Ketoconazole Effects on the Daily Cortisol Rhythm in Mild Autonomous Cortisol Secretion

NCT07649317 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: 10002658002658-DK
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Cortisol is a hormone in the blood. Cortisol levels normally go down at night and up in the morning. Mild autonomous cortisol secretion (MACS) is a disease in which the body makes too much cortisol. MACS can cause high blood pressure, diabetes, and/or weight gain. Researchers think these problems may be caused by higher cortisol levels at night. Objective: To compare daily cortisol levels in people with MACS with those in healthy people. Also, to test a drug (ketoconazole) that may help lower cortisol levels in people with MACS. Eligibility: People aged 18 years and older with MACS. Healthy volunteers are also needed. Design: Participants with MACS will have a 2-night stay in the hospital. Day 1: A thin tube called a catheter will be inserted into a vein in the arm. Blood will be collected through the catheter every 2 hours starting at 8 PM. Participants will begin a 24-hour urine collection. Saliva will be collected every 6 hours for 24 hours. Day 2: Participants will take 2 tablets of the study drug ketoconazole with their evening meal. Blood will be collected via the catheter at regular intervals throughout the night. Day 3: Participants will leave the hospital in the morning. Healthy volunteers will be screened with a physical exam and blood tests. They will be tested to make sure they do not have MACS. To do this, they will take a drug (dexamethasone) at 11 PM on a day they choose; then they will return the next morning for a blood test. Healthy volunteers will have a 1-night stay in the hospital. They will have blood, urine, and saliva collected for 24 hours.

Conditions

Mild Autonomous Cortisol Secretion

Keywords

Cortisol; KETOCONAZOLE; Mild Autonomous Cortisol Secretion

Outcome Measures

Primary Outcomes (1)

• To assess the circadian rhythm of serum cortisol in participants with MACS compared to that in matched healthy volunteers (HV).

  Difference in serum cortisol between MACS and HV at timepoints 1600h, 1800h, 2000h, 2200h, 0000h and 0200h during 24-hour sampling.

  Baseline sampling obtained during 24 hours in each participant.

Secondary Outcomes (1)

• To determine the degree of serum cortisol reduction induced by a single dose of 400 mg ketoconazole (KTZ) in participants with MACS.

  Baseline sampling for 24 hours followed by post-KTZ sampling for 12 hours in participants with MACS.

Study Arms (2)

Healthy volunteers

NO INTERVENTION

Healthy volunteers, matched to MACS participants by age, sex, BMI and (women only) menopausal status. Will undergo 24-hour sampling to obtain healthy diurnal serum cortisol curves for comparison.

Mild autonomous cortisol secretion (MACS)

EXPERIMENTAL

Patients with mild autonomous cortisol secretion (MACS) who will undergo baseline sampling of diurnal cortisol , followed by sampling after a single dose of ketoconazole 400 mg.

Drug: Ketoconazole

Interventions

Ketoconazole DRUG

Antifungal medication that blocks adrenal steroidogenesis, including cortisol production, at higher doses

Mild autonomous cortisol secretion (MACS)

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• To be eligible to participate in this study, an individual must meet all of the following criteria:
• Aged 18 years or older.
• Stated willingness to comply with all study procedures and availability for the duration of the study.
• Agreement to adhere to Lifestyle Considerations throughout the study.
• A. Subjects with Mild Autonomous Cortisol Secretion (MACS):
• Co-enrollment in protocol 19DK0066.
• Abnormal low-dose overnight dexamethasone suppression test (morning serum cortisol \>1.8 mcg/dL following 1 mg oral dexamethasone between 2300-0000h the evening prior)
• One or more \>=1 cm adrenal nodule(s) on one or both adrenal glands on CT or MRI
• One normal 24-hour urine free cortisol value (per the reference range of the assay used).
• One morning plasma ACTH value \<10 pg/mL.
• B. Healthy volunteers:
• In good general health as evidenced by medical history and physical examination; and in a stable state of health without ongoing acute/temporary illness per the clinical judgment of the investigator.
• Normal low-dose overnight dexamethasone suppression test (morning serum cortisol \<=1.8 mcg/dL following 1 mg oral dexamethasone between 2300-0000h the evening prior)
• Matching a participant with MACS who has completed testing in regard to:
• Age: Birth year within 5 years of that of the participant with MACS.

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:
• Inability to comply with all study procedures and visits.
• Inability of subject to understand or to sign a written informed consent document.
• Pregnancy or breastfeeding.
• Use of estrogen-containing oral contraceptives or oral estrogen therapy within 6 weeks before inpatient admission, due to possible increases in serum corticosteroid-binding globulin, and thereby total cortisol.
• Use of medications within 2 weeks before inpatient admission that can block glucocorticoid production or action: ketoconazole (systemic), levoketoconazole, metyrapone, osilodrostat, mifepristone.
• Use of oral, injectable, or inhaled glucocorticoids (unless intermittent, for symptomatic asthma) within the year before inpatient admission. Use of topical non-hydrocortisone containing potent glucocorticoids on more than 36 square inches within six months before inpatient admission.
• Anemia (hemoglobin \<13.7 g/dL for males, \<11.2 g/dL for females).
• Daily alcohol risk use (\>2 standard drinks per day by self-report during screening visit).
• Severely uncontrolled diabetes mellitus (HbA1c \>9.0%).
• Highly irregular sleep schedule in the week leading up to inpatient admission (e.g. shift work).
• Any contraindication to intravenous catheter use.
• Previous participation in this protocol.
• Any condition that in the opinion of the Investigator would jeopardize the participant s appropriate participation in this study.
• A. Subjects with Mild Autonomous Cortisol Secretion (MACS):

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

RECRUITING

Related Publications (3)

• 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.

  PMID: 37318239 BACKGROUND

• Debono M, Harrison RF, Chadarevian R, Gueroult C, Abitbol JL, Newell-Price J. Resetting the Abnormal Circadian Cortisol Rhythm in Adrenal Incidentaloma Patients With Mild Autonomous Cortisol Secretion. J Clin Endocrinol Metab. 2017 Sep 1;102(9):3461-3469. doi: 10.1210/jc.2017-00823.

  PMID: 28911138 BACKGROUND

• Saini J, Singh S, Ebbehoj A, Zhang CD, Nathani R, Fell V, Atkinson E, Achenbach S, Rivard A, Singh R, Grebe S, Bancos I. Steroid Profiling and Circadian Cortisol Secretion in Patients With Mild Autonomous Cortisol Secretion: A Cross-sectional Study. J Clin Endocrinol Metab. 2025 Jan 21;110(2):542-553. doi: 10.1210/clinem/dgae468.

  PMID: 38981002 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Interventions

Ketoconazole

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Lynnette K Nieman, M.D.

  National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Raven N McGlotten, R.N.

CONTACT

(301) 827-0190; mcglottenr@mail.nih.gov

Lynnette K Nieman, M.D.

CONTACT

(301) 496-8935; niemanl@mail.nih.gov

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 13, 2026
• First Posted: June 16, 2026
• Study Start: July 27, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: July 30, 2026

Record last verified: 2026-06-26

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, CSR
• Time Frame: Starting six months after publication, for two years.
• Access Criteria: The principal investigator will review requests from qualified investigators.

Locations

US (1)