 study of RELA (NCT02804750). In the surgical study, coagulation markers were assessed in 30 patients before curative surgery and in remission. In the RELA study, patients received either RELA 100-200 mg for 12 weeks or RELA 250-400 mg for 16 weeks; coagulation markers were assessed in 34 patients throughout the study. In the surgical study, baseline (BL) mean 24-h urinary free cortisol (UFC) was 615.6 mcg/day (by immunoassay; 2.1x upper limit of normal [ULN]); mean and median time to hemostasis assessment after remission were 6.2 and 6 mos, respectively. Significant mean changes from BL were observed in activated partial thromboplastin time (aPTT; +2.0 sec, P=0.031), factor VIII (fVIII; -24.2%, P=0.044), and von Willebrand factor (vWF; -20.6%, P=0.018), whereas platelet count was unchanged. In the RELA study, BL mean UFC was 211.9 mcg/day (by tandem mass spectrometry; 4.2x ULN). Similar to the surgical study, significant mean changes from BL to last observed visit were reported in aPTT (+1.5 sec, P=0.046), fVIII (-18.9%, P=0.022), and platelet count (-68.8*109/L, P<0.0001), while vWF was unchanged. Significant improvements in other coagulation factors, eg, fIX and fX, were seen in patients with abnormal values at BL. These studies showed that coagulation markers in patients with CS improve 6 mos after curative surgery, and that treatment with RELA may have similar effects after 3-4 mos. The previously observed transient increase in fVIII immediately after surgery was absent with RELA, where negative mean changes from BL were seen throughout the study. This is presumably due to the less abrupt reduction of cortisol activity with RELA compared to surgery. RELA’s effects on hypercoagulopathy support further investigation of preoperative use and in patients with CS who are not eligible for surgery.