Adrenal IncidentalomasPhase 4NCT06801249
Effect of Metyrapone on Cardiovascular Risk Factors in Patients With Adrenal Incidentalomas and Cushing's Syndrome
A Phase 4 study testing Metarapone and Standardized antihypertensive therapy in people with Adrenal Incidentalomas and Cushing Syndrome, run by IRCCS Azienda Ospedaliero-Universitaria di Bologna at 3 sites in Italy.
Trial summary
Drug interventional, controlled, randomized open-label, parallel-group, multicenter study in patients with bilateral adrenal incidentalomas associated with subclinical Cushing's syndrome Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Adrenal Incidentalomas, Cushing Syndrome
- What is being tested?
- Metarapone and Standardized antihypertensive therapy
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 50 participants
- Where
- 3 sitesItaly
- Study dates
- 23 Feb 2021to 17 Feb 2025
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Unilateral or bilateral adrenal nodules with benign features associated with thickening of the adrenal arms >5 mm on abdominal CT scan
- SCS (detected 2 times in the 6 months before run-in) defined by the absence of catabolic signs of Cushing's syndrome in association with any of these 3 conditions:
- Cortisol levels after dexamethasone 1 mg test >50 nmol/L associated with baseline ACTH <10 pg/mL
- Cortisol levels after dexamethasone 1 mg test >50 nmol/L associated with increased nocturnal (11 pm) salivary cortisol
- Cortisol levels after dexamethasone 1 mg test >138 nmol/L
- Hypertension (BP ≥140/90 mmHg and/or ongoing antihypertensive treatment)
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- Patients who cannot undergo surgery
- Acquisition of informed consent.
- BP >100/60 mmHg and <130/85 mmHg on antihypertensive therapy (lowest effective dose) within 6-10 months after enrollment.
Who cannot join
- Body mass index ≥40 kg/m2
- Pregnant or lactating women; diagnosis of pregnancy will be made by serum β-HCG assay
- Women of childbearing age using contraceptive measures other than barrier contraception. Barrier contraceptive measures are: o Male or female condom with or without spermicide o Cervical cup, diaphragm or sponges with spermicide o Combination of male condom and cervical cup, diaphragm or sponges with spermicide (dual barrier methods)
- Treatment with steroids in the last year before enrollment
- Taking medications known to interfere with Metirapone
- Known or suspected hypersensitivity to the drug or drug class under study
Show all 11Show fewer
- Patients with serious clinical conditions that, in the opinion of the Investigator, contraindicate the patient's participation in the study
- Patients with primary corticosurrenal insufficiency, impaired adrenal secretion, and severe hypopituitarism
- Patients with impaired liver function
- Patients with untreated hypothyroidism or being treated with drugs that have an action on the hypothalamic-pituitary-adrenal axis
- Patients with hypersensitivity to the active ingredient or any of the excipients listed in section 6.1 of the RCP - Metirapone.
Trial locations and contacts
3 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Italy3 sites, 3 recruiting
- Recruiting
IRCCS Azienda Ospedaliero-Universitaria di Bologna
Bologna, 40138
Guido Di Dalmazi, MD, +390512143009, guido.didalmazi@unibo.it
Guido Di Dalmazi, MD
- Recruiting
Azienda Ospedaliera Universitaria Federico II
Naples, 80131
Chiara Simeoli, MD, +390817462510, chiara.simeoli@unina.it
Chiara Simeoli, MD
- Recruiting
Azienda Ospedale-Università Padova
Padova, 35128
Mattia Barbot, MD, +390498213000, mattia.barbot@unipd.it
Mattia Barbot, MD
About this study
Official title: "Effect of Metyrapone on Cardiovascular Risk Factors in Patients With Adrenal Incidentalomas and Subclinical/Mild Cushing's Syndrome
Drug interventional, controlled, randomized open-label, parallel-group, multicenter study in patients with bilateral adrenal incidentalomas associated with subclinical Cushing's syndrome
Read the detailed description
Drug interventional, controlled, randomized open-label, parallel-group, multicenter (3 centers in total), interventional study in patients with bilateral adrenal incidentalomas associated with SCS.
The study has 3 phases: run-in (phase 1), randomization (phase 2), and interventional phase (phase 3).
