Clinical trial NCT06430528: A Block-and-Replace Therapy With Osilodrostat and Concomitant Glucocorticoid Replacement
Official title: A Block-and-Replace Therapy With Osilodrostat and Concomitant Glucocorticoid Replacement
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Endogenous Cushing Syndrome
Adrenal Insufficiency
Hypercortisolism
Keywords: Osilodrostat
Glucocorticoid
Methylprednisolone
Medrol
Lead sponsor: University of Michigan
Sponsor class: OTHER
Collaborators: name: Recordati Rare Diseases
First posted: 2024-05-28
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients receiving care at the University of Michigan.

Brief summary: The major goal of this study is to determine the incidence of adrenal insufficiency in patients with endogenous Cushing syndrome receiving osilodrostat treatment combined with a replacement of glucocorticoid (block-and-replace approach).

The investigators are also evaluating new biomarker steroids to reflect adequate osilodrostat dosing, the durability and safety, and clinical improvement during treatment.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Endogenous Cushing syndrome, either following surgery or not candidates for surgery
* Under consideration to receive osilodrostat as part of their clinical care
* Able to provide informed consent.

Exclusion Criteria:

* Treatment with other investigational drugs within 30 days or five half-lives (whichever is longer).
* A history of hypersensitivity to osilodrostat or therapies of a similar chemical class.

Primary outcomes:
measure: Percent of participants who experience an adrenal insufficiency event during Phase 1 (titration phase)
timeFrame: Through phase 1, approximately 24 weeks
Secondary outcomes:
measure: Correlation between AM cortisol and 11OHA4 measurements
timeFrame: Up to end of study, approximately 48 weeks
measure: Rate of adrenal insufficient episodes per patient per year
timeFrame: Up to end of phase 2 (approximately 48 weeks)
measure: Frequency of cortisol withdrawal symptoms
timeFrame: Up to end of phase 2 (approximately 48 weeks)
measure: Change in weight
timeFrame: Baseline, end of phase 2 (approximately 48 weeks)
measure: Change in diastolic blood pressure
timeFrame: Baseline, end of phase 2 (approximately 48 weeks)
measure: Change in systolic blood pressure
timeFrame: Baseline, end of phase 2 (approximately 48 weeks)
measure: Mean change in HgbA1c for participant with HgbA1c > 6.4% at entry.
timeFrame: Baseline, end of phase 2 (approximately 48 weeks)
measure: Change in number of concomitant medications
timeFrame: Baseline, end of phase 2 (approximately 48 weeks)
measure: Adrenal Insufficiency Assessment Questionnaire scores
timeFrame: Up to end of study, approximately 48 weeks
measure: RAND Short Form (SF)-36 scores
timeFrame: Up to end of study, approximately 48 weeks
measure: Ease of titration
timeFrame: Up to end of phase 1 (approximately 48 weeks)
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
Study officials:
affiliation: University of Michigan
name: Richard Auchus, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: