Clinical trial NCT03708900: Pharmacokinetic (PK), Pharmacodynamic (PD) and Tolerability of Osilodrostat in Pediatric Patients With Cushing's Syndrome
Official title: 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 Syndrome
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Cushing Syndrome
Keywords: Cushing's syndrome (CS)
LCI699
osilodrostat
Pituitary Gland
Adrenocorticotropic Hormone (ACTH)
Urinary Free Cortisol (UFC)
mean Urinary Free Cortisol (mUFC)
Lead sponsor: RECORDATI GROUP
Sponsor class: INDUSTRY
First posted: 2018-10-17
Enrollment: 12
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Multicenter, open-label, non-comparative study to evaluate the pharmacokinetics, pharmacodynamics, and tolerability of osilodrostat in children and adolescent patients with Cushing's syndrome.

Detailed description: 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.

Eligibility criteria: Inclusion criteria

1. Male and female children and adolescents from 2 to \< 18 years of age with Cushing's syndrome of endogenous origin: Who have failed surgery (or) who are awaiting surgery (or) for whom surgery is not an immediate option. For patients who are awaiting surgery, the study treatment could be less than 12 weeks.
2. Patients must weigh \> 10 kg.
3. The diagnosis of Cushing's syndrome must be confirmed by each of the following:

3a) The clinical criterion of decreasing growth percentiles with increasing weight (as evidenced by the presence of a contrast in height and BMI SD scores, for example a SDS \< 0 and BMI SDS \> 0, or a strong clinical suspicion of Cushing's syndrome, such as photographic evidence of a change in facial appearance); 3b) Abnormal low-dose (0.5 mg Q6h x 48 hours, or overnight 15mcg/kg \[max 1 mg\]) dexamethasone suppression test, defined as plasma cortisol levels \> 1.8 mcg/dl, at time point 48 hours (0.5 mg Q6h x 48 hours) or 9 to 12 hours (overnight 15mcg/kg \[max 1 mg\]) after the first dose of dexamethasone; (OR) Midnight serum cortisol levels \> 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. 3c)Two 24-hour urinary free cortisol values \> 1.3 x ULN;

4. Able to swallow study drug tablets (not crushed or split) or the content of the capsules mixed with water.

5. Parents or legal guardians able to provide consent/assent.

Exclusion Criteria

1. 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).
2. Insufficient washout period from any other medication used to lower cortisol levels (5 half-lives of any drug).
3. 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.
4. History of hypersensitivity to drugs of the same or similar chemical classes as osilodrostat.
5. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
6. Patients with moderate to severe renal impairment (estimated GFR \< 60 mL/min by the Creatinine-based "Bedside Schwartz" equation).
7. Patients with serum ALT and/or AST \> 3 x ULN, or total bilirubin \> 1.5 x ULN.
8. History of thrombosis.
9. Patients with risk factors for QTc prolongation or Torsade de Pointes, including: 9a) patients with a baseline QTcF \> 450 ms 9b) personal or family history of long QT syndrome 9c) concomitant medications known to prolong the QT interval 9d) patients with hypokalemia, hypocalcaemia, or hypomagnesaemia, if not corrected before pre-dose Day 0. In case of uncorrected hypokalemia (\<3.5 mEq/L), the screening period may be used to correct hypokalemia prior to starting study drug. Use of potassium supplements and/or mineralocorticoid antagonists is permitted during the study. 9e) Patients with a history of significant cardiovascular disease (based on the opinion of the investigator) such as: structural cardiovascular abnormalities, arrhythmia,
10. Hypertensive patients with uncontrolled blood pressure defined as SBP \> 150 and/or DBP \> 100 or not optimally treated for hypertension as judged by the investigator.
11. Patients who have undergone any major surgery within 1 month.
12. Patients who have undergone trans-sphenoidal pituitary surgery within 6 weeks prior to screening are not eligible, unless they have clear evidence of persistent hypercortisolism or persistent biochemical changes consistent with Cushing's syndrome.
13. Use of or anticipated use of systemic glucocorticoid medications 1 month prior to screening.
14. Uncontrolled hypothyroidism as evidenced by Free T4 \< 0.8 ng/dl.
15. Uncontrolled hyper thyroidism.
16. Diabetic patients with poorly controlled diabetes as evidenced by HbA1c \> 8.5 % or not optimally treated for diabetes mellitus as judged by the investigator.
17. Positive pregnancy test in females of childbearing potential.
18. Female patients of childbearing potential who do not agree to use highly effective birth control methods .
19. Pregnant or nursing (lactating) women.
20. Any medical condition that would, in the investigator's judgment, prevent the patient's participation in the clinical study due to safety concerns or compliance with clinical study procedures. Any severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for the study.
21. Use of concomitant prohibited medications

