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

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.

Study Overview

• Status: Recruiting
• Conditions: Adrenal Insufficiency; Hypercortisolism; Endogenous Cushing Syndrome
• Intervention / Treatment: Drug: Osilodrostat

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.

• Study Type: Observational
• Enrollment (Estimated): 12

Contacts and Locations

• Study Contact: Name: Thaira Blanco Varela; Phone Number: 734-647-5661; Email: tbv@med.umich.edu
• Study Contact Backup: Name: Richard Auchus; Phone Number: 734-764-7764; Email: rauchus@med.umich.edu

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • University of Michigan
      • Contact: Eyad Alsafadi; Phone Number: 734-647-5661; Email: alsafade@med.umich.edu
      • Principal Investigator: Richard Auchus, MD, PhD
      • Contact: Thaira Blanco Varela; Phone Number: 734-647-5661; Email: tbv@med.umich.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients receiving care at the University of Michigan.

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Observational cohort; Participants with Cushing syndrome consented to participate in block-and-replace osilodrostat therapy.	Drug: Osilodrostat; Add methylprednisolone to osilodrostat therapy after first dose and continue during osilodrostat titration.; Other Names: Isturisa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of participants who experience an adrenal insufficiency event during Phase 1 (titration phase)	based on evidence of hypotension (systolic BP <90 mmHg) and/or hypoglycemia (glucose <45 mg/dL) with antecedent symptoms (examples: anorexia, nausea, abdominal pain, orthostasis) and with a resolution of signs upon receiving rescue glucocorticoid therapy	Through phase 1, approximately 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between AM cortisol and 11OHA4 measurements	compare biomarkers measured by mass spectrometry. This may be calculated Upon 12 participants completing phase 1 or at the end of the study, whichever comes first.	Up to end of study, approximately 48 weeks
Frequency of cortisol withdrawal symptoms	Based on patient-reported outcomes	Up to end of phase 2 (approximately 48 weeks)
Change in weight	Based on clinic measurements	Baseline, end of phase 2 (approximately 48 weeks)
Change in diastolic blood pressure	Based on clinic measurements	Baseline, end of phase 2 (approximately 48 weeks)
Change in systolic blood pressure	Based on clinic measurements	Baseline, end of phase 2 (approximately 48 weeks)
Change in number of concomitant medications	Based on clinic notes, total number of medications used to treat Cushing syndrome comorbidities	Baseline, end of phase 2 (approximately 48 weeks)
Adrenal Insufficiency Assessment Questionnaire scores	Custom questionnaire for adrenal insufficiency- 4 Likert questions with scores ranging from 4-20. Higher scores indicate worse symptoms.	Up to end of study, approximately 48 weeks
RAND Short Form (SF)-36 scores	The 36-Item Short Form Health Survey (SF-36) is standard RAND form used clinically. It is a set of generic, coherent, and easily administered quality-of-life measures. Scores for the scale range from 0-100 with higher scores indicating a better Health-related Quality of Life.	Up to end of study, approximately 48 weeks
Ease of titration	Investigators' judgment (1-5 scale)	Up to end of phase 1 (approximately 48 weeks)
Rate of adrenal insufficient episodes per patient per year	based on evidence of hypotension (systolic BP <90 mmHg) and/or hypoglycemia (glucose <45 mg/dL) with antecedent symptoms (examples: anorexia, nausea, abdominal pain, orthostasis) and with a resolution of signs upon receiving rescue glucocorticoid therapy	Up to end of phase 2 (approximately 48 weeks)
Mean change in HgbA1c for participant with HgbA1c > 6.4% at entry.	Based on clinic measurements	Baseline, end of phase 2 (approximately 48 weeks)

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: Recordati Rare Diseases
• Investigators: Principal Investigator: Richard Auchus, MD, PhD, University of Michigan

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2024
• Primary Completion (Estimated): May 1, 2027
• Study Completion (Estimated): August 1, 2027

Study Registration Dates

• First Submitted: April 24, 2024
• First Submitted That Met QC Criteria: May 23, 2024
• First Posted (Actual): May 28, 2024

Study Record Updates

• Last Update Posted (Actual): August 20, 2025
• Last Update Submitted That Met QC Criteria: August 14, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Methylprednisolone; Medrol; Glucocorticoid; Osilodrostat
• Additional Relevant MeSH Terms: Endocrine System Diseases; Adrenal Gland Diseases; Adrenocortical Hyperfunction; Adrenal Insufficiency; Cushing Syndrome
• Other Study ID Numbers: HUM00246263

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No