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.
Aperçu de l'étude
Statut
Description détaillée
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.
Type d'étude
Inscription (Estimé)
Phase
- Phase 2
Contacts et emplacements
Coordonnées de l'étude
- Nom: Beckey Trinh, PD, MD, PhD
- Numéro de téléphone: +41612655078
- E-mail: beckey.trinh@usb.ch
Lieux d'étude
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Basel, Suisse
- University Hospital Basel, Clinic of Endocrinology, Diabetology & Metabolism
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Contact:
- Beckey Trinh, PD, MD, PhD
- Numéro de téléphone: +41612655078
- E-mail: beckey.trinh@usb.ch
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Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
Accepte les volontaires sains
Sexes éligibles pour l'étude
La description
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
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: Randomisé
- Modèle interventionnel: Affectation parallèle
- Masquage: Quadruple
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
|---|---|
|
Expérimental: 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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Comparateur 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 |
Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
|
Change from baseline in HbA1c at week 12
Délai: Baseline and week 12
|
Between-group difference in HbA1c change (%). Time Frame: Baseline and week 12 |
Baseline and week 12
|
Mesures de résultats secondaires
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
|
CGM Time in Range (3.9-10.0 mmol/L, %)
Délai: 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, %)
Délai: 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, %)
Délai: 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 above range (>10.0 and >13.9 mmol/L, %)
Délai: 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
Délai: Baseline and week 12
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Baseline and week 12
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Change in lipid profile
Délai: Baseline and week 12
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Baseline and week 12
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Change in body weight and waist/hip circumference
Délai: Baseline and week 12
|
Baseline and week 12
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Change in DXA-derived body composition
Délai: 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)
Délai: Baseline to week 12
|
Baseline to week 12
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Change in antihypertensive medication
Délai: Baseline to week 12
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Baseline to week 12
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Change in plasma cortisol
Délai: Baseline and week 12
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Baseline and week 12
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Change in salivary cortisol
Délai: Baseline to week 12
|
Baseline to week 12
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Change in 24-h urinary cortisol
Délai: 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)
Délai: 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)
Délai: 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)
Délai: Baseline and week 12
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global score 0-21, higher = worse sleep |
Baseline and week 12
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Autres mesures de résultats
Mesure des résultats |
Description de la mesure |
Délai |
|---|---|---|
|
Change from baseline in bone mineral density by DXA (g/cm²)
Délai: 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)
Délai: 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)
Délai: 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)
Délai: Baseline and week 12
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Baseline and week 12
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Change from baseline in bone-specific alkaline phosphatase
Délai: 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
Délai: 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
Délai: 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
Délai: Baseline and week 12
|
seconds; lower = better |
Baseline and week 12
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Serum interleukin-6
Délai: Baseline and week 12
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Baseline and week 12
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Serum TNF-α
Délai: Baseline and week 12
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Baseline and week 12
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Serum IL-1Ra
Délai: Baseline and week 12
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Baseline and week 12
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Serum hs-CRP
Délai: Baseline and week 12
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Baseline and week 12
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Plasma and 24-h urinary steroid metabolome
Délai: Baseline and week 12
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Baseline and week 12
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Circadian clock-gene expression (whole-blood RNA)
Délai: Baseline and week 12
|
Baseline and week 12
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Collaborateurs et enquêteurs
Parrainer
Les enquêteurs
- Chercheur principal: Beckey Trinh, PD, MD, PhD, University Hospital, Basel, Switzerland
Publications et liens utiles
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude (Estimé)
Achèvement primaire (Estimé)
Achèvement de l'étude (Estimé)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Réel)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Termes MeSH pertinents supplémentaires
- Maladies du système endocrinien
- Maladies métaboliques
- Troubles du métabolisme du glucose
- Diabète sucré
- Maladies des glandes surrénales
- Hyperfonction corticosurrénalienne
- Maladies nutritionnelles et métaboliques
- Diabète sucré, Type 2
- Syndrome de Cushing
- Hormones
- Hormones, substituts hormonaux et antagonistes hormonaux
- Composés polycycliques
- Grossesse
- Stéroïdes
- Composés à anneau fusionné
- Grossenones
- Présceau
- 11-hydroxycorticostéroïdes
- Hydroxycorticostéroïdes
- Hormones cortex surrénaliques
- 17-hydroxycorticostéroïdes
- Hydrocortisone
- Osilodrostat
Autres numéros d'identification d'étude
- GLYCOSIL-MACS
- 2026-01499 (Autre identifiant: BASEC / Ethics Committee Northwest and Central Switzerland, EKNZ)
- 205.123670 (Autre identifiant: Swissmedic)
- SNCTP000007077 (Autre identifiant: Swiss National Clinical Trials Portal)
Plan pour les données individuelles des participants (IPD)
Prévoyez-vous de partager les données individuelles des participants (DPI) ?
Description du régime 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.
Informations sur les médicaments et les dispositifs, documents d'étude
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