Randomised Trial Comparing Thermal Ablation With Adrenalectomy in the Treatment of Unilateral Asymmetric PA (WAVE)

A Prospective Randomised Trial Comparing Thermal Ablation With Laparoscopic Adrenalectomy as an alternatiVE Treatment for Unilateral Asymmetric Primary Aldosteronism

The primary objective of WAVE is to test the hypothesis that thermal ablation (microwave or RFA) is non-inferior to surgery in the biochemical (and if so, in the clinical) cure of unilateral PA, according to the international consensus PASO criteria.

Secondary objectives are to determine whether either intervention is superior to the other in relation to the following outcomes. Where no superiority of either intervention is established, non-inferiority of thermal ablation against adrenalectomy will be sought.

• Frequency and severity of adverse events
• Length of inpatient stay
• Patient satisfaction
• Quality of life
• Return to activities of daily living

An additional secondary objective in the thermal ablation group alone will be anatomical efficacy of ablation.

Study Overview

• Status: Recruiting
• Conditions: Primary Aldosteronism
• Intervention / Treatment: Procedure: Thermal ablation of aldosterone producing adenoma.; Procedure: Unilateral adrenalectomy

Detailed Description

Primary aldosteronism (PA) results from renin-independent aldosterone hypersecretion and causes hypertension, often with associated hypokalaemia and metabolic alkalosis. These are due to enhanced mineralocorticoid receptor-mediated renal sodium retention and potassium excretion. PA is the commonest cause of secondary hypertension and is responsible for 5-10% of all hypertension, rising to in excess of 20% of resistant cases. Very low diagnosis rates result from a generation of doctors schooled on order-of-magnitude lower estimates, but recent findings suggest that even the 5-10% prevalence may be a considerable under-estimate. In addition to its frequency, PA is a high-risk subset of hypertension and is associated with a two-fold increased risk of cardiovascular events and atrial fibrillation compared to comparable patients with essential hypertension, as well as a reduced quality of life.

Aldosterone excess in PA can originate from one or both adrenal glands. Patients with PA are considered to divide ~50:50 into those with a curable unilateral aldosterone-producing adenoma (APA), and those with bilateral idiopathic adrenal hyperplasia (IAH). For patients with unilateral PA, surgical removal of the affected gland (adrenalectomy) is highly likely to cure the biochemical abnormality, reverse the excess cardiovascular and stroke risks, and is strongly supported by international guidelines.

Whilst directed medical therapies against aldosterone excess exist (e.g. mineralocorticoid receptor antagonists, MRAs), they are inferior to surgery in reducing the excess cardiovascular and stroke risk and improving quality of life. Furthermore, sufficient MRA dosing to de-suppress renin and reverse this excess risk is only achieved in one-third of medically-treated patients. The case for definitive intervention in unilateral PA is therefore compelling, and recommended whenever possible. At present, this is achieved by laparoscopic adrenalectomy (LA), which involves a general anaesthetic, inpatient admission and removal of the entire adrenal gland to treat a condition caused by a small (usually <2cm diameter, often <1cm) benign APA.

An alternative intervention to LA, and the focus of this trial, is selective thermal ablation (by radiofrequency or microwave) of the identified APA(s). Thermal ablation is a technique in which targeted and directed tissue death can be achieved with precision under image guidance, sparing the normal adrenal gland. It is widely established in the treatment of benign and malignant hepatic and renal neoplasms as an alternative to conventional surgery. For these indications, thermal ablation techniques have transformed practice, not only providing high-risk surgical patients with a previously unobtainable curative treatment option but also becoming an accepted mainstay of treatment for small lesions (of the size encountered in PA) in all patients regardless of surgical risk.

We propose a multi-centre prospective randomised trial comparing adrenalectomy (LA) and thermal ablation for the treatment of unilateral APAs. This study is powered to demonstrate non-inferiority of biochemical and clinical response to thermal ablation, compared to the current standard of care, adrenalectomy. The rationale for a non-inferiority trial is that subsequent preference for thermal ablation over surgery will be driven by thermal ablation's greater patient-acceptability and availability, rather than an implausible superior efficacy of sub-total than total adrenalectomy in curing PA. Once safety and efficacy are proven as comparable to those of adrenalectomy, thermal ablation has potential for superiority over medical treatment in several patient groups ineligible for WAVE, e.g., some with bilateral disease, or in whom lateralisation could not be performed.

• Study Type: Interventional
• Enrollment (Estimated): 110
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Aklima Khatun; Phone Number: 0203 765 8577; Email: aklima.khatun4@nhs.net
• Study Contact Backup: Name: Tumi Kaminsas; Phone Number: 0207 882 5994; Email: research.governance@qmul.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom, EC1A 7BE
    • Recruiting
    • St Bartholomew's Hospital
    • Contact: William Drake, FRCP DM; Email: w.m.drake@qmul.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria (all of):

• Age > 18 years
• Primary aldosteronism diagnosed according to international guidelines
• Unilateral disease by AVS or PET-CT criteria
• Ipsilateral radiological abnormality with benign imaging characteristics and technically amenable to both thermal ablation and surgery
• Able and willing to give informed consent
• Randomisation approved by MDT

Exclusion criteria (any of):

