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.

Study Overview

• Status: Not yet recruiting
• Conditions: Diabetes Mellitus (Type 2); Mild Autonomous Cortisol Secretion (MACS)
• Intervention / Treatment: Drug: Osilodrostat (Isturisa); Drug: hydrocortisone 10mg; Drug: Placebo; Drug: Placebo (for hydrocortisone)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 44
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Beckey Trinh, PD, MD, PhD; Phone Number: +41612655078; Email: beckey.trinh@usb.ch

Study Locations

• Switzerland
  • Basel, Switzerland
    • University Hospital Basel, Clinic of Endocrinology, Diabetology & Metabolism
    • Contact: Beckey Trinh, PD, MD, PhD; Phone Number: +41612655078; Email: beckey.trinh@usb.ch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Osilodrostat (Isturisa); 1 mg film-coated tablet, orally once daily at 18:00; optional single escalation to 2 mg after 14 days; 12 weeks.; Drug: hydrocortisone 10mg; blinded stress/sick-day (rescue) dosing only, per written instructions
Placebo Comparator: Placebo; Placebo once daily at 18:00 for 12 weeks, plus blinded placebo for hydrocortisone (identical schedule).	Drug: Placebo; placebo tablet, orally once daily at 18:00; 12 weeks; Drug: Placebo (for hydrocortisone); placebo tablet for stress-dosing regimen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in HbA1c at week 12	Between-group difference in HbA1c change (%). Time Frame: Baseline and week 12	Baseline and week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CGM Time in Range (3.9-10.0 mmol/L, %)	14-day windows preceding baseline, week 6 and week 12.	baseline, week 6 and week 12
CGM Time in Tight Range (3.9-7.8 mmol/L, %)	14-day windows preceding baseline, week 6 and week 12.	baseline, week 6 and week 12
CGM Time below range (<3.9 and <3.0 mmol/L, %)	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, %)	14-day windows preceding baseline, week 6 and week 12.	baseline, week 6 and week 12
Change in blood pressure		Baseline and week 12
Change in lipid profile		Baseline and week 12
Change in body weight and waist/hip circumference		Baseline and week 12
Change in DXA-derived body composition		Baseline and week 12
Proportion of participants requiring reduction of hypoglycemia-causing therapy (insulin/sulfonylurea)		Baseline to week 12
Change in antihypertensive medication		Baseline to week 12
Change in plasma cortisol		Baseline and week 12
Change in salivary cortisol		Baseline to week 12
Change in 24-h urinary cortisol		Baseline and week 12
Change from baseline in health-related quality of life (SF-36)	8 subscales + physical/mental component summaries, 0-100, higher = better	Baseline and week 12
Change from baseline in disease-specific quality of life (CushingQoL questionnaire)	higher = better	Baseline and week 12
Change from baseline in sleep quality (Pittsburgh Sleep Quality Index, PSQI)	global score 0-21, higher = worse sleep	Baseline and week 12

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in bone mineral density by DXA (g/cm²)		Baseline and week 12
Change from baseline in serum β-CTX (C-terminal telopeptide of type I collagen)		Baseline and week 12
Change from baseline in serum P1NP (procollagen type I N-terminal propeptide)		Baseline and week 12
Change from baseline in total alkaline phosphatase (U/L)		Baseline and week 12
Change from baseline in bone-specific alkaline phosphatase		Baseline and week 12
Change from baseline in the clinical Cushing severity score	Li et al. 2023 clinical severity score; 0-22, higher = more severe	Baseline and week 12
Change from baseline in handgrip strength	hand dynamometer; kg, best of three	Baseline and week 12
Change from baseline in the five-times sit-to-stand test	seconds; lower = better	Baseline and week 12
Serum interleukin-6		Baseline and week 12
Serum TNF-α		Baseline and week 12
Serum IL-1Ra		Baseline and week 12
Serum hs-CRP		Baseline and week 12
Plasma and 24-h urinary steroid metabolome		Baseline and week 12
Circadian clock-gene expression (whole-blood RNA)		Baseline and week 12

Collaborators and Investigators

• Sponsor: Beckey Trinh
• Collaborators: RECORDATI GROUP; Bangerter-Rhyner Foundation
• Investigators: Principal Investigator: Beckey Trinh, PD, MD, PhD, University Hospital, Basel, Switzerland

Publications and helpful links

General Publications

• Fassnacht M, Tsagarakis S, Terzolo M, Tabarin A, Sahdev A, Newell-Price J, Pelsma I, Marina L, Lorenz K, Bancos I, Arlt W, Dekkers OM. European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2023 Jul 20;189(1):G1-G42. doi: 10.1093/ejendo/lvad066.

Study record dates

Study Major Dates

• Study Start (Estimated): November 1, 2026
• Primary Completion (Estimated): April 1, 2029
• Study Completion (Estimated): October 1, 2029

Study Registration Dates

• First Submitted: September 23, 2026
• First Submitted That Met QC Criteria: November 1, 2026
• First Posted (Actual): November 6, 2026

Study Record Updates

• Last Update Posted (Actual): November 6, 2026
• Last Update Submitted That Met QC Criteria: November 1, 2026
• Last Verified: November 1, 2026

More Information

Terms related to this study

• Keywords: HbA1c; cortisol; osilodrostat; glycemic control; CGMS; MACS; hypercortisolism
• Additional Relevant MeSH Terms: Endocrine System Diseases; Metabolic Diseases; Glucose Metabolism Disorders; Diabetes Mellitus; Adrenal Gland Diseases; Adrenocortical Hyperfunction; Nutritional and Metabolic Diseases; Diabetes Mellitus, Type 2; Cushing Syndrome; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Pregnanes; Steroids; Fused-Ring Compounds; Pregnenediones; Pregnenes; 11-Hydroxycorticosteroids; Hydroxycorticosteroids; Adrenal Cortex Hormones; 17-Hydroxycorticosteroids; Hydrocortisone; Osilodrostat
• Other Study ID Numbers: GLYCOSIL-MACS; 2026-01499 (Other Identifier: BASEC / Ethics Committee Northwest and Central Switzerland, EKNZ); 205.123670 (Other Identifier: Swissmedic); SNCTP000007077 (Other Identifier: Swiss National Clinical Trials Portal)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No