Clinical trial NCT05405101: Randomised Trial Comparing Thermal Ablation With Adrenalectomy in the Treatment of Unilateral Asymmetric PA
Official title: A Prospective Randomised Trial Comparing Thermal Ablation With Laparoscopic Adrenalectomy as an alternatiVE Treatment for Unilateral Asymmetric Primary Aldosteronism
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Primary Aldosteronism
Keywords: Thermal
Ablation
Laparoscopic
Adrenalectomy
Lead sponsor: Queen Mary University of London
Sponsor class: OTHER
First posted: 2022-06-06
Enrollment: 122
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: PROBE: Prospective Randomised open blinded end point study. Patients are randomized using a minimization program. 2:3 Surgery: Ablation
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Complete biochemical cure of PA
timeFrame: 6 months post intervention
measure: Complete clinical cure of PA
timeFrame: 6 months post intervention
Secondary outcomes:
measure: Adverse events
timeFrame: Reported throughout the study period. Approximately 2 years
measure: Anaemia (FBC, requirement for blood transfusion)
timeFrame: 6, 12, 24 and 36 months post intervention
measure: Renal dysfunction and electrolyte abnormalities (U&Es)
timeFrame: 6, 12, 24 and 36 months post intervention
measure: Liver dysfunction (LFTs)
timeFrame: 6, 12, 24 and 36 months post intervention
measure: Pancreatitis (lipase/amylase)
timeFrame: 6, 12, 24 and 36 months post intervention
measure: Hypertensive urgency (physiological parameters, plasma metanephrines)
timeFrame: 6, 12, 24 and 36 months post intervention
measure: Length of inpatient stay (hospital episode data)
timeFrame: 6 weeks post intervention
measure: Patient satisfaction (Freiburg index of patient satisfaction)
timeFrame: 6 weeks post intervention
measure: Quality of life questionnaire
timeFrame: 6 months post intervention
measure: Return to usual activities of daily living (self-reported)
timeFrame: 6 weeks post intervention
measure: Anatomical efficacy of ablation
timeFrame: 6, 12, 24 and 36 months post intervention
Other outcomes:
measure: Hierarchical analysis testing
timeFrame: 6 months post intervention
Locations:
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
state: Smlg
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: London
country: United Kingdom
facility: University College London Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: Guy's and St Thomas' NHS Foundation Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals NHS Foundation Trust
Study officials:
affiliation: Queen Mary University of London
name: Morris Brown
role: PRINCIPAL_INVESTIGATOR
References: