Neoplasms

All Conditions

Gland and Hormone Related Diseases

Behaviors and Mental Disorders

Rare Diseases

Adenoma

Hyperaldosteronism

Adrenocortical Adenoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adrenocortical Hyperfunction

Adrenal Gland Diseases

Endocrine System Diseases

Adrenal Cortex Neoplasms

Adrenal Gland Neoplasms

Endocrine Gland Neoplasms

Adrenal Cortex Diseases

Quality of Life

Adenoma of the Adrenal Gland

Hyperadrenalism

Natriuretic Agents

All Drugs and Chemicals

Antihypertensive Agents

Spironolactone

Eplerenone

Mineralocorticoid Receptor Antagonists

Mineralocorticoids

Hormones

Hormone Antagonists

Diuretics

Diuretics, Potassium Sparing

Minimally invasive surgery is performed via the lateral transperitoneal approach or the posterior retroperitoneal approach, with or without robotic assistance, according to the surgeon's preference.

Unilateral adrenalectomy

The initial dose of eplerenone is 25 mg twice daily. The dose will be increased by 50 mg every fourth week until systolic blood pressure of 140 mmHg and diastolic blood pressure of 90 mmHg or lower has been reached and biochemical control (plasma renin above the middle of the reference range, i.e \> \~20 mIU/L) is attained and/or hyperkalemia develops. The maximal dose of eplerenone is 300 mg twice daily.

Medical treatment (eplerenone)

Oskar Ragnarsson, MD

Oskar Ragnarsson, MD, PHD

Andreas Muth, MD,PHD

Gudmundur Johannsson, Professor

Oskar Ragnarsson, MD,PHD

Penelope Trimpou, MD,PHD

Eleftheria Gkaniatsa

Cristina Volpe, MD,PHD

Per Dahlqvist, MD, PHD

This is a prospective randomized controlled trial where quality of life and the effectiveness of treatment will be evaluated in 80 patients with confirmed unilateral primary aldosteronism ,randomly assigned to be either treated surgically with unilateral adrenalectomy or to receive medical treatment with eplerenone.

Background

Primary aldosteronism (PA) is caused by hypersecretion of the adrenal hormone aldosterone and is the most common cause of secondary hypertension . The estimated prevalence of PA is 5-13% in the hypertensive population.

In half of the cases, PA is caused by unilateral hypersecretion of aldosterone, most commonly from an aldosterone producing adenoma. Overproduction from both adrenals is seen in the other half, usually caused by bilateral idiopathic hyperplasia. Unilateral adrenalectomy is considered to be the treatment of choice for unilateral PA and mineralocorticoid receptor antagonists (MRAs, i.e. spironolactone or eplerenone) for bilateral PA . Untreated PA is associated with a greatly increased risk for several comorbidities, especially cardiovascular diseases and renal failure, as well as death.

Studies comparing surgical and medical treatment for PA are scarce. Nevertheless, a recent meta-analysis indicated that cardiovascular outcome is better in surgically than medically treated patients . In addition, quality of life seems to improve more after surgery, and the need for antihypertensive medications, and overall health care consumption,seems to be lower following surgery . However, suboptimal dosing of MRA is common in medically treated patients with PA, which makes a fair comparison between surgically treated patients difficult.

To identify candidates for surgical treatment, adrenal venous sampling (AVS) is necessary to confirm unilateral disease . However, AVS is a technically demanding procedure, with a mean success rate in non-specialized centres of only 32% . This, and the fact that AVS is not widely available, suggests that a substantial number of patients with unilateral PA are never identified and thereby not considered for surgical treatment .

Rationale, aim and hypotheses

Given the above, medical treatment with MRA has become the de-facto standard treatment for a large number of patients with unilateral PA, despite observational studies indicating that surgical treatment is more effective in terms of improving cardiovascular outcome, quality of life and drug load, and that it is more cost-effective.

