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.
Přehled studie
Postavení
Detailní popis
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.
Typ studie
Zápis (Odhadovaný)
Fáze
- Fáze 2
Kontakty a umístění
Studijní kontakt
- Jméno: Beckey Trinh, PD, MD, PhD
- Telefonní číslo: +41612655078
- E-mail: beckey.trinh@usb.ch
Studijní místa
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Basel, Švýcarsko
- University Hospital Basel, Clinic of Endocrinology, Diabetology & Metabolism
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Kontakt:
- Beckey Trinh, PD, MD, PhD
- Telefonní číslo: +41612655078
- E-mail: beckey.trinh@usb.ch
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Kritéria účasti
Kritéria způsobilosti
Věk způsobilý ke studiu
Přijímá zdravé dobrovolníky
Pohlaví způsobilá ke studiu
Popis
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
Studijní plán
Jak je studie koncipována?
Detaily designu
- Primární účel: Léčba
- Přidělení: Randomizované
- Intervenční model: Paralelní přiřazení
- Maskování: Čtyřnásobek
Zbraně a zásahy
Skupina účastníků / Arm |
Intervence / Léčba |
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Experimentální: 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 |
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Komparátor placeba: 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 |
Co je měření studie?
Primární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
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Change from baseline in HbA1c at week 12
Časové okno: 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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Sekundární výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
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CGM Time in Range (3.9-10.0 mmol/L, %)
Časové okno: baseline, week 6 and week 12
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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, %)
Časové okno: baseline, week 6 and week 12
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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, %)
Časové okno: baseline, week 6 and week 12
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14-day windows preceding baseline, week 6 and week 12 |
baseline, week 6 and week 12
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CGM Time above range (>10.0 and >13.9 mmol/L, %)
Časové okno: baseline, week 6 and week 12
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14-day windows preceding baseline, week 6 and week 12. |
baseline, week 6 and week 12
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Change in blood pressure
Časové okno: Baseline and week 12
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Baseline and week 12
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Change in lipid profile
Časové okno: Baseline and week 12
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Baseline and week 12
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Change in body weight and waist/hip circumference
Časové okno: Baseline and week 12
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Baseline and week 12
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Change in DXA-derived body composition
Časové okno: 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)
Časové okno: Baseline to week 12
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Baseline to week 12
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Change in antihypertensive medication
Časové okno: Baseline to week 12
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Baseline to week 12
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Change in plasma cortisol
Časové okno: Baseline and week 12
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Baseline and week 12
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Change in salivary cortisol
Časové okno: Baseline to week 12
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Baseline to week 12
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Change in 24-h urinary cortisol
Časové okno: Baseline and week 12
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Baseline and week 12
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Change from baseline in health-related quality of life (SF-36)
Časové okno: Baseline and week 12
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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)
Časové okno: 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)
Časové okno: Baseline and week 12
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global score 0-21, higher = worse sleep |
Baseline and week 12
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Další výstupní opatření
Měření výsledku |
Popis opatření |
Časové okno |
|---|---|---|
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Change from baseline in bone mineral density by DXA (g/cm²)
Časové okno: 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)
Časové okno: 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)
Časové okno: 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)
Časové okno: Baseline and week 12
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Baseline and week 12
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Change from baseline in bone-specific alkaline phosphatase
Časové okno: 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
Časové okno: 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
Časové okno: Baseline and week 12
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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
Časové okno: Baseline and week 12
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seconds; lower = better |
Baseline and week 12
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Serum interleukin-6
Časové okno: Baseline and week 12
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Baseline and week 12
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Serum TNF-α
Časové okno: Baseline and week 12
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Baseline and week 12
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Serum IL-1Ra
Časové okno: Baseline and week 12
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Baseline and week 12
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Serum hs-CRP
Časové okno: Baseline and week 12
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Baseline and week 12
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Plasma and 24-h urinary steroid metabolome
Časové okno: Baseline and week 12
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Baseline and week 12
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Circadian clock-gene expression (whole-blood RNA)
Časové okno: Baseline and week 12
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Baseline and week 12
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Spolupracovníci a vyšetřovatelé
Sponzor
Vyšetřovatelé
- Vrchní vyšetřovatel: Beckey Trinh, PD, MD, PhD, University Hospital, Basel, Switzerland
Publikace a užitečné odkazy
Termíny studijních záznamů
Hlavní termíny studia
Začátek studia (Odhadovaný)
Primární dokončení (Odhadovaný)
Dokončení studie (Odhadovaný)
Termíny zápisu do studia
První předloženo
První předloženo, které splnilo kritéria kontroly kvality
První zveřejněno (Aktuální)
Aktualizace studijních záznamů
Poslední zveřejněná aktualizace (Aktuální)
Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality
Naposledy ověřeno
Více informací
Termíny související s touto studií
Klíčová slova
Další relevantní podmínky MeSH
- Onemocnění endokrinního systému
- Metabolické choroby
- Poruchy metabolismu glukózy
- Diabetes Mellitus
- Onemocnění nadledvinek
- Adrenokortikální hyperfunkce
- Nutriční a metabolické nemoci
- Diabetes mellitus, typ 2
- Cushingův syndrom
- Hormony
- Hormony, hormonální náhražky a antagonisté hormonů
- Polycyklické sloučeniny
- Těhotenství
- Steroidy
- Sloučeniny roztaveného kruhu
- Těhotenství
- Těhotenství
- 11-Hydroxycorticosteroids
- Hydroxycorticosteroidy
- Hormony kůry nadledvin
- 17-Hydroxycorticosteroids
- Hydrokortison
- Osilodrostat
Další identifikační čísla studie
- GLYCOSIL-MACS
- 2026-01499 (Jiný identifikátor: BASEC / Ethics Committee Northwest and Central Switzerland, EKNZ)
- 205.123670 (Jiný identifikátor: Swissmedic)
- SNCTP000007077 (Jiný identifikátor: Swiss National Clinical Trials Portal)
Plán pro data jednotlivých účastníků (IPD)
Plánujete sdílet data jednotlivých účastníků (IPD)?
Popis plánu IPD
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.
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