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

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ClinicalTrials.gov Identifier: NCT03405025
Recruitment Status : Recruiting
First Posted : January 19, 2018
Last Update Posted : May 25, 2018
Sponsor:
Collaborators:
Queen Mary University of London
British Heart Foundation
University of Cambridge
Cambridge University Hospitals NHS Foundation Trust
Barts & The London NHS Trust
University College London Hospitals
Information provided by (Responsible Party):
University College, London

Tracking Information
First Submitted Date  ICMJE December 21, 2017
First Posted Date  ICMJE January 19, 2018
Last Update Posted Date May 25, 2018
Actual Study Start Date  ICMJE February 21, 2018
Estimated Primary Completion Date January 28, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 18, 2018)
  • Incidence of Treatment-Emergent Adverse Events of endoscopic ultrasound-guided radiofrequency ablation. [ Time Frame: 48 hours post procedure ]
    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 on 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
  • Efficacy of endoscopic ultrasound-guided radiofrequency ablation [ Time Frame: 3 months ]
    The second co-primary end point is efficacy of endoscopic radifrequency ablation. This will be assess based on biochemical cure of primary hyperaldosteronism at 3 months, via measurement of plasma potassium, aldosterone and renin levels.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03405025 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 18, 2018)
  • Evidence of 'biochemical cure' post endoscopic ultrasound-guided radiofrequency ablation [ Time Frame: 6 months ]
    Difference in measurement of plasma electrolytes, renin and aldosterone at baseline and 6 months following ablation looking for normalisation post procedure.
  • Evidence of 'radiological cure' post endoscopic ultrasound-guided radiofrequency ablation [ Time Frame: 6 months ]
    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.
  • Evidence of home BP improvement post endoscopic ultrasound-guided radiofrequency ablation [ Time Frame: 6 months ]
    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.
  • Evidence of clinic BP improvement post endoscopic ultrasound-guided radiofrequency [ Time Frame: 6 months ]
    Difference in BP measurements in clinic at baseline and 6 months following ablation
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Radiofrequency Endoscopic Ablation With Ultrasound Guidance: a Non-surgical Treatment for Aldosterone-producing Adenomas
Official Title  ICMJE Feasibility Study of RadioFrequency Endoscopic ABlation, With ULtrasound Guidance, as a Non-surgical, Adrenal Sparing Treatment for Aldosterone-producing Adenomas
Brief Summary 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 bengin 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.
Detailed Description

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 adrenolectomy, 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 A multicentre phase 1 study 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 enrollment 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

There will be a hierarchical co-primary endpoint. The first co-primary is whether the recorded patient safety outcome data establishes that perforation, haemorrhage infarction of major organs does not occur. This will be assessed at 48 hours. The second co-primary endpoint is efficacy, assessed biochemically at 3 months post ablation. 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. DNA obtained will be sent for genotyping.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Intervention Model: Single Group Assignment
Intervention Model Description:
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
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE
  • Primary Hyperaldosteronism
  • Primary Hyperaldosteronism Due to Adrenal Adenoma
Intervention  ICMJE
  • Procedure: Endoscopic ultrasound guided radiofrequency ablation
    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.
  • Device: ultrasound
    ultrasound
Study Arms  ICMJE Safety and Feasibility
All patients will undergo endoscopic US guided radiofrequency ablation, to assess safety and feasibility.
Interventions:
  • Procedure: Endoscopic ultrasound guided radiofrequency ablation
  • Device: ultrasound
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 18, 2018)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 28, 2022
Estimated Primary Completion Date January 28, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients aged 18 and above
  2. Diagnosis of PHA based on published Endocrine Society guidelines
  3. Positive serum aldosterone renin ratio (ARR) with another local diagnostic confirmatory test (MRI or CT imaging)

There are 3 inclusion subset groups:

Group 1

  1. Left-sided APA proven on either AVS or PET CT.
  2. Patients wishing to take fewer drugs for their hypertension.
  3. Patients not usually referred for surgery because the benefit: risk is considered too low.
  4. Patients aged ≥60 whose BP is at or near target (BP140/90 for most patient groups, BP 130/80 if co-morbidities listed in Hypertension guidelines) on treatment with four or more drugs.
  5. patients with identified macroadenomas (APAs >= 1 cm in diameter), who have at least 1 cm of peri-adrenal fat on axial and coronal projections.

Group 2

Patients aged 18 years and above with diagnosis of PA and either:

[i] a definite unilateral left APA, but the patient does not want surgery; or [ii] probable but not unequivocal evidence of a unilateral left adrenal APA.

Group 3 Patients over 18 years of age meeting criteria for surgery, but consent to undergo endoscopic ablation instead.

Exclusion Criteria:

  1. Inability to give informed consent.
  2. Any patients continuing on beta blockers/direct renin blockers.
  3. Pregnant women or those unable or unwilling to take secure contraceptive precautions.
  4. Any illness, condition or drug regimen considered a contraindication by the PI/CI.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Stephen Pereira +44 7918 030401 stephen.pereira@ucl.ac.uk
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03405025
Other Study ID Numbers  ICMJE 222446
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Please see below
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Time Frame:

Study protocol, SAP and ICF will be available within next 3-6 months and will remain available until close of study.

The CSR will be available following statistical analysis.

Responsible Party University College, London
Study Sponsor  ICMJE University College, London
Collaborators  ICMJE
  • Queen Mary University of London
  • British Heart Foundation
  • University of Cambridge
  • Cambridge University Hospitals NHS Foundation Trust
  • Barts & The London NHS Trust
  • University College London Hospitals
Investigators  ICMJE
Principal Investigator: Stephen Pereira University College, London
PRS Account University College, London
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP