Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS)

Pivonello, Rosario; Zacharieva, Sabina; Еленкова, Атанаска; Tóth, Miklós; Shimon, Ilan; Stigliano, Antonio; Badiu, Corin; Brue, Thierry; Georgescu, Carmen Emanuela; Tsagarakis, Stylianos; Cohen, Fredric J.; Fleseriu, Maria

doi:10.1007/s11102-022-01263-7

Cited by 20 publications

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“…However, considering only the 55 patients who completed the maintenance phase, levoketoconazole induced a complete response in 61.8%, and induced a partial response in 16.4%, with an overall control in 78.2%, of patients, regardless of dose up-titration [ 8 ]. The phase III double-blind, placebo-controlled, randomized withdrawal study LOGICS has shown that levoketoconazole, at dosages of 300–1200 mg/day, induced a complete response in 50% of patients at the end of randomized withdrawal, percentage significantly higher if compared to placebo (4.5%) [ 9 ]. Moreover, at the end of randomized withdrawal, significantly more patients on placebo (95.5%) achieved the primary endpoint of loss of mean urinary free cortisol (mUFC) response, defined as mUFC > 1.5 upper limit of normal range, or, for SONICS completers with mUFC above the upper limit of normal range at baseline, an increase in mUFC > 40% above the baseline value, than those who continued on levoketoconazole (40.9%) [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…The phase III double-blind, placebo-controlled, randomized withdrawal study LOGICS has shown that levoketoconazole, at dosages of 300–1200 mg/day, induced a complete response in 50% of patients at the end of randomized withdrawal, percentage significantly higher if compared to placebo (4.5%) [ 9 ]. Moreover, at the end of randomized withdrawal, significantly more patients on placebo (95.5%) achieved the primary endpoint of loss of mean urinary free cortisol (mUFC) response, defined as mUFC > 1.5 upper limit of normal range, or, for SONICS completers with mUFC above the upper limit of normal range at baseline, an increase in mUFC > 40% above the baseline value, than those who continued on levoketoconazole (40.9%) [ 9 ]. The treatment with levoketoconazole was accompanied by an improvement in clinical syndrome and comorbidities of CS, including body weight, glucose metabolism, lipid profile, peripheral edema, quality of life and depressive status, as well as hirsutism and acne in women [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, at the end of randomized withdrawal, significantly more patients on placebo (95.5%) achieved the primary endpoint of loss of mean urinary free cortisol (mUFC) response, defined as mUFC > 1.5 upper limit of normal range, or, for SONICS completers with mUFC above the upper limit of normal range at baseline, an increase in mUFC > 40% above the baseline value, than those who continued on levoketoconazole (40.9%) [ 9 ]. The treatment with levoketoconazole was accompanied by an improvement in clinical syndrome and comorbidities of CS, including body weight, glucose metabolism, lipid profile, peripheral edema, quality of life and depressive status, as well as hirsutism and acne in women [ 8 , 9 ]. Data on pituitary tumor in patients treated with levoketoconazole are not yet available [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Data on pituitary tumor in patients treated with levoketoconazole are not yet available [ 8 ]. Regarding the safety profile, the most frequently reported AEs were nausea (29–31.9%), headache (23–27.6%), hypokalemia (10.6–26%), and hypertension (17–24%) [ 8 , 9 ]. Noteworthy, an increase in liver enzymes was observed, and specifically alanine amino transferase (ALT) in 14.9–44.6%, gamma-glutamyl transferase (GGT) in 12.8–38.6% and aspartate amino transferase (AST) in 11.7–28.9% of cases [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…Regarding the safety profile, the most frequently reported AEs were nausea (29–31.9%), headache (23–27.6%), hypokalemia (10.6–26%), and hypertension (17–24%) [ 8 , 9 ]. Noteworthy, an increase in liver enzymes was observed, and specifically alanine amino transferase (ALT) in 14.9–44.6%, gamma-glutamyl transferase (GGT) in 12.8–38.6% and aspartate amino transferase (AST) in 11.7–28.9% of cases [ 8 , 9 ]. AEs were also grouped in categories of special interest, including liver-related AEs (7.4–10.7%), QT prolongation (5.3–10.7%) and hypocortisolism-related AEs (3.2–9.5%) [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

