Pharmacokinetic (PK), Pharmacodynamic (PD) and Tolerability of Osilodrostat in Pediatric Patients With Cushing's Disease

Study Overview
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Brief Summary
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Multicenter, open-label, non-comparative study to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of osilodrostat in children and adolescent patients with Cushing's disease.

Detailed Description
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The period 1 study duration will be 12 weeks. The study will include a screening period of up to 4 weeks prior to Day 0 (baseline) (to allow for an adequate washout period from any medications that may modify cortisol levels). All subjects being treated with osilodrostat at 12 weeks and obtaining benefit from therapy, per investigator judgment, will be offered participation in an optional 9-month extension period, during which assessment of the PD activity and safety/tolerability of osilodrostat will be done. Patients who do not enter the optional extension period will have a safety follow up visit 4 weeks later.

Official Title
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A Phase II, Multicenter, Open-label, Non-comparative Study to Evaluate the Pharmacokinetics, Pharmacodynamics, and Tolerability of Osilodrostat in Children and Adolescent Patients With Cushing's Disease

Conditions
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Cushing's Disease

Intervention / Treatment
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* Drug: LCI699


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cushing's disease of endogenous origin: Who have failed surgery (or) who are awaiting surgery (or) for whom surgery is not an immediate option. The diagnosis of Cushing's disease must be confirmed by each of the following: The clinical criterion of decreasing growth percentiles with increasing weight (as evidenced by the presence of a contrast in height and BMI standard deviation (SD) scores, defined as height standard deviation score (SDS) < 0 and BMI SDS > 0, and a strong clinical suspicion of Cushing's disease, such as photographic evidence of a change in facial appearance); Abnormal low-dose (0.5 mg Q6h x 48 hours) dexamethasone suppression test, defined as plasma cortisol levels > 1.8 mcg/dl, at time point 48 hours after the first dose of dexamethasone; Measurable morning ACTH levels, assessed before 10 am; Two 24-hour urinary free cortisol values > 1.3 x ULN If the dexamethasone suppression test does not meet the above mentioned criteria, the diagnosis of Cushing's disease may be confirmed by the following: Midnight serum cortisol levels > upper limit of normal (ULN), assessed while the patient is sleeping and after pre-cannulation (OR) two samples of late night salivary cortisol greater than ULN for the assay Able to swallow study drug tablets (not crushed or split) Parents or legal guardians able to provide consent/assent Exclusion Criteria: Patients with macroadenoma complicated by compressive symptoms (requiring urgent surgical intervention) or at high risk for compressive symptoms due to mass effect of tumor (concern of corticotroph tumor progression) Hypercortisolism not due to Cushing's disease Insufficient washout period from any other medication used to lower cortisol levels (5 half-lives of any drug) Use of other investigational drugs at the time of enrollment, or within 30 days, or prior to completion of a wash-out duration that is at least 5 half- lives of the drug, at the time of enrollment, whichever is longer. Local regulations may require a longer wash-out period or specify other limitations for participation in an investigational trial, in which case they will be applicable as well. Body weight <30kg Other protocol-defined inclusion/exclusion may apply.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LCI699 (osilodrostat)<br>Subjects with cushing's disease taking LCI699 (osilodrostat) | Drug: LCI699<br>* osilodrostat (LCI699) is in the form of tablets for oral administration and comes in the following tablet strengths: 1 milligram (mg), 5 mg, and 10mg.<br>* Other names: osilodrostat;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Study: Evaluate the pharmacokinetics (PK) of osilodrostat using Pharmacokinetic parameter - Cmax - of osilodrostat up to Week 12 in children and adolescents 6 to less than 18 years of age with Cusihing's Disease | evaluate the pharmacokinetics (PK) by Cmax of osilodrostat in children and adolescents 6 to less than 18 years of age with Cushing's Disease | up to Week 12 | 
| Core Study: Evaluate the pharmacokinetics of osilodrostat using Pharmacokinetic parameter - Ctrough - of osilodrostat up to Week 12 in children and adolescents 6 to less than 18 years of age with Cushing's Disease | evaluate the pharmacokinetics (PK) by Ctrough of osilodrostat in children and adolescents 6 to less than 18 years of age with Cushing's Disease | up to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Study: Percentage of patients with normal mean urinary free cortisol (mUFC) at week 6 and week 12 (or end of treatment) | The assessment in the core period will be done by taking the percentage of patients with normal mUFC at week 6 and week 12 (or end of treatment). | week 6, week 12 (or end of treatment) | 
| Core Study: Change from baseline in mean urinary free cortisol (mUFC) during the core study period | The assessment will be done by comparison of change from the baseline in mUFC during core study period on patients | Baseline, 12 weeks | 
| Extension: Efficacy of osilodrostat as measured by mUFC levels up to Month 12 | The assessment of efficacy of osilodrostat to be measured by mUFC levels up to 12 months on patients | up to month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cushing's disease (CD), LCI699, osilodrostat, Pituitary Gland, Adrenocorticotropic Hormone (ACTH), Urinary Free Cortisol (UFC), mean Urinary Free Cortisol (mUFC)