Primary Aldosteronism
Conditions
Keywords
Primary aldosteronism, Aldosterone synthase, CYP11B2, [18F]-CETO, Baxdrostat, Molecular imaging, PET CT
Brief summary
The goal of this clinical trial is to find out whether treatment with baxdrostat changes aldosterone-producing activity in the adrenal glands of people with primary aldosteronism. The study will use specialised imaging to measure changes in the adrenal glands before and after treatment. Participants will receive baxdrostat for 24 weeks and will be followed for changes in their adrenal imaging, blood pressure and hormone levels. The study will also investigate whether changes caused by treatment continue after baxdrostat is stopped. This is a single-group study, meaning that all participants receive baxdrostat and there is no placebo or comparison group.
Detailed description
Primary aldosteronism (PA) is a common cause of hypertension in which the adrenal glands produce excess aldosterone. In some participants, the source of excess aldosterone can be associated with a small adrenal nodule. Aldosterone synthase, encoded by the CYP11B2 gene, is the enzyme responsible for the final steps of aldosterone production. Molecular imaging using \[18F\]-CETO PET-CT can be used to visualise aldosterone-producing tissue in the adrenal glands. This study will investigate whether treatment with the aldosterone synthase inhibitor baxdrostat produces a measurable reduction in aldosterone-producing activity on molecular imaging. This is an open-label, single-arm experimental medicine study. All participants will receive baxdrostat and there is no placebo or control group. Participants will receive baxdrostat 2 mg once daily for 24 weeks. Molecular imaging will be performed before treatment and following the treatment period, allowing the adrenal imaging signal to be compared within the same participant before and after treatment. The study is designed to investigate whether pharmacological inhibition of aldosterone synthase is associated with a quantitative reduction in the molecular imaging signal from aldosterone-producing adrenal tissue. It will also investigate whether changes in imaging are associated with changes in biochemical measures of aldosterone production and clinical measures such as blood pressure, and how long suppression of aldosterone production persists after treatment has ended. \[18F\]-CETO PET-CT is performed following dexamethasone pretreatment to suppress background uptake and improve visualisation of aldosterone-producing adrenal tissue. The radioligand is administered intravenously and PET imaging is performed together with a low-dose anatomical CT scan. Imaging will be undertaken at St Bartholomew's Hospital or Cambridge University Hospitals. Participants will undergo regular follow-up during and after treatment. Assessments include blood pressure measurements, blood tests for electrolytes and adrenal hormones, 24-hour urine collections for measurement of aldosterone-related biomarkers, and quality-of-life assessment. Follow-up after treatment will allow the investigators to assess whether biochemical and clinical effects of baxdrostat persist after treatment has stopped. The study also provides an opportunity to investigate the relationship between molecular imaging findings and subsequent clinical management. Where participants subsequently undergo adrenalectomy or ablation as part of their usual clinical care, adrenal tissue may be used for exploratory laboratory analyses of aldosterone synthase expression and markers of apoptosis. Adrenalectomy or ablation is not a research intervention and is not required by the study. The study uses a within-participant comparison of adrenal molecular imaging before and after baxdrostat treatment. Participants are stratified according to the characteristics of the largest \[18F\]-CETO-positive adrenal nodule, but there is no randomisation or allocation to different treatment groups. The study is intended to improve understanding of the effects of aldosterone synthase inhibition on aldosterone-producing adrenal tissue. The findings may help clarify the relationship between biochemical suppression of aldosterone production and changes in adrenal molecular imaging, and may inform the development of future approaches to the treatment and investigation of primary aldosteronism.
Interventions
DRUGbaxdrostat
Baxdrostat 2 mg administered orally once daily for 24 weeks as an aldosterone synthase inhibitor. Treatment begins after the baseline \[18F\]-CETO PET-CT has confirmed eligibility for study treatment.
