Dataset Information

Long-term efficacy and safety of osilodrostat in patients with Cushing's disease: results from the LINC 4 study extension.

ABSTRACT:

Objective

To evaluate the long-term efficacy and safety of osilodrostat in patients with Cushing's disease.

Methods

The 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.

Results

Of 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.

Conclusion

Osilodrostat 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 registration

ClinicalTrials.gov, identifier NCT02180217.

SUBMITTER: Gadelha M

PROVIDER: S-EPMC10482037 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Publications

Long-term efficacy and safety of osilodrostat in patients with Cushing's disease: results from the LINC 4 study extension.

Gadelha Mônica M Snyder Peter J PJ Witek Przemysław P Bex Marie M Belaya Zhanna Z Turcu Adina F AF Feelders Richard A RA Heaney Anthony P AP Paul Michaela M Pedroncelli Alberto M AM Auchus Richard J RJ

Frontiers in endocrinology 20230823

<h4>Objective</h4>To evaluate the long-term efficacy and safety of osilodrostat in patients with Cushing's disease.<h4>Methods</h4>The 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 a ...[more]

PMID: 37680892

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Project description:Abstract Background: In a Phase II study, osilodrostat, a potent oral 11β-hydroxylase inhibitor, normalized mean urinary free cortisol (mUFC) in most patients with CD (Fleseriu M et al. Pituitary 2016;19:138-48). We report the efficacy and safety of osilodrostat in a large CD patient population in the first randomized withdrawal Phase III study in this rare, serious disorder (clinicaltrials.gov: NCT02180217). Methods: Phase III, multicenter, double-blind, randomized withdrawal study following a 24-week, open-label, single-arm treatment phase. Open-label osilodrostat was initiated at 2 mg bid in 137 adults with CD and mUFC (mean of three 24-h samples) >1.5xULN (ULN=50.0 µg/24h), with dose adjustments every 2 weeks (dose range 1-30 mg bid) up to week (W) 12 based on efficacy (if mUFC >ULN) and tolerability. At W26, 71 eligible patients (mUFC ≤ULN at W24 without a dose increase after W12) were randomized to continue osilodrostat (n=36) or matching placebo (n=35) for 8 weeks, followed by open-label osilodrostat until W48. Patients who remained on treatment at W26 but were not eligible for randomization continued open-label osilodrostat (n=47). Primary endpoint: patients in each randomized group with mUFC ≤ULN at the end of the randomized withdrawal phase (W34) without a dose increase after W26. For all mUFC assessments, patients who discontinued were classed as non-responders at subsequent time points. Results: At baseline, median (range) mUFC was 3.5xULN (0.3-69.6) in enrolled patients. At the end of the randomized withdrawal period (W34), significantly more patients maintained mUFC ≤ULN (without a dose increase after W26) in the osilodrostat group than in the placebo group (86% vs 29%; OR 13.7, P<0.001). Other endpoints: at W24, 53% of enrolled patients had mUFC ≤ULN without a dose increase after W12 (key secondary endpoint); at W48, 66% of enrolled patients had mUFC ≤ULN; 96% of enrolled patients had mUFC ≤ULN at least once during the study; median time to first mUFC ≤ULN was 41 days. Median (range) duration of osilodrostat exposure was 75 weeks (1-165). By W48, 24 (18%) patients had discontinued the study, 15 (11%) because of AEs. Overall, the most common AEs were nausea (42%), headache (34%) and fatigue (28%). AEs related to hypocortisolism and adrenal-hormone-precursor accumulation occurred in 51% and 42% of patients, respectively. The most common AEs reported in the osilodrostat group during the randomized withdrawal period were nausea (11% vs 0% for placebo), anemia (8% vs 9%), arthralgia (8% vs 0%) and headache (8% vs 0%). Conclusion: Osilodrostat was significantly superior to placebo at maintaining mUFC ≤ULN after randomized withdrawal and normalized mUFC in two-thirds of enrolled patients at W48, with few patients discontinuing treatment because of AEs. This randomized withdrawal study demonstrates osilodrostat to be a highly effective treatment for CD, with good tolerability.

Project description:PurposeCushing's disease is associated with substantial morbidity and impaired quality of life (QoL) resulting from excess cortisol exposure. The current study explored improvements in clinical signs and additional specific manifestations of hypercortisolism during osilodrostat (potent oral 11β-hydroxylase inhibitor) therapy by degree of control of mean urinary free cortisol (mUFC).MethodsLINC 3 (NCT02180217) was a prospective, open-label, 48-week study of osilodrostat (starting dose: 2 mg bid; maximum: 30 mg bid) that enrolled 137 adults with Cushing's disease and mUFC > 1.5 times the upper limit of normal (ULN). mUFC (normal range 11‒138 nmol/24 h), cardiometabolic parameters (blood pressure, weight, waist circumference, body mass index, total cholesterol, fasting plasma glucose, glycated haemoglobin), physical manifestations of hypercortisolism (facial rubor, striae, fat distribution, bruising, hirsutism [females], muscle atrophy) and QoL were evaluated. mUFC was defined as controlled if ≤ ULN, partially controlled if > ULN but ≥ 50% reduction from baseline, and uncontrolled if > ULN and < 50% reduction from baseline. Concomitant medications were permitted throughout the study.ResultsAt weeks 24 and 48, respectively, mUFC was controlled in 93 (67.9%) and 91 (66.4%) patients, partially controlled in 20 (14.6%) and 13 (9.5%), and uncontrolled in 24 (17.5%) and 33 (24.1%). Overall, mean improvements from baseline in cardiometabolic at week 24 were greater in patients with controlled or partially controlled versus uncontrolled mUFC; at week 48, improvements occurred irrespective of mUFC control. Generally, physical manifestations and QoL progressively improved from baseline irrespective of mUFC control.ConclusionsImprovements in clinical signs and additional specific manifestations of hypercortisolism associated with Cushing's disease occurred alongside decreases in mUFC. Trial registration NCT02180217 (first posted July 2014).

Dataset Information

Long-term efficacy and safety of osilodrostat in patients with Cushing's disease: results from the LINC 4 study extension.

Objective

Methods

Results

Conclusion

Clinical trial registration

Publications

Long-term efficacy and safety of osilodrostat in patients with Cushing's disease: results from the LINC 4 study extension.

Similar Datasets

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