Phase 1. During run-in, patients will receive standardized antihypertensive therapy, as provided in the normal course of care and in accordance with current European guidelines. Four classes of antihypertensives will be used: Angiotensin-Converting Enzyme inhibitors (ACEi) or angiotesnine receptor antagonists (ARBs), calcium channel blockers, thiazide diuretics, and beta-blockers with vasodilator properties (Carvedilol or Nebivolol). Treatment will be chosen according to the recommendations of European guidelines and the patient's clinical condition. Patients will be evaluated monthly to check BP and to identify the lowest effective dose of antihypertensive to maintain BP <130/85 mmHg. BP will be measured during medical visits. Home PA monitoring will also be performed during the 7 days before each medical visit. Echocardiogram, electrocardiogram, 24-hour Holter PA, carotid echodoppler, albumin/creatinine ratio, and indices of glucose and lipid metabolism will also be performed, according to the normal procedures of routine clinical practice performed in patients with this problem. The run-in period will be prolonged until pressor values are stabilized (BP >100/60 mmHg and <130/85 mmHg, under minimal effective dose of antihypertensive therapy), with a minimum duration of 2 months and a maximum of 6 months. If stabilization of blood pressure values (according to the criteria outlined above) is not obtained by the sixth month after enrollment, the run-in period may be extended to a maximum of 10 months. If stabilization of the pressor values (according to the criteria outlined above) is not obtained by that time, the patient will be excluded from the study.
Phase 2. After run-in, patients will be randomized (1:1) to treatment with Metirapone (Group A) or observation (Group B) by computer-generated random sequence.
Phase 3. During the interventional phase, patients (Group A and Group B) will be seen every 4 weeks (+/- 7 days). In addition, patients receiving Metirapone (Group A) will be evaluated every 7 days (+/- 2 days) during the first month to titrate Metirapone according to cortisol and cortisone values, monitor electrolytes, and analyze potential side effects. In some patients, titration of Metirapone up to the maximum tolerated dose (and in any case no more than 750 mg/day) may be prolonged beyond 4 weeks. In this case, weekly visits will continue until the maximum tolerated dose is reached (and in any case no more than 750 mg/day) for a period of up to 4 months, after which the achieved dose of Metirapone will be maintained. Patients assigned to Metirapone treatment will not be allowed to take Paracetamol, Phenytoin and estrogen during the interventional phase. Ambulatory and home PA will be assessed monthly to optimize antihypertensive treatment to maintain PA values <130/85 mmHg. Hypotension (BP <100/60 mmHg) will be treated with modification of antihypertensive therapy. At the end of the interventional phase, cardiovascular and metabolic reevaluation will be performed.
Blood samples for serum and plasma collection will be collected after fasting from the previous evening, before randomization and at the end of the study. Saliva samples will be collected during the entire day before blood collection at 10 predetermined times. Blood samples will be collected monthly in patients treated with Metirapone. Serum and saliva will be used for steroid profiles by LC-MS/MS. The following steroids will be measured: cortisol, 21-desoxycortisol, 11-DF, 17-hydroxyprogesterone (17OHP), Delta4-androstenedione, DHEA, testosterone, progesterone, cortisone, DOC and corticosterone. Cortisol, cortisone, 17OHP, Delta4-androstenedione, DHEA and testosterone will be measured in saliva. Waist circumference and body mass index will be assessed at each visit.
Within 6 months after completion of the study, an abdominal CT scan will be repeated. This investigation will be performed as part of the patients' normal course of care, which involves performing follow-up abdomen CT scans periodically (every 18-36 months).
- Conditions
- Adrenal Incidentalomas, Cushing Syndrome
- Being tested
- Metarapone, Standardized antihypertensive therapy
- Medical subject headings
- Adrenal incidentaloma, Cushing Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetaraponeDrug
Metirapone is an inhibitor of the enzyme 11-β-adrenal hydroxylase, which is deputed to catalyze the conversion of 11-desoxycortisol (11-S) to cortisol and 11-deoxycorticosterone (DOC) to corticosterone.
Standardized antihypertensive therapyDrug
Standardized antihypertensive therapy, as provided in the normal course of care and in accordance with current European guidelines.
| Study group | Role | What they receive |
|---|---|---|
| Group A | Experimental | Metirapone in addition to standardized antihypertensive therapy, as provided in the normal course of care and in accordance with current European guidelines. Metirapone will be provided in 250-mg capsules, in the form of commercially available packs. In Group A, patients will receive Metirapone at the initial dosage of 250 mg, 1 capsule per day. Dosage may be adjusted according to clinical response and tolerability, up to a maximum of 750 mg (3 capsules per day). The drug should be taken after a meal. The drug should be stored at room temperature. The expected duration of study treatment is 12 months, after which patients will discontinue Metirapone and continue with therapies as per the normal course of care. Receives: Drug: Metarapone |
| Group B | Active comparator | Standardized antihypertensive therapy, as provided in the normal course of care and in accordance with current European guidelines. Receives: Drug: Standardized antihypertensive therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Number and/or Dosage of Antihypertensive Drugs at 12 Months with Metirapone Treatment, Maintaining Target Blood Pressure Range
This measure will assess any change in the number or dosage of antihypertensive medications required after 12 months of treatment with Metirapone, while maintaining the target blood pressure range (BP >100/60 mmHg and <130/85 mmHg).
