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

Adrenal Insufficiency Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06430528
• Other study ID #: HUM00246263
• Status: Recruiting
• Start date: May 2024
• Est. completion date: August 2027

Study information

• Verified date: May 2024
• Source: University of Michigan
• Contact: Eyad Alsafadi
• Phone: 734-647-5661
• Email: alsafade[@]med.umich.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 12
• Est. completion date: August 2027
• Est. primary completion date: May 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Adrenal Insufficiency
• Adrenocortical Hyperfunction
• Cushing Syndrome
• Hypercortisolism

Intervention

Drug:
• Osilodrostat
Add methylprednisolone to osilodrostat therapy after first dose and continue during osilodrostat titration.

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
University of Michigan	Recordati Rare Diseases

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Adrenal insufficiency episodes during Phase 2 (maintenance)	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)
Secondary	Frequency of cortisol withdrawal symptoms	Based on patient-reported outcomes	Up to end of phase 2 (approximately 48 weeks)
Secondary	Change in weight	Based on clinic measurements	Baseline, end of phase 2 (approximately 48 weeks)
Secondary	Change in diastolic blood pressure	Based on clinic measurements	Baseline, end of phase 2 (approximately 48 weeks)
Secondary	Change in systolic blood pressure	Based on clinic measurements	Baseline, end of phase 2 (approximately 48 weeks)
Secondary	Change in HgbA1c	Based on clinical laboratory measurements	Baseline, end of phase 2 (approximately 48 weeks)
Secondary	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)
Secondary	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
Secondary	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
Secondary	Ease of titration	Investigators' judgment (1-5 scale)	Up to end of phase 1 (approximately 48 weeks)