CXCR4-directed [68Ga]Ga-PentixaFor PET/CT vs AVS performance in a diagnoStic randomized Trial Ultimately comparing hypertenSion outcome in primary aldosteronism

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.

This study has been transitioned to CTIS with ID 2024-512628-12-00 check the CTIS register for the current data.

Primary objectives
-To assess the concordance between [68Ga]Ga-PentixaFor PET/CT and AVS for
identification and/or lateralization of APAs in patients with PA. (Step 1)
-To assess non-inferiority in terms of clinical outcomes of [68Ga]Ga-PentixaFor
PET/CT imaging vs. AVS in subtyping of patients with PA randomized to either
[68Ga]Ga-PentixaFor PET/CT imaging or AVS confirmed by the surrogate Standard
of Truth (SoT) daily defined doses (DDD) in patients after 6 months follow-up.
(Step 2)


Secondary objectives
Step 1:
- To establish definitive quantitative criteria of [68Ga]Ga-PentixaFor uptake
in unilateral and bilateral PA for SUVs, liver-to-lesion ratio and
lesion-to-contralateral ratio.
- In patients who receive unilateral adrenalectomy, compare quantitative data
in PET/CT imaging between immunohistochemically (CYP11B2 and CXCR4 staining)
diagnosed multinodular hyperplasia and solitary adenomas.
- To assess biochemical and clinical outcomes based on PASO criteria (2)

Step 2:
- To asses biochemical and clinical outcomes after adrenalectomy of
[68Ga]Ga-PentixaFor PET/CT imaging vs AVS in subtyping patients with PA by
using the PASO criteria for clinical and biochemical outcome measures
(complete, partial or absent)
- To evaluate reproducibility of [68Ga]Ga-PentixaFor PET/CT by comparison of
two [68Ga]Ga-PentixaFor PET/CT scans with an interval of 1-14 days in the first
10 patients undergoing [68Ga]Ga-PentixaFor PET/CT.
- To assess intra- and inter-reader agreement of [68Ga]Ga-PentixaFor PET/CT for
subtyping for each imaging center.
- To analyze inter-observer agreement of [68Ga]Ga-PentixaFor PET/CT between the
imaging centers in terms of subtyping.
- In patients who receive unilateral adrenalectomy, compare quantitative data
in PET/CT imaging between immunohistochemically (CYP11B2 and CXCR4 staining)
diagnosed multinodular hyperplasia and solitary adenomas.
- To perform cost effectiveness analysis of AVS versus [68Ga]Ga-PentixaFor
PET/CT management.
- To evaluate quality of life as assessed by EQ-5D-5L questionnaire and the
Short Form health survey (SF36) of [68Ga]Ga-PentixaFor PET/CT versus AVS
management
- Determination of the rate of inconclusive results and/or failure of subtype
diagnosis by [68Ga]Ga-PentixaFor PET/CT imaging or AVS.
- To assess safety and intolerability.
- To assess image quality of [68Ga]Ga-PentixaFor PET/CT imaging, using the
SUVmean, SUVmax, and SUVpeak, lesion-to-liver ratio, contrast-to-noise ratio,
and signal-to-noise ratio.

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 five-center,
prospective, two-armed, diagnostic randomized controlled trial.

[68Ga]Ga-PentixaFor PET/CT

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.

In the second step, patients randomized to PET/CT will not undergo AVS. Those
patients receive 3.4 mSv in totaal for the PET/CT.
The first 10 patients the subpopulation undergoing PET/CT twice (in order to
assess reproducibility) receive 6.8 mSv in total for both PET/CTs. Both doses
are acceptable according to the NFU guidelines.