[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"trial:NCT07649317":3,"trial-entities:NCT07649317":112,"trial-summary:NCT07649317":116},{"id":4,"nct_id":4,"org_study_id":5,"brief_title":6,"official_title":7,"overall_status":8,"completion_date":9,"status_verified_date":10,"last_update_date":11,"start_date":12,"sponsor_name":13,"lead_sponsor_class":14,"has_dmc":15,"brief_summary":16,"detailed_description":17,"conditions":18,"keywords":20,"study_type":23,"primary_purpose":24,"phases":25,"enrollment_info":27,"interventions":30,"primary_outcomes":37,"secondary_outcomes":42,"sex":47,"minimum_age":48,"maximum_age":49,"healthy_volunteers":50,"eligibility_criteria":51,"std_ages":65,"locations":68,"central_contacts":85,"overall_officials":94,"references":97,"see_also_links":108},"NCT07649317","10002658","Ketoconazole Effects on the Daily Cortisol Rhythm in Mild Autonomous Cortisol Secretion","Ketoconazole Effects on Cortisol Circadian Rhythm in Mild Autonomous Cortisol Secretion: A Pilot Study","RECRUITING","2027-12-31","2026-08-27","2026-08-31","2026-07-27","National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)","NIH",null,"Background:\n\nCortisol 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\u002For weight gain. Researchers think these problems may be caused by higher cortisol levels at night.\n\nObjective:\n\nTo 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.\n\nEligibility:\n\nPeople aged 18 years and older with MACS. Healthy volunteers are also needed.\n\nDesign:\n\nParticipants with MACS will have a 2-night stay in the hospital.\n\nDay 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.\n\nDay 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.\n\nDay 3: Participants will leave the hospital in the morning.\n\nHealthy 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.\n\nHealthy volunteers will have a 1-night stay in the hospital. They will have blood, urine, and saliva collected for 24 hours.","Study Description:\n\nThis study will compare the circadian rhythm of serum cortisol in subjects with Mild Autonomous Cortisol Secretion (MACS) and healthy volunteers (HVs). At the end of 24-hour baseline sampling, participants with MACS will receive a single dose of ketoconazole (KTZ) and undergo continued serial sampling to assess its effect on cortisol production. We hypothesize that subjects with MACS have decreased diurnal variability of serum cortisol, leading to relative excess in the evening and early overnight hours. We also hypothesize that a single dose of KTZ lowers cortisol enough to restore a near-normal diurnal pattern.\n\nObjectives:\n\nPrimary Objective:\n\nTo assess the circadian rhythm of serum cortisol in participants with MACS compared to that in matched HVs.\n\nSecondary Objective:\n\nTo determine the degree of serum cortisol reduction induced by a single dose of 400 mg KTZ in participants with MACS.\n\nExploratory Objectives:\n\n1. To define the time to greatest decrease of cortisol after a dose of KTZ;\n2. To compare serum levels of cortisol precursors in MACS and HVs;\n3. To assess which steroidogenic enzymes are most affected by KTZ;\n4. To compare the nadir-to-peak cortisol excursion in MACS and HVs;\n5. To compare awake and asleep urine cortisol levels in MACS and HVs;\n6. To assess the correlation of salivary cortisol and cortisone with serum Cortisol.\n\nEndpoints:\n\nPrimary Endpoints:\n\nDifference in serum cortisol between MACS and HV at timepoints 1600h, 1800h, 2000h, 2200h, 0000h and 0200h during 24-hour sampling.\n\nSecondary Endpoints:\n\nAbsolute and relative reduction of serum cortisol from pre-dose baseline to 1, 2, 3, 4, 5, 6, 8, 10 and 12 hours after KTZ.\n\nExploratory Endpoints:\n\nTime to maximum cortisol reduction after KTZ compared to baseline sampling; serum cortisol precursors during serial sampling before (MACS and HV) and after (MACS only) KTZ dosing; absolute and relative difference in serum cortisol from nadir to peak; urine free cortisol values while awake and asleep; salivary cortisol\u002Fcortisone and serum cortisol levels at timepoints 0000h, 0600h, 1200h and 1800h.",[19],"Mild Autonomous Cortisol Secretion",[21,22,19],"Cortisol","KETOCONAZOLE","INTERVENTIONAL","BASIC_SCIENCE",[26],"PHASE1",{"count":28,"type":29},36,"ESTIMATED",[31],{"type":32,"name":33,"description":34,"armGroupLabels":35},"DRUG","Ketoconazole","Antifungal medication that blocks adrenal steroidogenesis, including cortisol production, at higher doses",[36],"Mild autonomous cortisol secretion (MACS)",[38],{"measure":39,"description":40,"timeFrame":41},"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.",[43],{"measure":44,"description":45,"timeFrame":46},"To determine