In this context the investigators have designed a prospective randomized controlled trial where we aim to compare medical and surgical treatment for unilateral PA. The investigator´s main hypothesis is that surgical treatment (adrenalectomy; standard treatment) results in better QoL at one year of follow-up compared to medical treatment with eplerenone (intervention) in patients with unilateral PA.

The secondary hypotheses are: Surgical treatment is more effective than medical treatment for unilateral PA regarding a) antihypertensive effect, b) improvement in cardiometabolic risk profile, and c) health care consumption (cost-efficiency).

Study Design

The UPA-MEST (Unilateral Primary Aldosteronism - MinEralocorticoid antagonists versusSurgical Treatment) study is an unblinded, prospective, randomized, controlled trial. Eighty patients will be randomized to be either treated surgically with unilateral adrenalectomy or to receive medical treatment with eplerenone. After 12 months of follow-up, medically treated patients will be able to either continue with medical treatment or to be operated with unilateral adrenalectomy.

Participants

80 patients with confirmed unilateral PA, aged 18-70 will participate.

Inclusion and randomization

After unilateral PA has been confirmed, when the patients will be informed about the disease, the patients will be informed orally, and with written information about the study, and asked to participate.

Randomization will be done with random permutated blocks, generated by using a freely available software (www.randomizer.org).

Treatments

Surgical treatment: Minimally invasive surgery is performed via the lateral transperitoneal approach or the posterior retroperitoneal approach, with or without robotic assistance, according to the surgeon's preference. Potassium substitution \> 7.5 g will be reduced by 50% on postoperative day (POD) 1, and discontinued on POD 2. Potassium substitution \< 7.5 g will be discontinued on POD 1. Preoperative antihypertensive medication will be titrated to a goal blood pressure of 140/90 mmHg (14) or lower. Immunohistochemical method, using monoclonal antibodies identifying the enzymes CYP11B1 and B2, will be used to differentiate between adenoma and hyperplasia.

Medical treatment: The initial dose of eplerenone is 25 mg twice daily. The dose will be increased by 50 mg every fourth week until systolic blood pressure of 140 mmHg and diastolic blood pressure of 90 mmHg or lower has been reached and biochemical control (plasma renin above the middle of the reference range, i.e \> \~20 mIU/L) is attained and/or hyperkalemia develops. The maximal dose of eplerenone is 300 mg twice daily. During eplerenone dose titration, the doses of other antihypertensive medications will be reduced or, if possible, discontinued. Also, potassium replacement should be discontinued. In patients who develop significant hyperkalemia (\>4.6 mmol/L), the first step is to discontinue ACE inhibitors and/or angiotensin II receptor blocker (ARB). In patients not receiving treatment with ACE inhibitors or ARB, the dose of eplerenone will be decreased by 25-50 mg per day. Similarly, patients on monotherapy with eplerenone who develop very high renin concentrations and/or symptomatic hypotension, the dose of eplerenone should be decreased by 25-50 mg per day. Patients who do not attain optimal blood pressure on the maximal eplerenone dose will continue with other antihypertensive medications. It is expected that creatinine will increase in some patients, reflecting diminished renal hyperfiltration that is characteristic for patients with untreated PA. In these cases, the eplerenone dose should not be automatically reduced, and should only be considered in cases with severely worsening GFR (\>1.5 from the baseline value).

Follow-up

Total follow-up time is 24 months. For patients in the MRA arm, there will be a possibility to cross over (opt for surgery) after 12 months. The participants will be followed on at least 7 occasions throughout the study.

Outcome measures

Primary endpoint: The primary endpoint is the difference in improvement of QoL between surgically and medically treated patients at 12 months, measured with EQ5D (total score and the VAS scale).

