## Protocol Section
### Identification Module
**NCT ID:** NCT06430528

**Brief Title:** A Block-and-Replace Therapy With Osilodrostat and Concomitant Glucocorticoid Replacement

**Official Title:** A Block-and-Replace Therapy With Osilodrostat and Concomitant Glucocorticoid Replacement

#### Organization Study ID Info
**ID:** HUM00246263
#### Organization
**Class:** OTHER
**Full Name:** University of Michigan
### Status Module
#### Completion Date
**Date:** 2027-08

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-28

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-23

**Overall Status:** RECRUITING

#### Primary Completion Date
**Date:** 2027-05

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-05

**Type:** ESTIMATED

**Status Verified Date:** 2024-05

#### Study First Post Date
**Date:** 2024-05-28
**Type:** ACTUAL
**Study First Submit Date:** 2024-04-24
**Study First Submit QC Date:** 2024-05-23
### Sponsor Collaborators Module

#### Collaborators

**Class:** INDUSTRY

**Name:** Recordati Rare Diseases

#### Lead Sponsor

**Class:** OTHER

**Name:** University of Michigan

#### Responsible Party

**Investigator Affiliation:** University of Michigan

**Investigator Full Name:** Richard J. Auchus, MD PhD

**Investigator Title:** Professor of Translational Medicine, Professor of Internal Medicine and Professor of Pharmacology

**Type:** PRINCIPAL_INVESTIGATOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** True

**Is US Export:** False

**Oversight Has DMC:** False

### Description Module

**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.

### Conditions Module

**Conditions:**

- Endogenous Cushing Syndrome

- Adrenal Insufficiency

- Hypercortisolism

**Keywords:**

- Osilodrostat

- Glucocorticoid

- Methylprednisolone

- Medrol

### Design Module

#### Bio Spec

**Description:** Serum samples for steroid measurements.

**Retention:** SAMPLES_WITHOUT_DNA

#### Design Info

**Observational Model:** COHORT

**Time Perspective:** PROSPECTIVE

#### Enrollment Info

**Count:** 12

**Type:** ESTIMATED

**Study Type:** OBSERVATIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** Participants with Cushing syndrome consented to participate in block-and-replace osilodrostat therapy.

**Intervention Names:**

- Drug: Osilodrostat

**Label:** Observational cohort

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Observational cohort

**Description:** Add methylprednisolone to osilodrostat therapy after first dose and continue during osilodrostat titration.

**Name:** Osilodrostat

**Other Names:**

- Isturisa

**Type:** DRUG

### Outcomes Module

#### Primary Outcomes

**Description:** 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

**Measure:** Percent of participants who experience an adrenal insufficiency event during Phase 1 (titration phase)

**Time Frame:** Through phase 1, approximately 24 weeks

#### Secondary Outcomes

**Description:** 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.

**Measure:** Correlation between AM cortisol and 11OHA4 measurements

**Time Frame:** Up to end of study, approximately 48 weeks

**Description:** 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

**Measure:** Adrenal insufficiency episodes during Phase 2 (maintenance)

**Time Frame:** Up to end of phase 2 (approximately 48 weeks)

**Description:** Based on patient-reported outcomes

**Measure:** Frequency of cortisol withdrawal symptoms

**Time Frame:** Up to end of phase 2 (approximately 48 weeks)

**Description:** Based on clinic measurements

**Measure:** Change in weight

**Time Frame:** Baseline, end of phase 2 (approximately 48 weeks)

**Description:** Based on clinic measurements

**Measure:** Change in diastolic blood pressure

**Time Frame:** Baseline, end of phase 2 (approximately 48 weeks)

**Description:** Based on clinic measurements

**Measure:** Change in systolic blood pressure

**Time Frame:** Baseline, end of phase 2 (approximately 48 weeks)

**Description:** Based on clinical laboratory measurements

**Measure:** Change in HgbA1c

**Time Frame:** Baseline, end of phase 2 (approximately 48 weeks)

**Description:** Based on clinic notes, total number of medications used to treat Cushing syndrome comorbidities

**Measure:** Change in number of concomitant medications

**Time Frame:** Baseline, end of phase 2 (approximately 48 weeks)

**Description:** Custom questionnaire for adrenal insufficiency- 4 Likert questions with scores ranging from 4-20. Higher scores indicate worse symptoms.