the degree of serum cortisol reduction induced by a single dose of 400 mg ketoconazole (KTZ) in participants with MACS.","Difference in serum cortisol after KTZ compared to baseline sampling during the same timepoints the day prior.","Baseline sampling for 24 hours followed by post-KTZ sampling for 12 hours in participants with MACS.","ALL","18 Years","100 Years",false,{"inclusion":52,"exclusion":57,"raw_text":64},[53,54,55,56],"Age: Birth year within 5 years of that of the participant with MACS.","Sex","BMI (kg\u002Fm2) category: \\\u003C18.5 (underweight); 18.5-24.9 (normal weight); 25-29.9 (overweight); 30-34.9 (obesity class 1); 35-39.9 (obesity class 2); \\>=40 (obesity class 3).","For women: menopausal status as judged by absence of menses for one year and FSH\\>15 mIU\u002FmL.",[58,59,60,61,62,63],"Prolong QT when combined with ketoconazole (KTZ):","Cause toxicity from increased concentration due to KTZ-induced CYP3A4 inhibition:","methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine, methylergometrine, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin and colchicine.","Inhibit CYP3A4 and increase KTZ bioavailability:","Induce CYP3A4 and decrease KTZ bioavailability:","Isoniazid, rifabutin, rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine. 7. Inability to pause, for 24 hours, use of medication that reduces KTZ absorption: proton pump inhibitors (dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole) and H2 antagonists (cimetidine, famotidine, nizatidine).","* INCLUSION CRITERIA:\n\nTo be eligible to participate in this study, an individual must meet all of the following criteria:\n\n1. Aged 18 years or older.\n2. Stated willingness to comply with all study procedures and availability for the duration of the study.\n3. Agreement to adhere to Lifestyle Considerations throughout the study.\n\nA. Subjects with Mild Autonomous Cortisol Secretion (MACS):\n\n1. Co-enrollment in protocol 19DK0066.\n2. Abnormal low-dose overnight dexamethasone suppression test (morning serum cortisol \\>1.8 mcg\u002FdL following 1 mg oral dexamethasone between 2300-0000h the evening prior)\n3. One or more \\>=1 cm adrenal nodule(s) on one or both adrenal glands on CT or MRI\n4. One normal 24-hour urine free cortisol value (per the reference range of the assay used).\n5. One morning plasma ACTH value \\\u003C10 pg\u002FmL.\n\nB. Healthy volunteers:\n\n1. In good general health as evidenced by medical history and physical examination; and in a stable state of health without ongoing acute\u002Ftemporary illness per the clinical judgment of the investigator.\n2. Normal low-dose overnight dexamethasone suppression test (morning serum cortisol \\\u003C=1.8 mcg\u002FdL following 1 mg oral dexamethasone between 2300-0000h the evening prior)\n3. Matching a participant with MACS who has completed testing in regard to:\n\n   * Age: Birth year within 5 years of that of the participant with MACS.\n   * Sex\n   * BMI (kg\u002Fm2) category: \\\u003C18.5 (underweight); 18.5-24.9 (normal weight); 25-29.9 (overweight); 30-34.9 (obesity class 1); 35-39.9 (obesity class 2); \\>=40 (obesity class 3).\n   * For women: menopausal status as judged by absence of menses for one year and FSH\\>15 mIU\u002FmL.\n\nEXCLUSION CRITERIA:\n\nAn individual who meets any of the following criteria will be excluded from participation in this study:\n\n1. Inability to comply with all study procedures and visits.\n2. Inability of subject to understand or to sign a written informed consent document.\n3. Pregnancy or breastfeeding.\n4. 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.\n5. Use of medications within 2 weeks before inpatient admission that can block glucocorticoid production or action: ketoconazole (systemic), levoketoconazole, metyrapone, osilodrostat, mifepristone.\n6. 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.\n7. Anemia (hemoglobin \\\u003C13.7 g\u002FdL for males, \\\u003C11.2 g\u002FdL for females).\n8. Daily alcohol risk use (\\>2 standard drinks per day by self-report during screening visit).\n9. Severely uncontrolled diabetes mellitus (HbA1c \\>9.0%).\n10. Highly irregular sleep schedule in the week leading up to inpatient admission (e.g. shift work).\n11. Any contraindication to intravenous catheter use.\n12. Previous participation in this protocol.\n13. Any condition that in the opinion of the Investigator would jeopardize the participant s appropriate participation in this study.\n14. Any hematology or chemistry screening laboratory value drawn at screening that the Investigator deems clinically significant for exclusion.