Secondary endpoints: The secondary endpoints are: 1) Difference in improvement of QoL at 24 months, evaluated with EQ5D, 2) Difference in improvement of QoL at 12 and 24 months, evaluated with the SF-36/RAND-36 questionnaire, 3) The proportion of patients with complete, partial, and absent success of clinical and biochemical outcomes (based on blood pressure, use of antihypertensive drugs, plasma potassium, plasma renin and plasma aldosterone 1) according to the PASO criteria (15) at 12 and 24 months, 4) cardiovascular risk profile at 12 and 24 months, 5) difference in left ventricular mass on echocardiography at 12 and 24 months, 6) difference in renal function, evaluated by measuring eGFR and urinaryalbumin excretion at 12 and 24 months, and 7) total societal cost

Statistics and power calculation

Difference in treatment effects between the two groups will be analysed with paired t-test and Fishers exact test, as well as regression analyses with adjustments for age, gender, duration ofhypertension, as well as blood pressure and number of antihypertensive drugs at baseline.

For power calculation we used quality of life data from Velema et al. (EQ-5D) and Ahmedet al. (RAND SF-36) . With a significance level of 5% and power of 80%, inclusion of 50-54 subjects is needed (25-27 subjects in each treatment arm) to detect a difference betweensurgically and medically treated patients. Allowing for a 20% drop out rate, inclusion is set to 80 subjects (i.e. 40 in each treatment arm).

To ensure external validity, a screening log will be kept at each centre.

Clinical benefits

Contemporary treatment guidelines advocate surgical treatment in patients with unilateral disease. However, since AVS is not always successful, and not widely available, life-long medical treatment is often preferred for patients with PA, without any attempts to find out if they are candidates for curative surgical treatment. It is therefore of great importance to investigate if medical treatment is as effective as surgery in these patients. Currently, a head to head comparison of surgical versus medical treatments for patients with unilateral PA is lacking.

If it turns out that medical treatment is as efficient and safe as surgical treatment for patients with unilateral dominant disease, a large number of patients worldwide will benefit from the study. This concerns patients treated at centres where AVS is not available, patients where the AVS has not been successful as well as patients with unilateral dominant PA who are not considered candidates for surgical intervention. Thus, the study's results have a great potential to be quickly implemented in clinical practice.

Ethical considerations

The main ethical issue to acknowledge is that half of the patients will be randomized to receive medical treatment, i.e. they will not receive surgical treatment that is currently considered to be standard of care for unilateral PA. However, the reasons for considering the trial to be ethical are: a) Medical treatment with mineralocorticoid receptor antagonist forpatients with bilateral PA is effective and safe, b) Thorough information about the study willbe provided before participation, c) Participation is voluntary, d) After 12 months, all medically treated patients will have the option to receive surgical treatment i.e. adrenalectomy.

The study was approved by the Regional Research Ethics Committee in Gothenburg, Sweden on June 3rd, 2020 (DNR 2020-02008).

Unblinded, prospective, multi-center,randomized, controlled trial.

Unilateral Primary Aldosteronism, Mineralocorticoid Antagonists Versus Surgical Treatment

Unilateral Primary Aldosteronism, Mineralocorticoid Antagonists Versus Surgical Treatment - A Randomized Controlled Trial

All data will be available for other researcher upon request

Improvement in quality of life in surgically and medically treated patients 1 year after treatment of unilateral primary aldosteronism evaluated with EuroQol-5D (EQ-5D-5LTM)

Improvement in quality of life in surgically and medically treated patients 1 year after treatment of unilateral primary aldosteronism evaluated with RAND SF-36.

Improvement in quality of life 2 years after treatment of unilateral primary aldosteronism evaluated with EuroQol-5D (EQ-5D-5LTM)

Improvement in quality of life 2 years after treatment of unilateral primary aldosteronism evaluated with RAND SF-36.

To evaluate treatment effects. The proportion of patients with complete, partial or absent clinical success according to the PASO criteria

To evaluate treatment effects. The proportion of patients with complete, partial or absent biochemical success according to the PASO criteria.