Measured: through study completion, an average of 2 months
Secondary outcomes (2)
"Concentration of Key Biomarkers in Plasma for Monitoring Efficacy of Metirapone Therapy
This outcome measure evaluates the efficacy of Metirapone therapy by quantifying the concentration of specific biomarkers in plasma.
Each biomarker will be measured at predefined time points during the study to monitor changes over time and assess therapeutic response. The values for each biomarker will be reported separately to ensure clarity in units of measure and clinical significance.
Measured: through study completion, an average of 2 months
"Assessment of Changes in Adrenal Gland Morphology Following Metirapone Therapy
This outcome measure evaluates morphological changes in the adrenal glands after treatment with Metirapone. Changes will be summarized as mean differences in adrenal gland size and percentage of participants showing notable structural changes.
Measured: through study completion, an average of 2 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Jan 2025
- Study start23 Feb 2021
- Primary completion30 Nov 2024
- Study completion17 Feb 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Adrenal IncidentalomasStudies of the same condition, open and under way.
- More trials run by IRCCS Azienda Ospedaliero-Universitaria di BolognaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Guido Di Dalmazi, MD, Principal investigator, IRCCS Azienda Ospedaliero-Universitaria di Bologna
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06801249
- Sponsor's protocol ID
- GR-MET-19
- Status last verified
- Dec 2024
- First submitted
- 1 Dec 2024
- Last updated
- 30 Jan 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 30 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- "Effect of Metyrapone on Cardiovascular Risk Factors in Patients With Adrenal Incidentalomas and Subclinical/Mild Cushing's Syndrome
- ClinicalTrials.gov ID
- NCT06801249
- Acronym / sponsor ID
- GR-MET-19
- Conditions
- Adrenal Incidentalomas, Cushing Syndrome
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- IRCCS Azienda Ospedaliero-Universitaria di BolognaUniversity, hospital or other
- Study start
- 23 Feb 2021 (actual)
- Primary completion
- 30 Nov 2024 (actual)
- Study completion
- 17 Feb 2025 (estimated)
- First posted
- 30 Jan 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Drug interventional, controlled, randomized open-label, parallel-group, multicenter study in patients with bilateral adrenal incidentalomas associated with subclinical Cushing's syndrome
Detailed description
Drug interventional, controlled, randomized open-label, parallel-group, multicenter (3 centers in total), interventional study in patients with bilateral adrenal incidentalomas associated with SCS.
The study has 3 phases: run-in (phase 1), randomization (phase 2), and interventional phase (phase 3).
Phase 1. During run-in, patients will receive standardized antihypertensive therapy, as provided in the normal course of care and in accordance with current European guidelines. Four classes of antihypertensives will be used: Angiotensin-Converting Enzyme inhibitors (ACEi) or angiotesnine receptor antagonists (ARBs), calcium channel blockers, thiazide diuretics, and beta-blockers with vasodilator properties (Carvedilol or Nebivolol). Treatment will be chosen according to the recommendations of European guidelines and the patient's clinical condition. Patients will be evaluated monthly to check BP and to identify the lowest effective dose of antihypertensive to maintain BP <130/85 mmHg. BP will be measured during medical visits. Home PA monitoring will also be performed during the 7 days before each medical visit. Echocardiogram, electrocardiogram, 24-hour Holter PA, carotid echodoppler, albumin/creatinine ratio, and indices of glucose and lipid metabolism will also be performed, according to the normal procedures of routine clinical practice performed in patients with this problem. The run-in period will be prolonged until pressor values are stabilized (BP >100/60 mmHg and <130/85 mmHg, under minimal effective dose of antihypertensive therapy), with a minimum duration of 2 months and a maximum of 6 months. If stabilization of blood pressure values (according to the criteria outlined above) is not obtained by the sixth month after enrollment, the run-in period may be extended to a maximum of 10 months. If stabilization of the pressor values (according to the criteria outlined above) is not obtained by that time, the patient will be excluded from the study.
Phase 2. After run-in, patients will be randomized (1:1) to treatment with Metirapone (Group A) or observation (Group B) by computer-generated random sequence.
Phase 3. During the interventional phase, patients (Group A and Group B) will be seen every 4 weeks (+/- 7 days). In addition, patients receiving Metirapone (Group A) will be evaluated every 7 days (+/- 2 days) during the first month to titrate Metirapone according to cortisol and cortisone values, monitor electrolytes, and analyze potential side effects. In some patients, titration of Metirapone up to the maximum tolerated dose (and in any case no more than 750 mg/day) may be prolonged beyond 4 weeks. In this case, weekly visits will continue until the maximum tolerated dose is reached (and in any case no more than 750 mg/day) for a period of up to 4 months, after which the achieved dose of Metirapone will be maintained. Patients assigned to Metirapone treatment will not be allowed to take Paracetamol, Phenytoin and estrogen during the interventional phase. Ambulatory and home PA will be assessed monthly to optimize antihypertensive treatment to maintain PA values <130/85 mmHg. Hypotension (BP <100/60 mmHg) will be treated with modification of antihypertensive therapy. At the end of the interventional phase, cardiovascular and metabolic reevaluation will be performed.