\n\nA. Subjects with Mild Autonomous Cortisol Secretion (MACS):\n\n1. Evidence of hyperaldosteronism, which must have been ruled out with serum aldosterone and plasma renin activity measurements if the participant has a history of hypertension or hypokalemia, per standard clinical care.\n2. Evidence of pheochromocytoma, which must have been ruled out with plasma or 24-hour urine metanephrines if an unenhanced adrenal nodule is \\>10 HU, per standard clinical care.\n3. Known allergy or hypersensitivity to ketoconazole.\n4. Significant liver disease or alanine aminotransferase (ALT) and\u002For aspartate aminotransferase (AST) \\>3xULN, and\u002For total bilirubin \\>1.5xULN during Screening.\n5. Prolonged QTc interval (\\>500 msec) on screening ECG.\n6. Use of medications in the 2 weeks before inpatient admission that can:\n\n   * Prolong QT when combined with ketoconazole (KTZ):\n\n     \\-- dofetilide, quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone, ranolazine.\n   * Cause toxicity from increased concentration due to KTZ-induced CYP3A4 inhibition:\n\n     --methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine, methylergometrine, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin and colchicine.\n   * Inhibit CYP3A4 and increase KTZ bioavailability:\n\n     \\-- ritonavir, darunavir, fosamprenavir.\n   * Induce CYP3A4 and decrease KTZ bioavailability:\n\n     * Isoniazid, rifabutin, rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine.\n7. Inability to pause, for 24 hours, use of medication that reduces KTZ absorption: proton pump inhibitors (dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole) and H2 antagonists (cimetidine, famotidine, nizatidine).\n\nInability to pause, for 3 hours, use of short-acting acid neutralizers that reduce KTZ absorption, e.g. aluminum hydroxide (acceptable if taken \\>=1 hour before or \\>=2 hours after KTZ).",[66,67],"ADULT","OLDER_ADULT",[69],{"facility":70,"status":8,"city":71,"state":72,"zip":73,"country":74,"contacts":75,"geoPoint":82},"National Institutes of Health Clinical Center","Bethesda","Maryland","20892","United States",[76],{"name":77,"role":78,"phone":79,"phoneExt":80,"email":81},"NIH Clinical Center Office of Patient Recruitment (OPR)","CONTACT","800-411-1222","TTY dial 711","ccopr@nih.gov",{"lat":83,"lon":84},38.98067,-77.10026,[86,90],{"name":87,"role":78,"phone":88,"email":89},"Raven N McGlotten, R.N.","(301) 827-0190","mcglottenr@mail.nih.gov",{"name":91,"role":78,"phone":92,"email":93},"Lynnette K Nieman, M.D.","(301) 496-8935","niemanl@mail.nih.gov",[95],{"name":91,"affiliation":13,"role":96},"PRINCIPAL_INVESTIGATOR",[98,102,105],{"pmid":99,"type":100,"citation":101},"37318239","BACKGROUND","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\u002Fejendo\u002Flvad066.",{"pmid":103,"type":100,"citation":104},"28911138","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\u002Fjc.2017-00823.",{"pmid":106,"type":100,"citation":107},"38981002","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\u002Fclinem\u002Fdgae468.",[109],{"label":110,"url":111},"NIH Clinical Center Detailed Web Page","https:\u002F\u002Fclinicalstudies.info.nih.gov\u002Fcgi\u002Fdetail.cgi?A_002658-DK.html",{"nct_id":4,"conditions":113,"biomarkers":115},[114,19],"Healthy Volunteers",[],{"nct_id":4,"found":117,"summary":118,"prompt_version":128},true,{"design":119,"status":120,"heading":121,"summary":122,"follow_up":123,"word_count":124,"commitments":125,"compensation":126,"drugs_mentioned":127},"This is an interventional study with a planned enrollment of 36 participants. It will compare cortisol rhythms in people with MACS to healthy volunteers.","completed","Ketoconazole for Mild Autonomous Cortisol Secretion","This study is looking at how ketoconazole, a medication that can lower cortisol levels, affects people with Mild Autonomous Cortisol Secretion (MACS). MACS is a condition where your body makes too much cortisol, a hormone that normally goes down at night. Researchers believe that higher nighttime cortisol in MACS may contribute to problems like high blood pressure. The study will compare the daily cortisol rhythm in people with MACS to healthy volunteers. It will also test if a single dose of ketoconazole can help restore a more normal daily cortisol pattern in people with MACS. You can join if you are 18 or older and have MACS, or if you are a healthy volunteer. The study aims to understand the differences in cortisol rhythms and how ketoconazole might help.","Cortisol levels will be measured during 24 hours at baseline and after receiving ketoconazole.",129,"If you have MACS, you will have a 2-night stay in the hospital, including having a thin tube (catheter) inserted into a vein for blood sampling.","Not stated in the trial record.",[33],"v2"]