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| ID | Type | Description | Link |
|---|---|---|---|
| 1K23DK142038-01A1 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
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The goal of this study is to learn how two treatments-adrenalectomy (surgical removal of an adrenal gland) and semaglutide (a medication used for weight management)-affect insulin resistance and cortisol regulation in adults with mild autonomous cortisol secretion (MACS). The study will also learn how these treatments impact body composition, blood pressure, cholesterol, inflammation, muscle strength, and quality of life.
The main questions the study aims to answer are:
Participants will:
This single-center, prospective, interventional study evaluates metabolic responses to surgical versus medical treatment in adults with mild autonomous cortisol secretion (MACS). The study includes:
The primary objective is to compare changes in insulin sensitivity measured by hyperinsulinemic-euglycemic clamp (M-value) from baseline to week 26. Secondary outcomes include cortisol dynamics, steroid profiling, cardiometabolic biomarkers, body composition, blood pressure, muscle strength, and patient-reported quality of life.
Semaglutide is administered within its FDA-approved indication for weight management; adrenalectomy is standard of care. No investigational drugs or devices are used, and no IND is required.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm 1: Adrenalectomy (MACS) | Active Comparator | Adults with mild autonomous cortisol secretion (MACS) who are clinically eligible for adrenalectomy undergo unilateral adrenalectomy as part of standard care. Participants complete all metabolic assessments before and after treatment. |
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| Arm 2: Semaglutide (MACS) | Active Comparator | Adults with MACS receive once-weekly semaglutide for 26 weeks using FDA-approved weight-management dosing. Participants undergo the same assessments as the surgery group. |
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| Arm 3: Semaglutide (Matched Controls) | Active Comparator | Matched adults without adrenal tumors receive semaglutide using the same dosing schedule as MACS participants. This arm allows comparison of semaglutide responses between individuals with and without cortisol dysregulation. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Intervention 1: Adrenalectomy | Procedure | Surgical removal of one adrenal gland performed by an endocrine surgeon following institutional standard-of-care practices. Includes postoperative monitoring for adrenal insufficiency and routine clinical follow-up. |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Insulin Sensitivity (M-value), mg/kg/min | Hyperinsulinemic-euglycemic clamp | Baseline to Week 26 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in fasting plasma glucose, mg/dL | Baseline to Week 26 | |
| Change in hemoglobin A1C, % | fasting blood test | Baseline to Week 26 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Oksana Hamidi, DO, MSCS | Contact | 214-645-6397 | oksana.hamidi@utsouthwestern.edu |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Texas Southwestern Medical Center | Recruiting | Dallas | Texas | 75390 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33593680 | Background | Yozamp N, Vaidya A. Assessment of mild autonomous cortisol secretion among incidentally discovered adrenal masses. Best Pract Res Clin Endocrinol Metab. 2021 Jan;35(1):101491. doi: 10.1016/j.beem.2021.101491. Epub 2021 Feb 6. | |
| 34260734 | Background | Bancos I, Prete A. Approach to the Patient With Adrenal Incidentaloma. J Clin Endocrinol Metab. 2021 Oct 21;106(11):3331-3353. doi: 10.1210/clinem/dgab512. |
| Label | URL |
|---|---|
| Related Info | View source |
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De-identified individual participant data (IPD) from the IMPACT-MACS study will be shared in accordance with NIH Data Management and Sharing Policy. Shared IPD will include primary and secondary outcome data such as insulin sensitivity (M-value), hormonal and cardiometabolic biomarkers, body composition measures, ambulatory blood pressure data, physical function tests, patient-reported outcomes, and adverse events. No genetic data will be shared. IPD will become available at the time of primary publication or by the end of the award period, expected by Q2 2030. Data will be accessible to qualified investigators for biomedical research through the NIDDK Central Repository, with requests managed under a Data Use Agreement. IRB approval or exemption is required, and data may not be used for ancestry or non-biomedical research.