To evaluate treatment effects in left ventricular mass by utilizing echocardiography at 12 months

To evaluate treatment effects in left ventricular mass by utilizing echocardiography at 24 months

To evaluate changes in renal function by assessment of glomerular filtration rate (GFR)

To evaluate changes in renal function by assessment of albuminuria by urine samples (urinary albumin/creatinine ratio)

An analysis of total costs for the society will be performed based on patient baseline demographics, an analysis of treatment (in- and outpatient) associated costs, sick leave and disease- and treatment-relatedincome loss to patients and significant others, as well as disease- and treatment-related costs related costs to society.

Karolinska Institutet

Umeå University

Göteborg University

MD, PHD, Associate Professor

Vasoconstrictor Agents

Respiratory System Agents

Epinephrine

Racepinephrine

Epinephryl borate

All patients will undergo endoscopic US guided radiofrequency ablation, to assess safety and feasibility.

To establish if radiofreuqency ablation of aldosterone producing adrenal adenomas can be carried out via the endoscopic route and to assess safety of the procedure.

Endoscopic ultrasound guided radiofrequency ablation

ultrasound

Stephen Pereira

High blood pressure (hypertension) causes strokes and heart attacks. While most patients need long-term treatment with pills, some have a cause which can be removed, curing the hypertension. The commonest curable cause is a benign nodule in one of the hormone glands, the adrenals. About one in 20 patients have such a nodule, but difficulties with diagnosis, and reluctance to proceed to surgery for a benign condition, limit the number having adrenal gland surgery to fewer than 300 per year in the UK. A potential, and exciting, solution to this dilemma is to use a momentary electric current to cauterise the nodule (radiofrequency ablation), without affecting the rest of the adrenal gland, and avoiding the need for surgery. Nodules in the left adrenal gland are easily reached under mild sedation using a similar procedure as is standard for investigating stomach ulcers (endoscopy). The study is designed to show that this approach (endoscopic ultrasound guided radiofrequency ablation) is very safe, and to provide initial evidence that the hormone abnormality is cured.

Primary hyperaldosteronism (PA) is one of the commonest causes of hypertension. It is estimated to be the root cause in 10% of all patients with hypertension and 20% of all patients with resistant hypertension. Conventionally, patients with PA are divided 50:50 into those with a curable, unilateral aldosterone-producing adenoma (APA), and those with bilateral idiopathic adrenal hyperplasia (IAH).

Individual clinicians may reasonably consider it unnecessary to diagnose a benign condition whose work-up for surgery can be arduous, and the benefits uncertain. Public health doctors could reasonably despair at a large increase in demand for scarce surgical resources, when long term comparison of medical and surgical approaches have not been undertaken. Yet PA is regarded as a high-risk subset of hypertension, with an estimated 4-12 fold excess rate of cardiovascular complications compared to otherwise comparable patients with Hypertension. The American Endocrine Society Guidance recommends that where resources permit, a unilateral APA should be removed in order to protect patients from the long-term consequences of excess aldosterone. At present, most APAs are removed by key-hole surgery, with a 2% conversion rate to open surgery.

While such surgery is justified by the serious cardiovascular risk of PA, the high level of proof (of unilateral disease) before surgical referral has the paradoxical outcome of reducing take-up of a procedure that can be life-prolonging. A further paradox is that the rigid division of PA into unilateral adenoma vs bilateral hyperplasia is probably incorrect and that an intervention which does not require the distinction may, in stages, come to be regarded as the more logical approach to cure of PA, with reduction/prevention of cardiovascular risk. The obvious alternative intervention is selective ablation of APA(s), sparing most of the adjacent adrenal gland. Several publications report anecdotal success using this technique. The eligibility criteria for ablation were variable, but generally the patients were medically unfit or declined to undergo surgery. Success rates, measured as reversal of the biochemical abnormalities of PA, and radiological resolution, were high. However, there were few major adverse events. Most patients were monitored in hospital after the procedures, with shorter stays than the 2-3 days typical of most centres following laparoscopic surgery.

The investigators wish to progress from the experience with percutaneous and retroperitoneoscopic ablation to an approach which should maximise the ease and applicability of ablation whilst reducing the risk of adverse events. The primary outcome of the study will be safety. However, by the end of the study the investigators also need to have sufficient evidence of efficacy to justify, and guide design of, a subsequent multi-centre comparison trial.

