A Block-and-Replace Therapy With Osilodrostat and Concomitant Glucocorticoid Replacement

Phase 1 (Titration):

Participants will provide written informed consent and receive the first dose of osilodrostat (1-2 mg) in the evening. The following morning, participants will add treatment with at least a physiologic replacement dose of methylprednisolone (4-6 mg/d based on body size in not more than 2 divided doses) and concurrently continue 1-2 mg BID of osilodrostat. Frequent communication is maintained with each participant, at least twice weekly for the first 3 months and weekly thereafter until target osilodrostat dose is reached. Study personnel will ask targeted questions related to the primary endpoint with parameters to notify the study physicians for early signs of adrenal insufficiency. Participants are instructed to double their methylprednisolone dose for intercurrent illness and for symptoms of cortisol deficiency or withdrawal that do not resolve with pausing osilodrostat dosing. Every 4-12 weeks, an AM cortisol, as well as a research sample for steroid profiling (including 11OHA4), is obtained prior to the first doses of methylprednisolone and osilodrostat. The osilodrostat dose is up-titrated as necessary to achieve an AM cortisol goal of \<5 µg/dL. Once the AM cortisol is at goal, a late-night saliva cortisol (LNSC) and 24 h urine free cortisol (UFC) is obtained per standard of care. Osilodrostat titration is continued if necessary until the UFC is also at goal of \<10 µg/24h. Once the AM cortisol and UFC are at goals (\<5 µg/dL and \<10 µg/24h, respectively), the primary endpoint measures are completed, and the participant enters Phase 2.

Phase 2 (Maintenance):

Once the participant reaches what the investigator considers the maintenance doses of osilodrostat and methylprednisolone, participants are followed for a total of 48 weeks from the first osilodrostat dose before being considered at the end of study. The AM serum cortisol, UFC, and LNSC are repeated at the end of the 48-week period and as clinically indicated throughout Phase 2, generally every 3-6 months.

• Correlation between AM cortisol and 11OHA4 measurements [Срок оценки: Up to end of study, approximately 48 weeks]
• Rate of adrenal insufficient episodes per patient per year [Срок оценки: Up to end of phase 2 (approximately 48 weeks)]
• Frequency of cortisol withdrawal symptoms [Срок оценки: Up to end of phase 2 (approximately 48 weeks)]
• Change in weight [Срок оценки: Baseline, end of phase 2 (approximately 48 weeks)]
• Change in diastolic blood pressure [Срок оценки: Baseline, end of phase 2 (approximately 48 weeks)]
• Change in systolic blood pressure [Срок оценки: Baseline, end of phase 2 (approximately 48 weeks)]
• Mean change in HgbA1c for participant with HgbA1c > 6.4% at entry. [Срок оценки: Baseline, end of phase 2 (approximately 48 weeks)]
• Change in number of concomitant medications [Срок оценки: Baseline, end of phase 2 (approximately 48 weeks)]
• Adrenal Insufficiency Assessment Questionnaire scores [Срок оценки: Up to end of study, approximately 48 weeks]
• RAND Short Form (SF)-36 scores [Срок оценки: Up to end of study, approximately 48 weeks]
• Ease of titration [Срок оценки: Up to end of phase 1 (approximately 48 weeks)]