Primary outcomes:
measure: Core Study: Evaluate the pharmacokinetics (PK) of osilodrostat using Pharmacokinetic parameters of osilodrostat up to Week 12 in children and adolescents 2 to less than 18 years of age with Cushing's Syndrome
timeFrame: up to Week 12
Secondary outcomes:
measure: Core Study: Percentage of patients with normal mean urinary free cortisol (mUFC) at week 3, 6, 9 and week 12 (or end of treatment)
timeFrame: week 3, 6, 9 and week 12 (or end of treatment)
measure: Core Study: Change from baseline in mean urinary free cortisol (mUFC) during the core study period
timeFrame: week 3, 6, 9 and week 12 (or end of treatment)
measure: Extension: Efficacy of osilodrostat as measured by mUFC levels up to Month 12
timeFrame: up to month 12
measure: Extension: Efficacy of osilodrostat as measured by mUFC levels up to Month 12
timeFrame: up to month 12
measure: assessment of the pharmacodynamics, safety and tolerability of osilodrostat.
timeFrame: week 3, 6, 9 and week 12 (or end of treatment)
measure: assessment of the pharmacodynamics, safety and tolerability of osilodrostat up to 12 months
timeFrame: up to 12 months
measure: assessment of the pharmacodynamics, safety and tolerability of osilodrostat.assessment of the pharmacodynamics, safety and tolerability of osilodrostat.
timeFrame: week 3, 6, 9 and week 12 (or end of treatment)
measure: assessment of the pharmacodynamics, safety and tolerability of osilodrostat.assessment of the pharmacodynamics, safety and tolerability of osilodrostat.
timeFrame: up to 12 months
measure: assessment of the pharmacodynamics, safety and tolerability of osilodrostat.
timeFrame: week 3, 6, 9 and week 12 (or end of treatment)
measure: assessment of the pharmacodynamics, safety and tolerability of osilodrostat.
timeFrame: up to 12 months
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco UCSF
state: California
city: Bethesda
country: United States
facility: National Institute of Child Health and Human Development
state: Maryland
city: Jette
country: Belgium
facility: UZ Brussel
state: Brussel
city: Varna
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment Sveta Marina EAD
city: Paris
country: France
facility: Hospital Necker Enfants Malades
city: Paris
country: France
facility: Robert Debre Hospital
city: Paris
country: France
facility: CHU Bicetre APHP Paris Saclay
city: Pisa
country: Italy
facility: Aziendal Ospedaliero Universitaria Pisana Presidio Ospedale di Cisanello
state: PI
city: Roma
country: Italy
facility: Ospedale Bambino Gesu
city: Ljubljana
country: Slovenia
facility: University Clinical Center Ljubljana
city: Liverpool
country: United Kingdom
facility: Alder Hey Childrens NHS Foundation Trust
city: London
country: United Kingdom
facility: The Royal London Childrens Hospital
Study officials:
affiliation: Recordati AG
name: Recordati AG
role: STUDY_DIRECTOR
References: