ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 63 P734 | DOI: 10.1530/endoabs.63.P734

A phase 2 study assessing osilodrostat in children and adolescent patients with Cushing's disease - Rationale and methods

Helen L Storr1, Nalini Shah2, Judi Wojna3, Kevin Han3, Michael Roughton4, François Pierre Combes3, Philippe Pultar3 & Martin O Savage1


1Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 2Department of Endocrinology, KEM Hospital, Mumbai, India; 3Novartis Pharmaceuticals Corporation, East Hanover, USA; 4Novartis Pharma AG, Basel, Switzerland.


Background: In children, Cushing’s disease (CD) presents with a combination of weight gain and slowed linear growth. First-line pituitary surgery is the treatment of choice for most patients. In paediatric patients, the transsphenoidal surgical success rate is 60%–98% when performed by an expert pituitary surgeon. There is a need for additional pharmacological interventions to control hypercortisolaemia, which are currently limited, in children and adolescents. In phase 2 and 3 trials in adult patients with CD, treatment with osilodrostat, an oral 11β-hydroxylase inhibitor, was effective and was generally well tolerated. The present phase 2, multicenter, open label, non-comparative study aims to evaluate the pharmacokinetics (PK), pharmacodynamics, safety/tolerability of osilodrostat in patients aged 6–<18 years with CD (NCT03708900).

Methods: 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 are eligible for enrolment. The target enrolment is 12 patients. CD will be confirmed by the clinical criteria of decreasing growth percentiles with increasing weight (defined by height standard deviation score [SDS]<0, body mass index SDS>0 and a strong clinical suspicion of CD), an abnormal low-dose dexamethasone suppression test, measurable morning adrenocorticotrophic hormone levels and two 24-hour urinary free cortisol (UFC) measurements >1.3×ULN (upper limit of normal). The study comprises a 4-week screening period, a 12-week core phase and an optional 9-month extension period for patients who obtain clinical benefit from osilodrostat as judged by the investigator. The starting dose of osilodrostat will be 1 mg once daily and 1 mg twice daily, for patients weighing 30-60 kg and ≥60 kg, respectively. The dose will then be titrated based on mean UFC (mUFC) and body weight. The primary objective is to assess the PK of osilodrostat. The primary endpoint is to evaluate the PK parameters (Cmax and Ctrough) up to week 12 core study. Secondary endpoints include the proportion of patients with normal mUFC (two 24-hour UFC samples) at weeks 6 and 12, change in mUFC during week 12, safety/tolerability up to week 12 of the core phase and month 12 of the extension phase and assessment of efficacy up to month 12.

Conclusion: This phase 2 study will be the first study of osilodrostat in children and adolescent patients with CD. The findings from this multicentre, open-label, non-comparative study may allow further clinical development of osilodrostat in this population.

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