Population Patients over the age of 18 diagnosed with left adrenal aldosterone producing adenoma meeting criteria from Endocrine Society clinical practice guidelines for primary hyperaldosteronism. The intervention (ultrasound guided endoscopic radiofrequency ablation) will be offered to those unsuitable for left adrenalectomy, who do not want surgery, or those who meet the criteria for surgery but wish to consent to radiofrequency ablation.

Design of study and intervention FABULAS is a three-center study, modelled on phase 1b/2a trials of novel drugs. It aims to determine the safety and efficacy study of endoscopic ultrasound-guided ablation as a nonsurgical, adrenal-sparing treatment for aldosterone-producing adenomas. Thirty patients will be enrolled onto the study comprised of three cohorts of ten patients. The three cohorts will run sequentially with overlapping stages, and the safety of the first six patients in each cohort/group will be reviewed before the next group commences.

Potential patients will be identified by referrals to our specialist Endocrine or Hypertension clinics. Once identified patients will be recruited at St. Bartholomew's Hospital in a Screening Visit where they will be clinically assessed, bloods and baseline investigations such as urinalysis and ECGs will be performed and informed consent gained for official enrolment onto the study.

Diagnostic PET CT scans using a tracer 11-C-Metomidate (or an alternative tracer, when available) will be used for confirmation of a left Conn's adenoma(s). Some patients may have already had this investigation as part of their work up. If so the PET CT does not need to be repeated. Group 1's (please see eligibility section for details) endoscopies will be managed in the Research Endoscopy Suite within the Clinical Research Facility at UCLH. Assuming group 1 is non-problematic, Barts Hospital will initiate ablations in year 2. The two-site approach maximises safety, assures recruitment of 1-2 eligible patients per month, and provides some early insight to the generalisability of the innovation.

Outcomes and assessment

The Primary Outcome Measures The primary outcome is safety, whether the recorded patient safety outcome data establishes that perforation, haemorrhage and infarction of major organs does not occur. This will be assessed at 48 hours.

This will be achieved by:

* Accurate adverse event reporting;
* Clinical assessment (history and examination) looking for features of blood loss, perforation, or inflammation/infarction of peri-adrenal tissues;
* Blood tests for Hb, WBC, and Renal function, amylase, LFTs, CRP; and.
* Urinalysis for blood and protein.

The Secondary Outcome Measures

The difference from baseline measurements at 3 and 6 months following ablation will be measured using the following clinical, biochemical and radiological parameters:

* Plasma electrolytes;,
* Aldosterone and renin ratio at 3 and 6 months;
* PET CT 3 months post ablation for radiological disappearance, diameter size and SUV measurements;.
* The reduced use or cessation of supplementary potassium medication; and
* Home BP (measured 3 readings twice a day for 4 days preceding clinic visit).Reduction in/or no longer taking antihypertensive medication

Assessment of cure will be performed at the site not involved in patient care. This will be subject to ratification by the safety committee who are not involved in the study.

Sample size / recruitment size A sample size of 30 patients will be recruited to the clinical trial. These statistical analyses have been performed by Dr Stephen Morant, University of Dundee (statistician). Patients will be identified through specialist endocrine / hypertension clinics and recruitment will be at St Bartholomew's Hospital.

The Intervention

Initially the patient's imaging (PET CT) will be reviewed at a multidisciplinary meeting to confirm the diagnosis and suitability for treatment by radiofrequency ablation for a left aldosterone producing adenoma. Currently this technique can only be used for the left adrenal gland due to its position near to the stomach.