Start Date:
Individual participant data (IPD) and supporting documents will become available at the time of primary results publication or by the end of the study award period, whichever occurs first. Availability is expected to begin by Q2 2030.
End Date:
IPD will remain available indefinitely through the NIDDK Central Repository, as long as the repository remains active and able to distribute the data under its Data Use Agreement procedures.
Individual participant data (IPD) and supporting materials will be available to qualified investigators conducting health-related, medical, or biomedical research. Requestors must submit a research proposal and obtain institutional IRB approval or exemption before access is granted.
Data will be shared in de-identified form through the NIDDK Central Repository, which manages requests under its governed Data Use Agreement (DUA) process. Approved investigators will be able to access the de-identified IPD, study protocol, and data dictionary through the repository's secure system. No identifiable information or genetic data will be shared.
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This study includes two coordinated components. First, a randomized controlled trial in adults with mild autonomous cortisol secretion (MACS) who are eligible for adrenalectomy. Participants are randomized 1:1 to adrenalectomy or semaglutide for 26 weeks, stratified by post-DST cortisol and sex. This evaluates surgical versus medical effects on insulin sensitivity and cortisol regulation.
Second, a matched case-control comparison in adults without adrenal tumors who receive semaglutide using the same schedule. Controls are matched 1:1 by age, sex, BMI, and diabetes status to isolate disease-specific metabolic responses.
Both components follow identical assessments in an open-label, parallel-assignment design without crossover, enabling evaluation of treatment modality in MACS and differential response to semaglutide.
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| Intervention 2: Semaglutide | Drug | Once-weekly subcutaneous semaglutide administered according to FDA-approved titration for chronic weight management (0.25 mg to 2.4 mg weekly as tolerated). Participants receive training on injection technique, dose escalation, and safety monitoring. |
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| Change in fasting insulin, µU/mL |
Fasting blood test |
| Baseline to Week 26 |
| Change in glucagon, pg/mL | Fasting blood test | Baseline to Week 26 |
| Change in c-peptide, nmol/L | Fasting blood test | Baseline to Week 26 |
| Change in IGF-1, ng/mL | Fasting blood glucose | Baseline to Week 26 |
| Change in IGF-II, ng/mL | Fasting blood test | Baseline to Week 26 |
| Change in IGFBP-1, ng/mL | Fasting blood test | Baseline to Week 26 |
| Change in leptin, ng/mL | Fasting blood glucose | Baseline to Week 26 |
| Change in adiponectin, μg/mL | Fasting blood test | Baseline to Week 26 |
| % of patients with normal dexamethasone suppression test, % | 1-mg dexamethasone suppression test | Baseline to Week 26 |
| Change in steroid profile, ng/24h | 25-steroid profiling in the 24-hour urine, reported as aggregate | Baseline to Week 26 |
| Mean change in systolic BP, mmHg | 24-hour Ambulatory BP | Baseline to Week 26 |
| Mean change in diastolic BP, mmHg | 24-hour Ambulatory BP | Baseline to Week 26 |
| Change in cholesterol, mg/dL | Fasting blood test | Baseline to Week 26 |
| Change in Free Fatty Acids, mmol/L | Fasting blood test | Baseline to Week 26Baseline to Week 26 |
| Change in C-reactive protein, pg/mL | Fasting blood test | Baseline to Week 26 |
| Change in TNF-alpha, pg/mL | Fasting blood glucose | Baseline to Week 26 |
| Change in Interleukin-1, pg/mL | Fasting blood test | Baseline to Week 26 |
| Change in Interleukin-6, pg/mL | Fasting blood test | Baseline to Week 26 |
