Evaluation of [68Ga]Ga-PentixaFor PET/CT Versus Adrenal Venous Sampling in Diagnosing Primary Aldosteronism in Hypertensive Patients

The primary objective of the CASTUS trial is to evaluate the **concordance** between [68Ga]Ga-PentixaFor PET/CT and adrenal venous sampling (AVS) in the identification and/or lateralization of aldosterone-producing adenomas (APAs) in patients with **primary aldosteronism**. This is clinically relevant as accurate identification and lateralization of APAs are crucial for determining the appropriate surgical or medical management of primary aldosteronism, which can significantly impact hypertension outcomes. Additionally, the trial aims to assess the non-inferiority of [68Ga]Ga-PentixaFor PET/CT imaging compared to AVS in subtyping patients with primary aldosteronism. This is evaluated by comparing clinical outcomes, specifically the daily defined doses (DDD) of antihypertensive medication, after a 6-month follow-up period. The findings could potentially offer a less invasive and more accessible diagnostic alternative to AVS, thereby improving patient care and management.

The clinical trial involves participants diagnosed with **primary aldosteronism**, confirmed through an elevated aldosterone/renin ratio and an intravenous salt-loading test, as per the Endocrine Society guidelines. The study population includes both male and female subjects, aged over 18 years, who have provided signed informed consent. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants. Participants were selected based on their diagnosis and age, with additional consensus required for those in the "grey area" of diagnosis. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of **[68Ga]Ga-PentixaFor** PET/CT imaging compared to adrenal venous sampling (AVS) in the diagnosis and management of **primary aldosteronism**. This is a randomized, double-blind, controlled trial with a duration extending from the estimated recruitment start date of November 1, 2021, to the estimated end date of September 1, 2028. The trial is structured in two main steps: Step 1 focuses on assessing the concordance between the two diagnostic methods for identifying and/or lateralizing aldosterone-producing adenomas (APAs), while Step 2 evaluates the non-inferiority of clinical outcomes between the two methods over a six-month follow-up period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a confirmed diagnosis of primary aldosteronism, age over 18 years, and signed informed consent. The trial will include follow-up visits to monitor clinical outcomes and imaging results, with the end-of-study visit marking the conclusion of the participant's involvement. The expected length of participant involvement is approximately six months, with conditions for early termination including withdrawal of consent or adverse events that compromise participant safety.

The trial will utilize **[68Ga]Ga-PentixaFor**, administered as a solution for injection via the intravenous route, with a maximum daily dose of 200 MBq. The primary endpoints include assessing the concordance between the imaging methods and evaluating clinical outcomes based on the surrogate Standard of Truth (SoT) daily defined doses. Secondary endpoints involve establishing quantitative criteria for imaging uptake, comparing imaging data post-adrenalectomy, and assessing safety, image quality, and cost-effectiveness. The trial will also evaluate the reproducibility of the imaging method and inter-observer agreement across imaging centers.

The clinical trial involves the use of the experimental medication **[68Ga]Ga-PentixaFor**, which is a **solution for injection**. This investigational product is composed of two active substances: **gallium (68Ga)** and **pentixafor**. The pharmaceutical form is a solution intended for intravenous administration. The maximum daily dose is set at 200 MBq, with a total maximum dose of 200 MBq over the treatment period. The administration is conducted intravenously, and the treatment period is limited to a maximum of 2 days. The product is manufactured by PentixaPharm AG and is classified under the ATC code V09IX, which pertains to other diagnostic radiopharmaceuticals for tumor detection.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of [68Ga]Ga-PentixaFor. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol. The trial aims to evaluate the efficacy of [68Ga]Ga-PentixaFor in the context of primary aldosteronism, specifically assessing its performance in comparison to adrenal venous sampling (AVS) for the identification and lateralization of aldosterone-producing adenomas (APAs).

Efficacy in the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on evaluating the concordance between **[68Ga]Ga-PentixaFor** PET/CT and adrenal venous sampling (AVS) for the identification and/or lateralization of aldosterone-producing adenomas (APAs) in patients with primary aldosteronism (PA). Additionally, the trial aims to assess the non-inferiority of **[68Ga]Ga-PentixaFor** PET/CT imaging compared to AVS in subtyping patients with PA, confirmed by the surrogate Standard of Truth (SoT) daily defined doses (DDD) after a 6-month follow-up period.

Secondary endpoints include establishing quantitative criteria for **[68Ga]Ga-PentixaFor** uptake in unilateral and bilateral PA, comparing quantitative PET/CT imaging data between different adrenal conditions, and assessing biochemical and clinical outcomes using the PASO criteria. The trial will also evaluate the reproducibility of **[68Ga]Ga-PentixaFor** PET/CT, intra- and inter-reader agreement, and inter-observer agreement between imaging centers. Additional assessments involve cost-effectiveness analysis, quality of life evaluation using the EQ-5D-5L questionnaire and the Short Form health survey (SF36), and determination of the rate of inconclusive results or failure of subtype diagnosis. Image quality will be assessed using parameters such as SUVmean, SUVmax, SUVpeak, lesion-to-liver ratio, contrast-to-noise ratio, and signal-to-noise ratio.