Is Metomidate PET CT superior to Adrenal venous sampling in predicting ouTCome from adrenalectomy in patients with primary Hyperaldosteronism (MATCH): a multi-centre, randomised, within-patient comparison of diagnostic techniques

Background Hypertension is a major risk factor for heart attacks and stroke. Primary aldosteronism (PA) is reported in ~10% of patients, and in 20-25% of patients with treatment resistant hypertension. In ~50% of PA, it is caused by an aldosterone-producing adenoma (APA) in one adrenal gland, and surgery (adrenalectomy) offers a potential cure. However, <1/10 of eligible patients are diagnosed and proceed to surgery. One of the main barriers is the difficulty of proving that only one adrenal gland is the culprit. On diagnostic CT or MRI, smaller (<1 cm) adenomas may be overlooked, while conversely incidental adenomas occur in 4% of the population. Hence, guidelines recommend that most PA patients should undergo adrenal venous sampling (AVS) if being considered for surgery. This invasive procedure is time-consuming, technically demanding and fails in 20-50% of cases. In a previous, non-randomised proof-of-concept study we found that a non-invasive alternative to AVS, 11C-metomidate PET CT, is comparable to AVS in distinguishing unilateral from bilateral PA. If PET CT is shown in a multi-centre, randomised study to be superior to AVS, this together with greater patient preference and convenience would improve access to diagnosis, and encourage doctors to look for PA in many more patients. Hypotheses: Original: Our primary hypothesis is that 11C-metomidate PET CT is superior to AVS in the diagnosis of unilateral PHA. Our secondary hypothesis is that we can recognise patients in whom there is a high likelihood that hypertension, in addition to PHA will be completely cured. This is particularly important for older patients, in whom cure is currently achieved in only 50% of cases. Additional: We will also test a non-inferiority hypothesis, that the lower bound of 95% confidence intervals around difference in accuracy between 11C-metomidate PET CT and AVS is -17%. In a 25-patient extension to the main study, we will test whether 11C-metomidate, which has a half-life of only 20 minutes, could be replaced by Para-chloro-2-[18F]fluoroethyletomidate (CETO). Population The patients are those with a diagnosis of PA, who are eligible and willing to proceed to adrenalectomy if found to have a unilateral cause of PA. Design of study and interventions The study is a multi-centre within-patient comparison of the diagnostic accuracy of AVS and 11C-metomidate PET CT, performed in random order. Patients will be offered surgery if one or both techniques indicate unilateral disease. Outcomes and assessments Original The hierarchical co-primary outcomes are the proportion of patients achieving (a) cure of PA (= normalisation of plasma renin, aldosterone and potassium levels), and (b) improved BP control (= home BP at least 10% lower at 6 months after adrenalectomy than prior to treatment with an aldosterone antagonist). Secondary outcomes are the proportion of patients with complete cure of hypertension, and whether this is predicted by either the BP response to spironolactone, the PET CT analyses, or pathological and molecular diagnoses of the post-surgical sample. Correlation between pre- and post- operative findings will improve future selection of patients for surgery. Revised Publication in 2018 of internationally agreed criteria for assessing outcomes enabled us to pre-specify these ‘PASO’ criteria as a 4-step hierarchical primary outcome, evaluating in order the difference in accuracy between the two diagnostic procedures in predicting partial or complete biochemical success, then partial or complete clinical success. The additional outcome of the extension study is the agreement between 11C-metomidate and 18F-CETO in predicting high probability of unilateral PA, evaluated by a kappa statistic. Sample size/recruitment rate Recruitment of 142 patients across 6 centres over 3 years (<1/centre/month), with an estimated 70 proceeding to adrenalectomy, permits 90% power at alpha=0.01 of detecting superiority of PET CT over AVS. Statistical analysis will compare the accuracy of AVS and PET CT. A further 25 patients will be recruited to permit comparison of surgical and medical outcomes, and the comparison of PET ligands. Economic benefit For a modest investment, if shown to be superior to AVS, then PET CT (priced equivalently to AVS in most centres) has the potential to increase at least 5-fold the numbers of patients being cured of hypertension per year, with major health and economic benefits in terms of reduction in the risk of heart attack and stroke in PHA patients. If CETO is found to be comparable to 11C-metomidate it will also improve patient access. CETO has a half-life of 2 hours, meaning the radioligand can be produced centrally and transported to hospitals with PET-CT facilities, unlike 11C-metomidate which requires synthesis in an on-site cyclotron to accommodate its short half-life.