**Measure:** Adrenal Insufficiency Assessment Questionnaire scores

**Time Frame:** Up to end of study, approximately 48 weeks

**Description:** 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.

**Measure:** RAND Short Form (SF)-36 scores

**Time Frame:** Up to end of study, approximately 48 weeks

**Description:** Investigators' judgment (1-5 scale)

**Measure:** Ease of titration

**Time Frame:** Up to end of phase 1 (approximately 48 weeks)

### Eligibility Module

**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.

**Maximum Age:** 75 Years

**Minimum Age:** 18 Years

**Sampling Method:** NON_PROBABILITY_SAMPLE

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

**Study Population:** Patients receiving care at the University of Michigan.

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** alsafade@med.umich.edu

**Name:** Eyad Alsafadi

**Phone:** 734-647-5661

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Ann Arbor

**Contacts:**

***Contact 1:***

- **Email:** alsafade@med.umich.edu

- **Name:** Eyad Alsafadi

- **Phone:** 734-647-5661

- **Role:** CONTACT

***Contact 2:***

- **Name:** Richard Auchus, MD, PhD

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** United States

**Facility:** University of Michigan

**State:** Michigan

**Status:** RECRUITING

**Zip:** 48109

#### Overall Officials

**Official 1:**

**Affiliation:** University of Michigan

**Name:** Richard Auchus, MD, PhD

**Role:** PRINCIPAL_INVESTIGATOR

### IPD Sharing Statement Module

**IPD Sharing:** NO

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000000307

- Term: Adrenal Gland Diseases

- ID: D000004700

- Term: Endocrine System Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC19

- Name: Gland and Hormone Related Diseases

- Abbrev: Rare

- Name: Rare Diseases

### Condition Browse Module - Browse Leaves

- ID: M16355

- Name: Syndrome

- Relevance: LOW

- As Found: Unknown

- ID: M3661

- Name: Adrenal Insufficiency

- Relevance: HIGH

- As Found: Adrenal Insufficiency

- ID: M6689

- Name: Cushing Syndrome

- Relevance: HIGH

- As Found: Cushing's Syndrome

- ID: M3660

- Name: Adrenocortical Hyperfunction

- Relevance: HIGH

- As Found: Hypercortisolism

- ID: M3659

- Name: Adrenal Gland Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M7862

- Name: Endocrine System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: T1679

- Name: Cushing's Syndrome

- Relevance: HIGH

- As Found: Cushing's Syndrome

- ID: T2879

- Name: Hyperadrenalism

- Relevance: HIGH

- As Found: Hypercortisolism

### Condition Browse Module - Meshes

- ID: D000000309

- Term: Adrenal Insufficiency

- ID: D000003480

- Term: Cushing Syndrome

- ID: D000000308

- Term: Adrenocortical Hyperfunction

### Intervention Browse Module - Browse Branches

- Abbrev: Infl

- Name: Anti-Inflammatory Agents

- Abbrev: ANeo

- Name: Antineoplastic Agents

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: AnEm

- Name: Antiemetics

- Abbrev: NeuroAg

- Name: Neuroprotective Agents

- Abbrev: Gast

- Name: Gastrointestinal Agents

### Intervention Browse Module - Browse Leaves

- ID: M14120

- Name: Prednisolone

- Relevance: LOW

- As Found: Unknown

- ID: M9047

- Name: Glucocorticoids

- Relevance: LOW

- As Found: Unknown

- ID: M11749

- Name: Methylprednisolone

- Relevance: LOW

- As Found: Unknown

- ID: M1833

- Name: Methylprednisolone Acetate

- Relevance: LOW

- As Found: Unknown

- ID: M11750

- Name: Methylprednisolone Hemisuccinate

- Relevance: LOW

- As Found: Unknown

- ID: M229449

- Name: Prednisolone acetate

- Relevance: LOW

- As Found: Unknown

- ID: M211887

- Name: Prednisolone hemisuccinate

- Relevance: LOW

- As Found: Unknown

- ID: M248881

- Name: Prednisolone phosphate

- Relevance: LOW

- As Found: Unknown

### Misc Info Module

- Version Holder: 2024-05-31
