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.