| Change in body weight, kg | electronic scale | Baseline to Week 26 |
| Change in BMI, kg/m2 | calculated from weight and height | Baseline to Week 26 |
| Change in waist circumference, cm | Tape measure | Baseline to Week 26 |
| Change in fat area, cm2 | Limited unenhanced CT | Baseline to Week 26 |
| Change in muscle area, cm2 | Limited unenhanced CT | Baseline to Week 26 |
| Change in bone mineral density, mg/cm³ | Limited unenhanced CT | Baseline to Week 26 |
| Change in chair rise test, stands/30s | Time test, number of stands from chair in 30 seconds | Baseline to Week 26 |
| Change in Hand Grip Strength, kg | Dynamometer | Baseline to Week 26 |
| Change in overall quality of life, score | PROMIS Global Health Questionnaire, domain-specific scales; The Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health v1.2 Questionnaire assesses overall health-related quality of life across multiple domains, including physical health, mental health, social functioning, fatigue, and general well-being. It yields two standardized T-score summary measures (Global Physical Health and Global Mental Health). Score Range: T-scores typically range from 20 to 80. Interpretation: Higher T-scores indicate better health-related quality of life. Assessment Method: Self-report questionnaire; estimated completion time 2-5 minutes. | Baseline to Week 26 |
| Change in disease-specific QoL, score | Cushing Quality of Life Questionnaire (CushingQoL) Description: The Cushing Quality of Life Questionnaire (CushingQoL) is a disease-specific tool assessing health-related quality of life in individuals with hypercortisolism. It contains 12 items scored on a 5-point Likert scale. Score Range: 12 (minimum) to 60 (maximum). Interpretation: Higher scores indicate better quality of life; lower scores indicate poorer quality of life. Domains: Sleep disturbances, mood, physical appearance, social interaction, health concerns. Assessment Method: Self-administered; estimated completion time ~5 minutes. | Baseline to Week 26 |
| Change in mood, score | PROMIS Depression Short Form & PROMIS Anxiety Short Form Description: The PROMIS Depression Short Form and PROMIS Anxiety Short Form measure depressive and anxiety symptoms over the past seven days, assessing emotional distress, negative affect, and somatic symptoms. Responses are on a 5-point Likert scale ("Never" to "Always"), converted to standardized T-scores. Score Range: T-scores typically range from 20 to 80. Interpretation: Higher scores indicate worse depressive or anxiety symptoms. Assessment Method: Self-report questionnaires; estimated completion time 2-4 minutes each. | Baseline to Week 26 |
| Change in cognition, seconds | Trail Making Test - Part A and Part B (TMT-A and TMT-B) Description: The Trail Making Test Parts A and B assess visual attention, processing speed, cognitive flexibility, and executive function. Part A requires sequential connection of numbers; Part B requires alternating between numbers and letters. Score Range: 0 to 300 seconds (maximum test time). Interpretation: Higher (longer) completion times indicate worse cognitive performance. Assessment Method: Performance-based timed test administered by study personnel; expected duration ~5 minutes. | Baseline to Week 26 |
| Change in sleep, score | PROMIS Sleep Disturbance Short Form Description: The PROMIS Sleep Disturbance Short Form evaluates sleep quality, difficulty initiating and maintaining sleep, and overall sleep problems over the past seven days. Scores are converted into standardized T-scores. Score Range: T-scores typically range from 20 to 80. Interpretation: Higher scores indicate worse sleep disturbance. Assessment Method: Self-administered; estimated completion time 2-4 minutes. | Baseline to Week 26 |
