PMC:3724972 / 9883-14960 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/3724972","sourcedb":"PMC","sourceid":"3724972","source_url":"https://www.ncbi.nlm.nih.gov/pmc/3724972","text":"Clinical trial experience with pasireotide in Cushing’s disease\nAfter promising results in a 15-day Phase 2 trial [40], a randomized, double-blind phase 3 trial of pasireotide was conducted in adult patients with de novo, persistent, or recurrent CD (UFC ≥1.5× upper limit of normal [ULN]) who were not candidates for surgery and with no pituitary radiotherapy in the preceding 10 years. Eligible patients (N = 162) were randomized to receive 600 or 900 mcg of pasireotide twice daily for an initial period of 3 months. After 3 months, those with UFC \u003cbaseline and \u003c2× ULN continued blinded therapy for another 3 months. Other patients were unblinded, and their dose was increased by 300 mcg twice daily. At 6 months, all patients entered the open-label phase of the study and could have their dose increased again to a maximum of 1200 mcg twice daily, if necessary [43].\nFigure 3 shows changes from baseline to 6 months in UFC levels for patients in the two dose groups of the phase 3 trial. The majority of patients had declines in UFC levels at 6 months; 6 patients had increases. At 6 months, 15 % of patients in the 600 mcg group and 26 % of patients in the 900 mcg group met the primary endpoint of UFC level within the normal range without dose increase. Median percentage changes in UFC levels from baseline to 6 months were −47.9 % in the 600 mcg group and −47.9 % in the 900 mcg group. Among the 36 patients who achieved normalization of UFC levels at 6 months, 20 maintained normal levels at 12 months, including some patients who had dose reductions. Moreover, patients who responded to treatment could generally be identified within the first 2 months of treatment [43].\nFig. 3 Changes in UFC levels from baseline to 6 months in individual patients in the phase 3 trial of pasireotide. The dashed black line represents the upper limit of the normal range for UFC. From Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, et al., for the Pasireotide B2305 Study Group (2012) N Engl J Med, volume 366, page 918 [43]. Reproduced with permission\nMean plasma ACTH levels and serum and salivary cortisol levels were reduced at both 6 and 12 months, and patients had significant improvements in signs and symptoms of hypercortisolism during the trial, including reductions in systolic and diastolic blood pressure, triglycerides, low-density lipoprotein cholesterol, and body weight. The time-course of many of these improvements closely followed the time-course UFC reduction. Patients also reported significant increases in health-related quality of life. Finally, among the 75 patients who had measurable pituitary tumors on magnetic resonance images at baseline, tumor volume changed by an average of −9.1 and −43.8 % in the 600 and 900 mcg groups, respectively [43].\nHyperglycemia-related adverse events occurred in 118 of 162 patients (73 %), and 10 patients discontinued because of such events. Twenty one patients (13 %) had grade 3 or 4 hyperglycemia, and 74 patients initiated a new antidiabetic medication during the study [43]. While no glycemic intervention studies have been completed in pasireotide-treated CD patients, the mechanism of pasireotide-induced hyperglycemia was investigated in 90 healthy volunteers [44]. Results indicate that pasireotide-induced hyperglycemia is mediated by a reduction in secretion of insulin and incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). Glucagon secretion was only mildly inhibited, and pasireotide appears to have no effect on peripheral or hepatic insulin sensitivity in healthy individuals. Treatment with the GLP-1 analog liraglutide or the dipeptidyl peptidase 4 (DPP-4) inhibitor vildagliptin was most effective in countering hyperglycemia in this population, while metformin and nateglinide had little effect.\nPatients with CD, however, are often insulin-resistant. A recently published proposal for management of hyperglycemia in patients with CD treated with pasireotide recommends metformin as first-line medical treatment for CD patients who develop new or worsening hyperglycemia with pasireotide, with an adjunctive DPP-4 inhibitor, sulfonylurea/glinide, and/or GLP-1 analog as required to achieve glycemic control. Metformin plus insulin is recommended if such combination therapy is not tolerated or insufficient and early intervention with insulin is recommended on a case-by-case basis [45].\nOther than the degree and severity of hyperglycemia-related events, the safety and adverse event profiles of pasireotide in the phase 3 trial were similar to those observed with other somatostatin analogs. Other common adverse events were diarrhea (58 %), nausea (52 %), cholelithiasis (30 %), headache (28 %), and abdominal pain (24 %). Among the 137 patients who had a normal gallbladder at baseline, 27 had gallstones at their latest assessment and 6 had a cholecystectomy [43]. Pasireotide was recently approved in the US [46] and Europe [47] for the treatment of adult CD patients for whom pituitary surgery is not an option or has failed.","divisions":[{"label":"title","span":{"begin":0,"end":63}},{"label":"p","span":{"begin":64,"end":871}},{"label":"p","span":{"begin":872,"end":2072}},{"label":"figure","span":{"begin":1684,"end":2072}},{"label":"label","span":{"begin":1684,"end":1690}},{"label":"caption","span":{"begin":1691,"end":2072}},{"label":"p","span":{"begin":1691,"end":2072}},{"label":"p","span":{"begin":2073,"end":2795}},{"label":"p","span":{"begin":2796,"end":3840}},{"label":"p","span":{"begin":3841,"end":4432}}],"tracks":[{"project":"2_test","denotations":[{"id":"23673515-18957506-63233621","span":{"begin":115,"end":117},"obj":"18957506"},{"id":"23673515-22397653-63233622","span":{"begin":867,"end":869},"obj":"22397653"},{"id":"23673515-22397653-63233623","span":{"begin":1679,"end":1681},"obj":"22397653"},{"id":"23673515-22397653-63233624","span":{"begin":2041,"end":2043},"obj":"22397653"},{"id":"23673515-22397653-63233625","span":{"begin":2791,"end":2793},"obj":"22397653"},{"id":"23673515-22397653-63233626","span":{"begin":3059,"end":3061},"obj":"22397653"},{"id":"23673515-23228667-63233627","span":{"begin":4428,"end":4430},"obj":"23228667"},{"id":"23673515-22397653-63233628","span":{"begin":4910,"end":4912},"obj":"22397653"}],"attributes":[{"subj":"23673515-18957506-63233621","pred":"source","obj":"2_test"},{"subj":"23673515-22397653-63233622","pred":"source","obj":"2_test"},{"subj":"23673515-22397653-63233623","pred":"source","obj":"2_test"},{"subj":"23673515-22397653-63233624","pred":"source","obj":"2_test"},{"subj":"23673515-22397653-63233625","pred":"source","obj":"2_test"},{"subj":"23673515-22397653-63233626","pred":"source","obj":"2_test"},{"subj":"23673515-23228667-63233627","pred":"source","obj":"2_test"},{"subj":"23673515-22397653-63233628","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#93ccec","default":true}]}]}}