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Long-term efficacy and safety of once-monthly pasireotide in Cushing's disease: A Phase III extension study.

ABSTRACT: OBJECTIVES:Many patients with Cushing's disease (CD) require chronic pharmacotherapy to control their hypercortisolism. We evaluated the efficacy and safety of long-acting pasireotide during a long-term extension study in patients with CD. DESIGN:Open-label extension to a 12-month Phase III study of long-acting pasireotide in CD (N = 150; NCT01374906). PATIENTS:Patients with mean urinary free cortisol (mUFC) ? upper limit of normal (ULN) or receiving clinical benefit at core study end could continue long-acting pasireotide during the extension. RESULTS:Eighty-one of 150 (54.0%) enrolled patients entered the extension. Median overall exposure to pasireotide at study end was 23.9 months; 39/81 (48.1%) patients completed the extension (received ? 12 months' treatment during the extension and could transit to a separate pasireotide safety study). mUFC was ?ULN in 42/81 (51.9%), 13/81 (16.0%) and 43/81 (53.1%) patients at extension baseline, month (M) 36 and last assessment. Median mUFC remained within normal limits. Median late-night salivary cortisol was 2.6 × ULN at core baseline and 1.3 × ULN at M36. Clinical improvements were sustained over time. Forty-two (51.9%) patients discontinued during the extension: 25 (30.9%) before M24 and 17 (21.0%) after M24. Hyperglycaemia-related AEs occurred in 39.5% of patients. Mean fasting glucose (FPG) and glycated haemoglobin (HbA1c ) were stable during the extension, with antidiabetic medication initiated/escalated in some patients. Sixty-six (81.5%) and 71 (88.9%) patients were classified as having diabetes (HbA1c ? 6.5%, FPG ? 7.0 mmol/L, antidiabetic medication use, or history of diabetes) at extension baseline and last assessment. CONCLUSIONS:Long-acting pasireotide provided sustained biochemical and clinical improvements, with no new safety signals emerging, supporting its use as an effective long-term therapy for CD.

SUBMITTER: Fleseriu M

PROVIDER: S-EPMC6899900 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Long-term efficacy and safety of once-monthly pasireotide in Cushing's disease: A Phase III extension study.

Fleseriu Maria M Petersenn Stephan S Biller Beverly M K BMK Kadioglu Pinar P De Block Christophe C T'Sjoen Guy G Vantyghem Marie-Christine MC Tauchmanova Libuse L Wojna Judi J Roughton Michael M Lacroix André A Newell-Price John J

Clinical endocrinology 20191001 6

<h4>Objectives</h4>Many patients with Cushing's disease (CD) require chronic pharmacotherapy to control their hypercortisolism. We evaluated the efficacy and safety of long-acting pasireotide during a long-term extension study in patients with CD.<h4>Design</h4>Open-label extension to a 12-month Phase III study of long-acting pasireotide in CD (N = 150; NCT01374906).<h4>Patients</h4>Patients with mean urinary free cortisol (mUFC) ≤ upper limit of normal (ULN) or receiving clinical benefit at cor ...[more]

PMID: 31465533

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Project description:ObjectiveTo evaluate the long-term efficacy and safety of osilodrostat in patients with Cushing's disease.MethodsThe multicenter, 48-week, Phase III LINC 4 clinical trial had an optional extension period that was initially intended to continue to week 96. Patients could continue in the extension until a managed-access program or alternative treatment became available locally, or until a protocol amendment was approved at their site that specified that patients should come for an end-of-treatment visit within 4 weeks or by week 96, whichever occurred first. Study outcomes assessed in the extension included: mean urinary free cortisol (mUFC) response rates; changes in mUFC, serum cortisol and late-night salivary cortisol (LNSC); changes in cardiovascular and metabolic-related parameters; blood pressure, waist circumference and weight; changes in physical manifestations of Cushing's disease; changes in patient-reported outcomes for health-related quality of life; changes in tumor volume; and adverse events. Results were analyzed descriptively; no formal statistical testing was performed.ResultsOf 60 patients who entered, 53 completed the extension, with 29 patients receiving osilodrostat for more than 96 weeks (median osilodrostat duration: 87.1 weeks). The proportion of patients with normalized mUFC observed in the core period was maintained throughout the extension. At their end-of-trial visit, 72.4% of patients had achieved normal mUFC. Substantial reductions in serum cortisol and LNSC were also observed. Improvements in most cardiovascular and metabolic-related parameters, as well as physical manifestations of Cushing's disease, observed in the core period were maintained or continued to improve in the extension. Osilodrostat was generally well tolerated; the safety profile was consistent with previous reports.ConclusionOsilodrostat provided long-term control of cortisol secretion that was associated with sustained improvements in clinical signs and physical manifestations of hypercortisolism. Osilodrostat is an effective long-term treatment for patients with Cushing's disease.Clinical trial registrationClinicalTrials.gov, identifier NCT02180217.

Project description:Objective: To evaluate the effect of aripiprazole once-monthly 400 mg (AOM 400; Abilify Maintena®) on symptom stability in acute treatment and maintenance therapy settings in patients with schizophrenia. Methods: Results were analyzed from two pivotal maintenance studies (Studies 246 and 247), a long-term (52 weeks), open-label extension of these studies (Study 248), an open-label, mirror-image study in patients switching from oral to long-acting injectable antipsychotic therapy (Study 283), and a study of AOM 400 in the acute setting (Study 291). Symptom stability was assessed using the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression (CGI) scale (CGI-Severity of Illness and CGI-Improvement). Results are reported for the total study population and in subgroups stratified by age. Results: In Study 246, AOM 400 resulted in significantly greater improvements from baseline vs placebo on all measures of symptom stability, with improvements maintained through 52 weeks. In Study 247, a non-inferiority study, AOM 400 resulted in improvements in PANSS and CGI scores comparable or significantly greater at all timepoints vs oral aripiprazole. In Study 248, AOM 400 resulted in the long-term stability of symptom improvements from the earlier studies. In Study 283, AOM 400 resulted in significant improvements from baseline in PANSS and CGI scores over 24 weeks. In Study 291, AOM 400 resulted in significantly greater improvements from baseline in PANSS and CGI scores vs placebo at all post-baseline timepoints. In post hoc analyses, AOM 400 showed similar efficacy in symptom improvement in adult patients aged ≤35 years and >35 years, with some evidence of a larger treatment effect on PANSS negative symptoms among younger patients in the acute treatment setting. Conclusion: In acute treatment and maintenance therapy settings, AOM 400 was effective in the rapid stabilization and long-term maintenance of symptoms in patients with schizophrenia.

Dataset Information

Long-term efficacy and safety of once-monthly pasireotide in Cushing's disease: A Phase III extension study.

Publications

Long-term efficacy and safety of once-monthly pasireotide in Cushing's disease: A Phase III extension study.

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