| Change in frailty, score | FRAIL Scale (Fatigue, Resistance, Ambulation, Illnesses, Loss of Weight) Description: The FRAIL Scale is a validated screening instrument assessing functional decline and physiological frailty. It consists of five yes/no items: fatigue, resistance, ambulation, illnesses, and weight loss. Score Range: 0 (minimum) to 5 (maximum). Interpretation: Higher scores indicate greater frailty. Frailty Categories: 0: Robust 1-2: Pre-frail 3-5: Frail Assessment Method: Administered by study personnel; duration ~1 minute. | Baseline to Week 26 |
| Change in eating behavior, score | Eating Behavior and Appetite Questionnaire (EBAQ) Description: The Eating Behavior and Appetite Questionnaire (EBAQ) evaluates hunger, satiety, food cravings, and changes in appetite and eating behavior. It generates domain-specific and total scores. Score Range: Varies by version; treated as continuous scores with defined minimum and maximum values per subscale. Interpretation: Higher scores indicate greater appetite or more pronounced eating-behavior disturbances. Assessment Method: Self-administered; estimated completion time 3-5 minutes. | Baseline to Week 26 |
| Adverse Events and Serious Adverse Events | Baseline through Week 30 |
| 34978855 | Background | Prete A, Subramanian A, Bancos I, Chortis V, Tsagarakis S, Lang K, Macech M, Delivanis DA, Pupovac ID, Reimondo G, Marina LV, Deutschbein T, Balomenaki M, O'Reilly MW, Gilligan LC, Jenkinson C, Bednarczuk T, Zhang CD, Dusek T, Diamantopoulos A, Asia M, Kondracka A, Li D, Masjkur JR, Quinkler M, Ueland GA, Dennedy MC, Beuschlein F, Tabarin A, Fassnacht M, Ivovic M, Terzolo M, Kastelan D, Young WF Jr, Manolopoulos KN, Ambroziak U, Vassiliadi DA, Taylor AE, Sitch AJ, Nirantharakumar K, Arlt W; ENSAT EURINE-ACT Investigators*; ENSAT EURINE-ACT Investigators. Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study. Ann Intern Med. 2022 Mar;175(3):325-334. doi: 10.7326/M21-1737. Epub 2022 Jan 4. |
| 33065059 | Background | Ebbehoj A, Li D, Kaur RJ, Zhang C, Singh S, Li T, Atkinson E, Achenbach S, Khosla S, Arlt W, Young WF, Rocca WA, Bancos I. Epidemiology of adrenal tumours in Olmsted County, Minnesota, USA: a population-based cohort study. Lancet Diabetes Endocrinol. 2020 Nov;8(11):894-902. doi: 10.1016/S2213-8587(20)30314-4. |
| 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/ejendo/lvad066. |
| 20588242 | Background | Kolanska K, Owecki M, Nikisch E, Sowinski J. High prevalence of obesity in patients with non-functioning adrenal incidentalomas. Neuro Endocrinol Lett. 2010;31(3):418-22. |
| 31900474 | Background | Reimondo G, Castellano E, Grosso M, Priotto R, Puglisi S, Pia A, Pellegrino M, Borretta G, Terzolo M. Adrenal Incidentalomas are Tied to Increased Risk of Diabetes: Findings from a Prospective Study. J Clin Endocrinol Metab. 2020 Apr 1;105(4):dgz284. doi: 10.1210/clinem/dgz284. |
| 16699294 | Background | Bovio S, Cataldi A, Reimondo G, Sperone P, Novello S, Berruti A, Borasio P, Fava C, Dogliotti L, Scagliotti GV, Angeli A, Terzolo M. Prevalence of adrenal incidentaloma in a contemporary computerized tomography series. J Endocrinol Invest. 2006 Apr;29(4):298-302. doi: 10.1007/BF03344099. |
| ID | Term |
|---|---|
| C538238 | Adrenal incidentaloma |
| D000182 | ACTH Syndrome, Ectopic |
| D003480 | Cushing Syndrome |
| D015431 | Weight Loss |
| D007333 | Insulin Resistance |
| ID | Term |
|---|---|
| D009384 | Paraneoplastic Endocrine Syndromes |
| D010257 | Paraneoplastic Syndromes |
| D009369 | Neoplasms |
| D000308 | Adrenocortical Hyperfunction |
| D000307 | Adrenal Gland Diseases |
| D004700 | Endocrine System Diseases |
| D001836 | Body Weight Changes |
| D001835 | Body Weight |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006946 | Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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