Osilodrostat for Glycemic Control in Mild Autonomous Cortisol Secretion (MACS) With Difficult-To-Control Type 2 Diabetes - A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study (GLYCOSIL-MACS)
This single-centre, randomized, double-blind, placebo-controlled phase 2 trial investigates whether lowering cortisol with osilodrostat improves blood-glucose control in adults with mild autonomous cortisol secretion (MACS) and difficult-to-control type 2 diabetes. Forty-four participants are randomly assigned 1:1 to osilodrostat or matching placebo, taken once daily for 12 weeks, together with a blinded hydrocortisone/placebo for stress (sick-day) dosing. The primary outcome is the change in HbA1c from baseline to week 12; secondary outcomes include continuous glucose monitoring (CGM) metrics, cardiometabolic parameters, cortisol measures and quality of life. Participants are followed for a safety visit 4 weeks after the end of treatment.
調査の概要
状態
詳細な説明
MACS is a common, mild form of endogenous hypercortisolism that may adversely affect glucose metabolism. In participants with confirmed MACS and difficult-to-control type 2 diabetes, this trial tests whether pharmacological cortisol reduction with osilodrostat improves glycaemic control. After a screening visit and a 14-day CGM run-in, participants are randomized 1:1 to osilodrostat 1 mg once daily at 18:00 (single optional escalation to 2 mg after 14 days, safety-guided) or matching placebo for 12 weeks; both arms receive a blinded hydrocortisone/placebo for stress dosing (double-dummy). Background glucose- and blood-pressure-lowering therapy is continued and adjusted only per predefined safety algorithms. Assessments include HbA1c, continuous glucose monitoring, blood pressure, lipids, anthropometrics, DXA body composition and bone density, plasma/salivary/urinary cortisol, quality-of-life and sleep questionnaires, and safety laboratory and ECG monitoring. The primary analysis is an ANCOVA of the change in HbA1c at week 12 in the intention-to-treat population under a treatment-policy estimand; CGM endpoints are analysed with mixed-effects models for repeated measures.
研究の種類
入学 (推定)
段階
- フェーズ2
連絡先と場所
研究連絡先
- 名前：Beckey Trinh, PD, MD, PhD
- 電話番号：+41612655078
- メール：beckey.trinh@usb.ch
研究場所
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Basel、スイス
- University Hospital Basel, Clinic of Endocrinology, Diabetology & Metabolism
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コンタクト：
- Beckey Trinh, PD, MD, PhD
- 電話番号：+41612655078
- メール：beckey.trinh@usb.ch
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-
参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion Criteria:
- Age 18 to <75 years.
- Confirmed MACS per ESE 2023 guidelines: serum cortisol >50 nmol/L after 1 mg dexamethasone suppression test, low ACTH and DHEAS, and uni-/bilateral adrenal adenoma(s) or macronodular/micronodular/diffuse bilateral adrenal hyperplasia on CT or MRI.
- Morning serum cortisol >300 nmol/L.
- Difficult-to-control type 2 diabetes: HbA1c >7.0% despite one of - ≥3 glucose-lowering medications; insulin plus ≥1 glucose-lowering medication; ≥2 glucose-lowering medications and ≥1 micro-/macrovascular complication; or ≥2 glucose-lowering and ≥2 blood-pressure-lowering medications.
- Stable background pharmacotherapy for ≥4 weeks before the first study visit.
- For persons of childbearing potential: agreement to abstinence or contraception with a failure rate ≤1%/year during treatment and for 1 month after the last dose.
Exclusion Criteria:
- Age ≥75 years (osilodrostat not sufficiently studied in this age group per the SmPC).
- Known hypersensitivity to osilodrostat, its excipients, or the placebo.
- Planned adrenalectomy before completion of the study.
- Malignant adrenal tumour.
- Type 1 diabetes; new-onset diabetes (<1 year).
- Systemic glucocorticoid therapy within 3 months, or planned use.
- Current/recent intake of medications affecting adrenal steroidogenesis or cortisol assessment.
- Concomitant therapy with clinically relevant drug-drug interactions with osilodrostat (strong CYP3A4 inhibitors; strong CYP3A4/CYP2B6 inducers; QT-prolonging medicinal products).
- Participation in another interventional trial within the last 30 days.
- Pregnancy or breastfeeding; WOCBP unwilling to use highly effective contraception.
- Excessive alcohol consumption; severe untreated sleep apnea; night-shift work.
- Severe psychiatric, medical or surgical illness.
- Severe renal impairment (eGFR < 30 mL/min/1.73 m²), hemodialysis or end-stage renal disease.
- Liver cirrhosis Child-Pugh B or C.
- Refractory hypokalemia or hypomagnesemia (not correctable to K ≥4.0 and Mg ≥1.0 mmol/L before first dose).
- QTc > 480 ms on baseline ECG, or known congenital long QT syndrome.