Sponsors
Queen Mary University of London
AstraZeneca
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a single-arm, open-label experimental medicine study. All participants will receive the same intervention, baxdrostat 2 mg once daily for 24 weeks. There is no randomisation, placebo or control group. Participants will be stratified according to the characteristics of the largest \[18F\]-CETO-positive adrenal nodule for study analysis.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female * Age \> 18 years at time of signing informed consent. * Diagnosed with Primary Aldosteronism (PA) according to Endocrine Society guidelines * Presence of one or more adrenal nodules, (diameter 0.5-2.5 cm) on CT, PET-CT, or MRI, with characteristics (e.g. washout) of adenomas * Suppressed cortisol after overnight dexamethasone * Willing to take baxdrostat for 6 months and attend follow-up visits * Willing to undergo PET-CT imaging * Estimated glomerular filtration rate ≥ 45 mL/min/1.73m2 at Screening. * Serum potassium (K+) level ≥ 3.5 and \< 5.0 mmol/L * Negative pregnancy test for female participants of childbearing potential * Able and willing to provide written consent
Exclusion criteria
* \<18 years of age * Current or prior treatment (within 1 month before screening) with angiotensin-receptor blockers in combination with ACEIs. * Serum sodium level \< 135 mmol/L at screening, determined as per central laboratory. * The following known secondary causes of hypertension: renal artery stenosis, uncontrolled or untreated hyperthyroidism, uncontrolled or untreated hypothyroidism, pheochromocytoma, Cushing's syndrome, aortic coarctation. * New York Heart Association functional Heart Failure class IV at Screening. * Known current severe left ventricular outflow obstruction, such as obstructive hypertrophic cardiomyopathy and/or severe aortic valvular disease. * Known severe hepatic impairment. * Uncontrolled diabetes with HbA1c \> 10.0% (86 mmol/mol) at screening. * Participants suspected to have severe cardiac hypertrophy. * Treatment with any MRAs or potassium-sparing diuretics within 1 month prior to screening. * Treatment with potassium binders within 1 month prior to screening. * Is expected to receive or is receiving any of the exclusionary drugs such as strong inducers of cytochrome P450 (CYP) 3A, chronic (taken more than 3 times a week for more than 3 months) use of NSAIDs, MRAs or chronic use of systemic steroids. * Treatment with K+ supplements is not prohibited but the use should be continuously assessed throughout the trial. * Inability or unwillingness to undergo PET-CT imaging * Significant comorbidities that would interfere with participation * Pregnancy or breastfeeding * Unable to give informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in total lesion uptake of [18F]-CETO in adrenal lesions | Baseline to approximately 8 months | Change, between pre- and post-baxdrostat PET-CT images, in total \[18F\]-CETO-positive lesion uptake, calculated by multiplying the volume (ml) of each lesion by its mean standardised uptake value (SUVmean) (unitless) and summing these values across all lesions. SUVmean is a dimensionless ratio of measured to injected radioactivity. This calculation generates a single reported value, expressed in SUV·ml, the conventional unit for this measurement. \[Each lesion will be defined according to the 2025 European Association of Nuclear Medicine guideline.\] |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in SUVmax between pre- and post-baxdrostat PET-CT images | Baseline to approximately 8 months | Change, between pre- and post-baxdrostat PET-CT images, in maximum standardised uptake value (SUVmax) (unitless) of individual \[18F\]-CETO-positive lesions. SUVmax is a dimensionless ratio of measured to administered radioactivity. Where more than one lesion is present, SUVmax will be measured separately for each lesion and the values averaged to provide a single participant-level result. |
| Voxel level change between pre- and post-baxdrostat PET-CT images | Baseline to approximately 8 months | Voxel-level change in standardised uptake value (SUV) (unitless) between corresponding voxels across \[18F\]-CETO-positive lesions in pre- and post-baxdrostat PET-CT images. Pre- and post-treatment images will be registered to permit comparison of corresponding voxels, and the mean difference in SUV between paired voxels will be reported. SUV is a dimensionless ratio of measured to injected radioactivity. |