On the day of the procedure the patient will receive a general anaesthetic or conscious sedation for the treatment. An endoscope with an ultrasound probe in the tip will be passed in to the stomach or small bowel to identify the adrenal adenoma.. A fine needle is then inserted into the adenoma via the endoscope and its contents aspirated. Samples will be sent to the laboratory for routine analysis. Following aspiration of the adenoma, the patient will undergo Endoscopic Ultrasound-Guided Radiofrequency Ablation (EUS-RFA) treatment. The radiofrequency probe will be placed into the adenoma via the needle. The needle will be withdrawn slightly so the probe lies within the adenoma. A low power current of 10 Watts for 90 seconds will then be applied to the lesion on up to 10 occasions to ablate the tumour. It is anticipated the treatment will cause destruction of the adenoma.

The 30 patients recruited to this study, will need to stay in hospital for approximately 48 hours following treatment. A CT scan will be performed 24-48 hours post ablation. Based on the experience so far, it is hoped that the side effects of radiofrequency ablation will be minor and that ultimately the treatment will be performed as a day-case procedure. If our initial experience confirms this, patients recruited to this study may be discharged on the same day as treatment, following review by the medical team. Patients will be followed up at one, three and six months in outpatients to recheck blood pressure and blood tests to check if the treatment has been successful, with a repeat PET CT scan prior to the appointment. Blood tests will also be performed on the day of the appointment, as part of standard care. If the adenoma has not been completely ablated at 3 months the patient may be offered a further EUS-RFA treatment.

Patients will be asked to measure their blood pressure at home 4 days before each study visit with a monitor loaned to them whilst on the clinical trial. In addition to formally checking for any adverse effects at each clinic visit, patients were also asked to report any side-effects encountered to the medical team.

Sample management Cytology from the fine needle aspiration will be sent for immunohistochemistry staining. RNA will be obtained to look expression of the enzymes that produce aldosterone.

All participants will undergo the intervention: endoscopic ultra-sound guided radiofrequency ablation of their left adrenal aldosterone producing adenoma. The primary outcome is safety and feasibility

Radiofrequency Endoscopic Ablation With Ultrasound Guidance: a Non-surgical Treatment for Aldosterone-producing Adenomas

Feasibility Study of RadioFrequency Endoscopic ABlation, With ULtrasound Guidance, as a Non-surgical, Adrenal Sparing Treatment for Aldosterone-producing Adenomas

The primary objective is to test the primary hypothesis which states that endoscopic ultrasound-guided radiofrequency ablation of aldosterone-producing adenomas of the adrenal gland is a safe method for achieving sustained reduction in plasma aldosterone.

Specifically this will be assess via number of patients in whom one of the following is reported:

1. Major haemorrhage (seen on 24-48 hour safety CT)
2. Fall in Hb
3. Evidence of infarction of peri-adrenal organs on blood tests and CT
4. Evidence of rupture of stomach on CT

Difference in measurement of plasma electrolytes, renin and aldosterone at baseline and 6 months following ablation looking for normalisation post procedure. Definition of biochemical success defined as per PASO consensus

Metomidate PET CT will be performed at 6 months after ablation and compared with baseline PET CT looking for 'radiological cure', ie successful ablation of previous 'hot' aldosterone producing adrenal adenoma.

Difference in Home BP measurements (3 readings morning and 3 in the evening for 4 days) before clinic visits at baseline and at 6 months. Definition of clinical success defined as per PASO consensus. If home BP is not available, clinic BPs will be used.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Unilateral Primary Aldosteronism, Mineralocorticoid Antagonists Versus Surgical Treatment	NCT05797558	Primary Hyperal...	Unilateral adre... Medical treatme...	18 Years - 70 Years	Göteborg University
Unilateral Primary Aldosteronism, Mineralocorticoid Antagonists Versus Surgical Treatment	NCT05797558	Primary Hyperal...	Unilateral adre... Medical treatme...	18 Years - 70 Years	Göteborg University
Radiofrequency Endoscopic Ablation With Ultrasound Guidance: a Non-surgical Treatment for Aldosterone-producing Adenomas	NCT03405025	Primary Hyperal... Primary Hyperal...	Endoscopic ultr... ultrasound	18 Years -	University College, London

Spots Global Cancer Trial Database for primary hyperaldosteronism due to adrenal adenoma