- Uncontrolled arterial hypertension (≥ 160/100 mmHg despite therapy)
- Uncontrolled thyroid disease
- Severe cardiovascular disease (NYHA class III-IV heart failure, myocardial infarction or unstable angina within the previous 6 months, or clinically significant arrhythmia)
- History of breast or endometrial carcinoma
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：4倍
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
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実験的：Osilodrostat
Osilodrostat 1 mg once daily at 18:00 for 12 weeks (single optional escalation to 2 mg after 14 days), plus blinded hydrocortisone 10 mg for stress/sick-day dosing only. |
1 mg film-coated tablet, orally once daily at 18:00; optional single escalation to 2 mg after 14 days; 12 weeks. blinded stress/sick-day (rescue) dosing only, per written instructions |
|
プラセボコンパレーター：Placebo
Placebo once daily at 18:00 for 12 weeks, plus blinded placebo for hydrocortisone (identical schedule). |
placebo tablet, orally once daily at 18:00; 12 weeks placebo tablet for stress-dosing regimen |
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Change from baseline in HbA1c at week 12
時間枠：Baseline and week 12
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Between-group difference in HbA1c change (%). Time Frame: Baseline and week 12 |
Baseline and week 12
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
CGM Time in Range (3.9-10.0 mmol/L, %)
時間枠：baseline, week 6 and week 12
|
14-day windows preceding baseline, week 6 and week 12. |
baseline, week 6 and week 12
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CGM Time in Tight Range (3.9-7.8 mmol/L, %)
時間枠：baseline, week 6 and week 12
|
14-day windows preceding baseline, week 6 and week 12. |
baseline, week 6 and week 12
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CGM Time below range (<3.9 and <3.0 mmol/L, %)
時間枠：baseline, week 6 and week 12
|
14-day windows preceding baseline, week 6 and week 12 |
baseline, week 6 and week 12
|
|
CGM Time above range (>10.0 and >13.9 mmol/L, %)
時間枠：baseline, week 6 and week 12
|
14-day windows preceding baseline, week 6 and week 12. |
baseline, week 6 and week 12
|
|
Change in blood pressure
時間枠：Baseline and week 12
|
Baseline and week 12
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Change in lipid profile
時間枠：Baseline and week 12
|
Baseline and week 12
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Change in body weight and waist/hip circumference
時間枠：Baseline and week 12
|
Baseline and week 12
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Change in DXA-derived body composition
時間枠：Baseline and week 12
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Baseline and week 12
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Proportion of participants requiring reduction of hypoglycemia-causing therapy (insulin/sulfonylurea)
時間枠：Baseline to week 12
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Baseline to week 12
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Change in antihypertensive medication
時間枠：Baseline to week 12
|
Baseline to week 12
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Change in plasma cortisol
時間枠：Baseline and week 12
|
Baseline and week 12
|
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Change in salivary cortisol
時間枠：Baseline to week 12
|
Baseline to week 12
|
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Change in 24-h urinary cortisol
時間枠：Baseline and week 12
|
Baseline and week 12
|
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Change from baseline in health-related quality of life (SF-36)
時間枠：Baseline and week 12
|
8 subscales + physical/mental component summaries, 0-100, higher = better |
Baseline and week 12
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Change from baseline in disease-specific quality of life (CushingQoL questionnaire)
時間枠：Baseline and week 12
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higher = better |
Baseline and week 12
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Change from baseline in sleep quality (Pittsburgh Sleep Quality Index, PSQI)
時間枠：Baseline and week 12
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global score 0-21, higher = worse sleep |
Baseline and week 12
|
その他の成果指標
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Change from baseline in bone mineral density by DXA (g/cm²)
時間枠：Baseline and week 12
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Baseline and week 12
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Change from baseline in serum β-CTX (C-terminal telopeptide of type I collagen)
時間枠：Baseline and week 12
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Baseline and week 12
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Change from baseline in serum P1NP (procollagen type I N-terminal propeptide)
時間枠：Baseline and week 12
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Baseline and week 12
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Change from baseline in total alkaline phosphatase (U/L)
時間枠：Baseline and week 12
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Baseline and week 12
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Change from baseline in bone-specific alkaline phosphatase
時間枠：Baseline and week 12
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Baseline and week 12
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Change from baseline in the clinical Cushing severity score
時間枠：Baseline and week 12
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Li et al. 2023 clinical severity score; 0-22, higher = more severe |
Baseline and week 12
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Change from baseline in handgrip strength
時間枠：Baseline and week 12
|
hand dynamometer; kg, best of three |
Baseline and week 12
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Change from baseline in the five-times sit-to-stand test
時間枠：Baseline and week 12
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seconds; lower = better |
Baseline and week 12
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Serum interleukin-6
時間枠：Baseline and week 12
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Baseline and week 12
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Serum TNF-α
時間枠：Baseline and week 12
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Baseline and week 12
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Serum IL-1Ra
時間枠：Baseline and week 12
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Baseline and week 12
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Serum hs-CRP
時間枠：Baseline and week 12
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Baseline and week 12
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Plasma and 24-h urinary steroid metabolome
時間枠：Baseline and week 12
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Baseline and week 12
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Circadian clock-gene expression (whole-blood RNA)
時間枠：Baseline and week 12
|
Baseline and week 12
|
協力者と研究者
スポンサー
捜査官
- 主任研究者：Beckey Trinh, PD, MD, PhD、University Hospital, Basel, Switzerland
出版物と役立つリンク
研究記録日
主要日程の研究
研究開始 (推定)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- GLYCOSIL-MACS
- 2026-01499 (その他の識別子：BASEC / Ethics Committee Northwest and Central Switzerland, EKNZ)
- 205.123670 (その他の識別子：Swissmedic)
- SNCTP000007077 (その他の識別子：Swiss National Clinical Trials Portal)
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
IPD プランの説明
Coded study data are held by the sponsor in Switzerland; only anonymised/aggregated data and the final report are shared externally, per the protocol data-protection section.
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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