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.
Panoramica dello studio
Stato
Intervento / Trattamento
Descrizione dettagliata
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.
Tipo di studio
Iscrizione (Stimato)
Fase
- Fase 2
Contatti e Sedi
Contatto studio
- Nome: Beckey Trinh, PD, MD, PhD
- Numero di telefono: +41612655078
- Email: beckey.trinh@usb.ch
Luoghi di studio
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Basel, Svizzera
- University Hospital Basel, Clinic of Endocrinology, Diabetology & Metabolism
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Contatto:
- Beckey Trinh, PD, MD, PhD
- Numero di telefono: +41612655078
- Email: beckey.trinh@usb.ch
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Criteri di partecipazione
Criteri di ammissibilità
Età idonea allo studio
Accetta volontari sani
Sessi ammissibili allo studio
Descrizione
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
Piano di studio
Come è strutturato lo studio?
Dettagli di progettazione
- Scopo principale: Trattamento
- Assegnazione: Randomizzato
- Modello interventistico: Assegnazione parallela
- Mascheramento: Quadruplicare
Armi e interventi
Gruppo di partecipanti / Arm |
Intervento / Trattamento |
|---|---|
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Sperimentale: 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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Comparatore placebo: 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 |
Cosa sta misurando lo studio?
Misure di risultato primarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
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Change from baseline in HbA1c at week 12
Lasso di tempo: 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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Misure di risultato secondarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
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CGM Time in Range (3.9-10.0 mmol/L, %)
Lasso di tempo: 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, %)
Lasso di tempo: 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, %)
Lasso di tempo: 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, %)
Lasso di tempo: 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
Lasso di tempo: Baseline and week 12
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Baseline and week 12
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Change in lipid profile
Lasso di tempo: Baseline and week 12
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Baseline and week 12
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Change in body weight and waist/hip circumference
Lasso di tempo: Baseline and week 12
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Baseline and week 12
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Change in DXA-derived body composition
Lasso di tempo: 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)
Lasso di tempo: Baseline to week 12
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Baseline to week 12
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Change in antihypertensive medication
Lasso di tempo: Baseline to week 12
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Baseline to week 12
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Change in plasma cortisol
Lasso di tempo: Baseline and week 12
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Baseline and week 12
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Change in salivary cortisol
Lasso di tempo: Baseline to week 12
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Baseline to week 12
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Change in 24-h urinary cortisol
Lasso di tempo: 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)
Lasso di tempo: 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)
Lasso di tempo: 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)
Lasso di tempo: Baseline and week 12
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global score 0-21, higher = worse sleep |
Baseline and week 12
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Altre misure di risultato
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
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Change from baseline in bone mineral density by DXA (g/cm²)
Lasso di tempo: 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)
Lasso di tempo: 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)
Lasso di tempo: 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)
Lasso di tempo: Baseline and week 12
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Baseline and week 12
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Change from baseline in bone-specific alkaline phosphatase
Lasso di tempo: 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
Lasso di tempo: 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
Lasso di tempo: 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
Lasso di tempo: Baseline and week 12
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seconds; lower = better |
Baseline and week 12
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Serum interleukin-6
Lasso di tempo: Baseline and week 12
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Baseline and week 12
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Serum TNF-α
Lasso di tempo: Baseline and week 12
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Baseline and week 12
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Serum IL-1Ra
Lasso di tempo: Baseline and week 12
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Baseline and week 12
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Serum hs-CRP
Lasso di tempo: Baseline and week 12
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Baseline and week 12
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Plasma and 24-h urinary steroid metabolome
Lasso di tempo: Baseline and week 12
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Baseline and week 12
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Circadian clock-gene expression (whole-blood RNA)
Lasso di tempo: Baseline and week 12
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Baseline and week 12
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Collaboratori e investigatori
Sponsor
Investigatori
- Investigatore principale: Beckey Trinh, PD, MD, PhD, University Hospital, Basel, Switzerland
Pubblicazioni e link utili
Studiare le date dei record
Studia le date principali
Inizio studio (Stimato)
Completamento primario (Stimato)
Completamento dello studio (Stimato)
Date di iscrizione allo studio
Primo inviato
Primo inviato che soddisfa i criteri di controllo qualità
Primo Inserito (Effettivo)
Aggiornamenti dei record di studio
Ultimo aggiornamento pubblicato (Effettivo)
Ultimo aggiornamento inviato che soddisfa i criteri QC
Ultimo verificato
Maggiori informazioni
Termini relativi a questo studio
Parole chiave
Termini MeSH pertinenti aggiuntivi
- Malattie del sistema endocrino
- Malattie metaboliche
- Disturbi del metabolismo del glucosio
- Diabete mellito
- Malattie della ghiandola surrenale
- Iperfunzione surrenalica
- Malattie nutrizionali e metaboliche
- Diabete mellito, tipo 2
- Sindrome di Cushing
- Ormoni
- Ormoni, sostituti ormonali e antagonisti ormonali
- Composti policiclici
- In gravidanza
- Steroidi
- Composti anelli fusi
- Gravideniones
- Incinta
- 11-idrossicosteroidi
- Idrossicorticosteroidi
- Ormoni della corteccia surrenale
- 17-idrossicosteroidi
- Idrocortisone
- Osilodrostat
Altri numeri di identificazione dello studio
- GLYCOSIL-MACS
- 2026-01499 (Altro identificatore: BASEC / Ethics Committee Northwest and Central Switzerland, EKNZ)
- 205.123670 (Altro identificatore: Swissmedic)
- SNCTP000007077 (Altro identificatore: Swiss National Clinical Trials Portal)
Piano per i dati dei singoli partecipanti (IPD)
Hai intenzione di condividere i dati dei singoli partecipanti (IPD)?
Descrizione del piano 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.
Informazioni su farmaci e dispositivi, documenti di studio
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