A Block-and-Replace Therapy With Osilodrostat and Concomitant Glucocorticoid Replacement
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 12
- 试验地点
- 2
- 主要终点
- Percent of participants who experience an adrenal insufficiency event during Phase 1 (titration phase)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Observational cohort
Participants with Cushing syndrome consented to participate in block-and-replace osilodrostat therapy.
干预措施: Osilodrostat (Drug)
结局指标
主要结局
Percent of participants who experience an adrenal insufficiency event during Phase 1 (titration phase)
时间窗: Through phase 1, approximately 24 weeks
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
次要结局
- Mean change in HgbA1c for participant with HgbA1c > 6.4% at entry.(Baseline, end of phase 2 (approximately 48 weeks))
- Change in weight(Baseline, end of phase 2 (approximately 48 weeks))
- Change in systolic blood pressure(Baseline, end of phase 2 (approximately 48 weeks))
- Correlation between AM cortisol and 11OHA4 measurements(Up to end of study, approximately 48 weeks)
- Change in diastolic blood pressure(Baseline, end of phase 2 (approximately 48 weeks))
- Adrenal Insufficiency Assessment Questionnaire scores(Up to end of study, approximately 48 weeks)
- Frequency of cortisol withdrawal symptoms(Up to end of phase 2 (approximately 48 weeks))
- Rate of adrenal insufficient episodes per patient per year(Up to end of phase 2 (approximately 48 weeks))
- Ease of titration(Up to end of phase 1 (approximately 48 weeks))
- Change in number of concomitant medications(Baseline, end of phase 2 (approximately 48 weeks))
- RAND Short Form (SF)-36 scores(Up to end of study, approximately 48 weeks)
研究者
Richard J. Auchus, MD PhD
Professor of Translational Medicine, Professor of Internal Medicine and Professor of Pharmacology
University of Michigan