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Cushing’s disease: adrenal steroidogenesis inhibitors

et al. 2022

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Cushing’s disease (CD), caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor, is the most common form of Cushing’s syndrome (CS), accounting for approximately 70% of cases. CD requires a prompt diagnosis, an adequate treatment selection, and long-term management to limit hypercortisolism duration and long-term complications and improve patient outcomes. Pituitary surgery is the first-line option, which is non-curative in one third of patients, therefore requiring additional treatments. Medical therapy has recently acquired an emerging role, with the availability of several drugs with different therapeutic targets, efficacy and safety profiles. The current review focuses on efficacy and safety of steroidogenesis inhibitors, and particularly the historical drugs, ketoconazole and metyrapone, and the novel drugs levoketoconazole and osilodrostat, which seem to offer a rapid, sustained, and effective disease control. Ketoconazole should be preferred in females and in patients without severe liver disease; levoketoconazole may offer an alternative to classical ketoconazole, appearing characterized by a higher potency and potential lower hepatotoxicity compared to ketoconazole. Metyrapone should be preferred in males and in patients without severe or uncontrolled hypokalemia. Both ketoconazole and metyrapone may be preferred for short-term more than for long-term treatment. Osilodrostat may represent the best choice for long-term treatment, in patients with poor compliance to the multiple daily administration schedule, and in patients without severe or uncontrolled hypokalemia. Steroidogenesis inhibitors may be used alone or in combination, and associated with pituitary directed drugs, to improve the efficacy of the single drugs, allowing a potential use of lower doses for each drug, and hypothetically reducing the rate of adverse events associated with the single drugs. Clinicians may tailor medical therapy on the specific clinical scenario, considering disease history together with patients’ characteristics and hypercortisolism’s degree, addressing the needs of each patient in order to improve the therapeutic outcome and to reduce the burden of illness, particularly in patients with persistent or recurrent CD.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cushing’s disease: adrenal steroidogenesis inhibitors

et al. 2022

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Cushing Syndrome

Reincke

Fleseriu

2023

JAMA

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ImportanceCushing syndrome is defined as a prolonged increase in plasma cortisol levels that is not due to a physiological etiology. Although the most frequent cause of Cushing syndrome is exogenous steroid use, the estimated incidence of Cushing syndrome due to endogenous overproduction of cortisol ranges from 2 to 8 per million people annually. Cushing syndrome is associated with hyperglycemia, protein catabolism, immunosuppression, hypertension, weight gain, neurocognitive changes, and mood disorders.ObservationsCushing syndrome characteristically presents with skin changes such as facial plethora, easy bruising, and purple striae and with metabolic manifestations such as hyperglycemia, hypertension, and excess fat deposition in the face, back of the neck, and visceral organs. Cushing disease, in which corticotropin excess is produced by a benign pituitary tumor, occurs in approximately 60% to 70% of patients with Cushing syndrome due to endogenous cortisol production. Evaluation of patients with possible Cushing syndrome begins with ruling out exogenous steroid use. Screening for elevated cortisol is performed with a 24-hour urinary free cortisol test or late-night salivary cortisol test or by evaluating whether cortisol is suppressed the morning after an evening dexamethasone dose. Plasma corticotropin levels can help distinguish between adrenal causes of hypercortisolism (suppressed corticotropin) and corticotropin-dependent forms of hypercortisolism (midnormal to elevated corticotropin levels). Pituitary magnetic resonance imaging, bilateral inferior petrosal sinus sampling, and adrenal or whole-body imaging can help identify tumor sources of hypercortisolism. Management of Cushing syndrome begins with surgery to remove the source of excess endogenous cortisol production followed by medication that includes adrenal steroidogenesis inhibitors, pituitary-targeted drugs, or glucocorticoid receptor blockers. For patients not responsive to surgery and medication, radiation therapy and bilateral adrenalectomy may be appropriate.Conclusions and RelevanceThe incidence of Cushing syndrome due to endogenous overproduction of cortisol is 2 to 8 people per million annually. First-line therapy for Cushing syndrome due to endogenous overproduction of cortisol is surgery to remove the causative tumor. Many patients will require additional treatment with medications, radiation, or bilateral adrenalectomy.

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