| Change in the individual components of the primary endpoint: 1. Volume | Baseline to approximately 8 months | Change, between pre- and post-baxdrostat PET-CT images, in total volume (ml) of all \[18F\]-CETO-positive lesions. Where more than one lesion is present, individual lesion volumes will be summed to generate a single reported value. |
| Change in the individual components of the primary endpoint - 2. mean SUV | Baseline to approximately 8 months | Change, between pre- and post-baxdrostat PET-CT images, in mean standardised uptake value (SUVmean) (unitless) across all \[18F\]-CETO-positive lesions. Where more than one lesion is present, a single overall SUVmean will be calculated across all lesions. SUVmean is a dimensionless ratio of measured to injected radioactivity. |
| Change in whole-adrenal [18F]-CETO uptake | Baseline to approximately 8 months | Change, between pre- and post-baxdrostat PET-CT images, in whole adrenal gland uptake of \[18F\]-CETO, calculated as the total volume (ml) of adrenal tissue with SUV ≥4 multiplied by the mean standardised uptake value (SUVmean) (unitless) within that volume. This calculation generates a single reported value, expressed in SUV·ml, the conventional unit for this measurement. SUVmean is a dimensionless ratio of measured to injected radioactivity. |
| Change in serum aldosterone 12 months after completion of baxdrostat treatment | End of baxdrostat treatment (24 weeks) to 12 months after treatment. | Change, between the end of baxdrostat treatment and 12 months after the end of treatment, in serum aldosterone (pmol/L). |
| Change in plasma renin activity 12 months after completion of baxdrostat treatment | End of baxdrostat treatment (24 weeks) to 12 months after treatment | Change, between the end of baxdrostat treatment and 12 months after the end of treatment, in plasma renin activity (nmol/L/hr). |
| Change in 24-hour urinary tetrahydroaldosterone 12 months after completion of baxdrostat treatment | End of baxdrostat treatment (24 weeks) to 12 months after treatment | Change, between the end of baxdrostat treatment and 12 months after the end of treatment, in 24h urine tetrahydroaldosterone (micromoles per 24h). |
| Change in systolic blood pressure 12 months after completion of baxdrostat treatment | End of baxdrostat treatment (24 weeks) to 12 months after treatment | Change, between the end of baxdrostat treatment (24 weeks) and 12 months after the end of treatment, in systolic blood pressure (mmHg). |
| Change in aldosterone-to-renin ratio 12 months after completion of baxdrostat treatment | End of baxdrostat treatment (24 weeks) to 12 months after treatment | Change, between the end of baxdrostat treatment (24 weeks) and 12 months after the end of treatment, in the ratio of serum aldosterone (pmol/L) to plasma renin activity (nmol/L/hr). The single measure resulting from division of aldosterone by plasma renin activity, termed the aldosterone-to-renin ratio (ARR), is expressed in (pmol/L)/(nmol/L/hr). |
| Change in serum 11-deoxycorticosterone after 12 weeks of baxdrostat treatment | Baseline to 12 weeks | Change, between baseline and 12 weeks of baxdrostat treatment, in serum 11-deoxycorticosterone (11-DOC) (pmol/L). |
| Change in serum 11-deoxycorticosterone after 24 weeks of baxdrostat treatment | Baseline to 24 weeks | Change, between baseline and 24 weeks of baxdrostat treatment, in serum 11-deoxycorticosterone (11-DOC) (pmol/L). |
| Change in serum 11-deoxycorticosterone 2 months after completion of baxdrostat treatment | Baseline to 2 months after completion of baxdrostat treatment | Change, between baseline and 2 months after completion of baxdrostat treatment, in serum 11-deoxycorticosterone (11-DOC) (pmol/L). |
| Change in serum 11-deoxycorticosterone 6 months after completion of baxdrostat treatment | Baseline to 6 months after completion of baxdrostat treatment | Change, between baseline and 6 months after completion of baxdrostat treatment, in serum 11-deoxycorticosterone (11-DOC) (pmol/L). |
| Change in serum 11-deoxycorticosterone 12 months after completion of baxdrostat treatment | Baseline to 12 months after completion of baxdrostat treatment | Change, between baseline and 12 months after completion of baxdrostat treatment, in serum 11-deoxycorticosterone (11-DOC) (pmol/L). |
Countries
United Kingdom
Contacts
CONTACTAklima Khatun
PRINCIPAL_INVESTIGATORMorris J Brown, FMedSci, FRS
Queen Mary University of London
Outcome results
None listed