Blood samples for serum and plasma collection will be collected after fasting from the previous evening, before randomization and at the end of the study. Saliva samples will be collected during the entire day before blood collection at 10 predetermined times. Blood samples will be collected monthly in patients treated with Metirapone. Serum and saliva will be used for steroid profiles by LC-MS/MS. The following steroids will be measured: cortisol, 21-desoxycortisol, 11-DF, 17-hydroxyprogesterone (17OHP), Delta4-androstenedione, DHEA, testosterone, progesterone, cortisone, DOC and corticosterone. Cortisol, cortisone, 17OHP, Delta4-androstenedione, DHEA and testosterone will be measured in saliva. Waist circumference and body mass index will be assessed at each visit.
Within 6 months after completion of the study, an abdominal CT scan will be repeated. This investigation will be performed as part of the patients' normal course of care, which involves performing follow-up abdomen CT scans periodically (every 18-36 months).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Group A | Experimental | Drug: MetaraponeMetirapone in addition to standardized antihypertensive therapy, as provided in the normal course of care and in accordance with current European guidelines. Metirapone will be provided in 250-mg capsules, in the form of commercially available packs. In Group A, patients will receive Metirapone at the initial dosage of 250 mg, 1 capsule per day. Dosage may be adjusted according to clinical response and tolerability, up to a maximum of 750 mg (3 capsules per day). The drug should be taken after a meal. The drug should be stored at room temperature. The expected duration of study treatment is 12 months, after which patients will discontinue Metirapone and continue with therapies as per the normal course of care. |
| Group B | Active comparator | Drug: Standardized antihypertensive therapyStandardized antihypertensive therapy, as provided in the normal course of care and in accordance with current European guidelines. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Unilateral or bilateral adrenal nodules with benign features associated with thickening of the adrenal arms >5 mm on abdominal CT scan
- SCS (detected 2 times in the 6 months before run-in) defined by the absence of catabolic signs of Cushing's syndrome in association with any of these 3 conditions:
- Hypertension (BP ≥140/90 mmHg and/or ongoing antihypertensive treatment)
- Patients who cannot undergo surgery
- Acquisition of informed consent.
Key exclusion criteria (11 listed)
- Body mass index ≥40 kg/m2
- Pregnant or lactating women; diagnosis of pregnancy will be made by serum β-HCG assay
- Women of childbearing age using contraceptive measures other than barrier contraception. Barrier contraceptive measures are: o Male or female condom with or without spermicide o Cervical cup, diaphragm or sponges with spermicide o Combination of male condom and cervical cup, diaphragm or sponges with spermicide (dual barrier methods)
- Treatment with steroids in the last year before enrollment
- Taking medications known to interfere with Metirapone
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MetaraponeMetirapone is an inhibitor of the enzyme 11-β-adrenal hydroxylase, which is deputed to catalyze the conversion of 11-desoxycortisol (11-S) to cortisol and 11-deoxycorticosterone (DOC) to corticosterone. | Drug | Group A |
| Standardized antihypertensive therapyStandardized antihypertensive therapy, as provided in the normal course of care and in accordance with current European guidelines. | Drug | Group B |
Primary outcome
Change in Number and/or Dosage of Antihypertensive Drugs at 12 Months with Metirapone Treatment, Maintaining Target Blood Pressure Range
Time frame: through study completion, an average of 2 months
This measure will assess any change in the number or dosage of antihypertensive medications required after 12 months of treatment with Metirapone, while maintaining the target blood pressure range (BP >100/60 mmHg and <130/85 mmHg).
2 secondary outcomes
"Concentration of Key Biomarkers in Plasma for Monitoring Efficacy of Metirapone Therapy
Time frame: through study completion, an average of 2 months
"Assessment of Changes in Adrenal Gland Morphology Following Metirapone Therapy
Time frame: through study completion, an average of 2 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Jan 2025.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Guido Di Dalmazi, MD principal investigator
IRCCS Azienda Ospedaliero-Universitaria di Bologna
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Metarapone and Standardized antihypertensive therapy in people with Adrenal Incidentalomas and Cushing Syndrome, run by IRCCS Azienda Ospedaliero-Universitaria di Bologna at 3 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 30 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Guido Di Dalmazi, MD (+390512143009, guido.didalmazi@unibo.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Number and/or Dosage of Antihypertensive Drugs at 12 Months with Metirapone Treatment, Maintaining Target Blood Pressure Range (time frame: through study completion, an average of 2 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jan 2025.