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SUN-454 Rationale and Methods for a Phase II Trial Evaluating Osilodrostat in Pediatric Patients with Cushing's Disease

ABSTRACT: Abstract Background: Cushing’s disease (CD) is a rare disease associated with significant morbidity and mortality, with 2-5 new cases per million per year, of which 10% occur in children (Stratakis CA. Endocrinol Metab Clin North Am 2012;41:793-803). In children, CD presents with a combination of weight gain and slowed linear growth. First-line surgery is the treatment of choice for most patients, with a success rate of 60-98% in pediatric patients if performed by an expert pituitary surgeon (Keil MF. J Clin Endocrinol Metab 2013;98:2667-78). When surgery is not successful, patients require additional pharmacologic interventions, which are currently limited in children. Osilodrostat is a potent oral 11?-hydroxylase inhibitor in clinical development for the treatment of CD. This Phase II, multicenter, open-label, non-comparative study will evaluate the pharmacokinetics (PK), pharmacodynamics and safety/tolerability of osilodrostat in patients aged 6-<18 years with Cushing’s disease (clinicaltrials.gov identifier: NCT03708900). Methods: This single-arm study will enroll 12 evaluable patients aged 6-<18 years with confirmed CD for whom pituitary surgery is not an option, for whom surgery has failed, or who are awaiting surgery. CD will be confirmed by the clinical criteria of decreasing growth percentiles with increasing weight (defined by height SDS <0, BMI SDS >0, and a strong clinical suspicion of CD), an abnormal low-dose dexamethasone suppression test, measurable morning ACTH levels, and two 24-hour UFC measurements >1.3 x ULN. This study consists of two phases: a 12-week core phase and an optional 9-month extension period for patients who obtain a clinical benefit from osilodrostat as judged by the investigator. The primary objective is to assess the PK (Cmax and Ctrough) of osilodrostat during the 12-week core study. A secondary objective is to assess the proportion of patients with normal mean UFC (mUFC; determined from two 24-hour UFC samples) at weeks 6 and 12. Other secondary objectives include: assessment of safety and tolerability up to week 12 of the core phase and up to month 12 of the extension phase; assessment of efficacy up to month 12. The starting dose of osilodrostat will be 1 mg once daily and 1 mg twice daily for patients weighing <60 kg and ?60 kg, respectively. The dose may be titrated based on mUFC response. PK parameter estimates will be calculated by pooling individual plasma osilodrostat concentration-time data and analyzed using non-compartmental analysis. Conclusion: This Phase II, multicenter, open-label, non-comparative study will be the first study of osilodrostat in pediatric patients with CD. The results of this study may allow further clinical development of osilodrostat in children with CD.

SUBMITTER: Savage M

PROVIDER: S-EPMC6553121 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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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: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.

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SUN-454 Rationale and Methods for a Phase II Trial Evaluating Osilodrostat in Pediatric Patients with Cushing's Disease

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