CXCR4-directed [68Ga]Ga-PentixaFor vs AVS performance in a diagnoStic randomized Trial Ultimately comparing hypertenSion outcome in primary aldosteronism (CASTUS trial)

Rationale:
Primary aldosteronism (PA) is the most frequent form of secondary hypertension. Correct diagnosis and targeted treatment of PA are essential because of high vascular morbidity associated with PA as compared to essential hypertension with comparable blood pressure levels. PA is usually caused by either a unilateral aldosterone-producing adenoma (APA) or by bilateral adrenal hyperplasia (BAH). Distinction between APA and BAH is critical since the former may be cured by adrenalectomy, and the latter necessitates life-long medical therapy with mineralocorticoid receptor antagonists (MRA). The distinction between unilateral and bilateral PA can be made by adrenal vein sampling (AVS), as recommended by The Endocrine Society 2016 guideline (1). Since AVS is invasive, not widely available, dependent on skilled radiologists and costly, there is a need for an accurate, non-invasive functional imaging modality. Based on clinical data obtained in retrospective studies so far, it appears that a potentially suitable imaging modality for this purpose is [68Ga]Ga-PentixaFor PET/CT. We propose to perform an two-step trial, in which the first step consists of a prospective feasibility study of [68Ga]Ga-PentixaFor PET/CT scanning. When the concordance of [68Ga]Ga-PentixaFor PET/CT and AVS appears to be >50%, we will continue to the second step: a prospective, randomized diagnostic study comparing outcomes of AVS-based and [68Ga]Ga-PentixaFor PET/CT based management of patients with primary aldosteronism.

Study design:
Two-step design in which step one is a two-center, single arm and open label study, followed, conditionally on the results of step one, by a two-center, prospective, two-armed, diagnostic randomized controlled trial.
Study population: Patients with primary aldosteronism, confirmed by an intravenous salt-loading test, >18 years old (according to the Endocrine Society guidelines)(1).
Intervention: In the first step patients will undergo AVS and a CT scan. Subsequently, in these patients a Ga-68-pentixafor PET/CT will be performed. Lateralization (based on [68Ga]Ga-PentixaFor uptake criteria) will be compared with lateralization results of the AVS. Based on the results of the adrenal vein sampling, patients will undergo unilateral adrenalectomy or MRA therapy (standard of care). When the concordance of [68Ga]Ga-PentixaFor PET/CT and AVS >50%, we will start with the randomized controlled trial (RCT).
In step 2 patients will be randomized to undergo either [68Ga]Ga-PentixaFor PET/CT or AVS. The result of these tests will determine the course of action: adrenalectomy for APA or MRA therapy for bilateral hyperplasia.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:
The extra burden of participation in the first step consists of a tracer injection and a PET/CT scan. The risks associated with a peptide injection in the microdose range are low. Adverse reactions have not been observed. Effective radiation dose of 150 +/- 50 MBq [68Ga]Ga-PentixaFor will be approximately 2.3 mSv, which is an acceptable dose.

[68Ga]Ga-PentixaFor PET/CT is non-inferior to adrenal vein sampling in subtyping in patients with primary aldosteronism

Step 1: The diagnosis of unilateral or bilateral disease will be based on AVS and CT scan. Subsequently, in these patients a [68Ga]Ga-PentixaFor PET/CT will be performed. . The [68Ga]Ga-PentixaFor PET/CT images will be interpreted by a clinician, blinded for the AVS and CT results, with extensive experience in radiolabeled imaging.

Step 2: Each subject will be randomly assigned to one of the diagnostic methods. Based on AVS or [68Ga]Ga-PentixaFor PET/CT results, patients with a unilateral cause of PA will receive surgery and patients with a bilateral cause of PA will receive antihypertensive medication. Both diagnostic methods will be compared by measuring the daily defined doses of antihypertensive medication from both groups after one year follow- up starting after the diagnosis has been given. Management of antihypertensive medication will be compared between groups in terms of daily defined doses.

[68Ga]Ga-PentixaFor PET/CT