• Absolute contraindication to α- or β-adrenoceptor antagonist therapy or CT contrast
• Contraindication or unwillingness for either surgery or thermal ablation
• Inability to withdraw β-adrenoceptor antagonist therapy for 2 weeks
• Unwilling to undergo either LA or thermal ablation
• Unwilling to comply with study visit schedule
• Pregnancy or unwillingness to undertake secure contraception for the study duration (female participants only)
• Life-limiting comorbidity (at the discretion of the PI)
• Clinical and/or biochemical evidence of autonomous cortisol secretion sufficient, in the opinion of the patient's physician, to mandate a unilateral adrenalectomy independent of autonomous aldosterone secretion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Thermal ablation of adrenal aldosterone producing adenoma (s); For patients randomized to ablation, thermal ablation (either microwave or radiofrequency ablation) will be deployed to treat the adrenal aldosterone producing adenoma(s)	Procedure: Thermal ablation of aldosterone producing adenoma.; On the left side, Radiofrequency ablation of aldosterone producing adenoma(s) will be undertaken via the stomach (endoscopically), under transgastric ultrasound guidance. On the right side, either Radiofrequency or Microwave Ablation of aldosterone producing adenoma(s) will be performed via a percutaneous approach, under CT guidance.
Other: Unilateral adrenalectomy for aldosterone producing adenoma (s); For patients randomized to surgery, unilateral adrenalectomy will be performed to remove aldosterone producing adenoma(s)	Procedure: Unilateral adrenalectomy; Unilateral total adrenalectomy for aldosterone producing adenoma. This will be laparoscopic in the vast majority of patients, with open conversion if surgically indicated (unlikely in >1-2 patients); Other Names: Laparoscopic adrenalectomy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete biochemical cure of PA	Complete biochemical cure of PA, defined (whilst off medications that might alter serum potassium or the RAS) by both: Normalisation of serum potassium, and; Normalisation of ARR, or; Elevated ARR and i. Baseline PAC <190pmol/L, or ii. Normal confirmatory test (as defined in the inclusion criteria)	6 months post intervention
Complete clinical cure of PA	Complete clinical cure of PA, defined as normotension without antihypertensive medication These criteria have been defined in the international consensus PASO statement8, which has become the established yardstick by which PA cure is judged. In this, normotension is defined, in accordance with the European Society of Hypertension guidelines22, as <140/80 in the office, <135/85 at home or daytime ambulatory monitoring and <130/80 for 24h ambulatory blood pressure monitoring (24hABPM).	6 months post intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse events	Will be directly sought at each study visit through history and physical examination where appropriate; Subjects will be encouraged to report between study visits and will have a mechanism to do so; Will be classified by system, seriousness, causal relationship and expectedness according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE)	Reported throughout the study period. Approximately 2 years
Anaemia (FBC, requirement for blood transfusion)	Blood test	6, 12, 24 and 36 months post intervention
Renal dysfunction and electrolyte abnormalities (U&Es)	Blood test	6, 12, 24 and 36 months post intervention
Liver dysfunction (LFTs)	Blood test	6, 12, 24 and 36 months post intervention
Pancreatitis (lipase/amylase)	Blood test	6, 12, 24 and 36 months post intervention
Hypertensive urgency (physiological parameters, plasma metanephrines)	Blood test	6, 12, 24 and 36 months post intervention
Length of inpatient stay (hospital episode data)	As reported by patient	6 weeks post intervention
Patient satisfaction (Freiburg index of patient satisfaction)	Completed by patient, using the FIPs score values to rate the treatment they have received.	6 weeks post intervention
Quality of life questionnaire	Completed by patient, using the - EQ-5D 5L and SF-36 questionnaire models to score self rated health and quality of life values. These 2 models are presented as one questionnaire to the patient.	6 months post intervention
Return to usual activities of daily living (self-reported)	As reported by patient	6 weeks post intervention
Anatomical efficacy of ablation	(ablation group only; post-ablation Metomidate/CETO PET-CT appearances)	6, 12, 24 and 36 months post intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hierarchical analysis testing	Hierarchical analysis testing will be applied to sequential testing of the following hypotheses. Each positive outcome permits the next limb to be tested as a co-primary hypothesis. A negative outcome converts subsequent limbs to secondary hypotheses. [i] Complete biochemical cure for left ablation vs all surgery (positive if non-inferiority (NI) margin <45%) [ii] Complete biochemical cure for all ablation vs all surgery (positive if NI margin <45%) [iii] Complete clinical cure for all ablation vs all surgery (positive if NI margin <30%) The first limb of the hierarchy will be tested if sufficient patients have been recruited on the left.	6 months post intervention

Collaborators and Investigators

• Sponsor: Queen Mary University of London
• Investigators: Principal Investigator: Morris Brown, Queen Mary University of London

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2022
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: March 15, 2022
• First Submitted That Met QC Criteria: May 31, 2022
• First Posted (Actual): June 6, 2022

Study Record Updates

• Last Update Posted (Actual): May 7, 2024
• Last Update Submitted That Met QC Criteria: May 3, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Ablation; Laparoscopic; Adrenalectomy; Thermal
• Additional Relevant MeSH Terms: Endocrine System Diseases; Adrenocortical Hyperfunction; Adrenal Gland Diseases; Hyperaldosteronism
• Other Study ID Numbers: 304174

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Once discussed with patient representative from patient and public Involvement, document will be uploaded on to system following first Trial Steering Committee involving PPI member

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No