CETO

A first in man phase 1 clinical trial evaluating the safety and efficacy of up to two administrations of the adrenal PET tracer [18F]CETO in healthy volunteers and patients with primary aldosteronism

Research summary

At least one-quarter of the UK adult population has hypertension, which is a major risk factor for heart attacks and stroke. Primary aldosteronism (PA), a treatable form of hypertension, accounts for 5-10% of all cases, and 20-25% of those with difficult to control (‘resistant’) hypertension. Determining whether one (potentially curable with surgery) or both (requiring long-term drug treatment) adrenal glands are the source of PA in any given patient remains challenging. Existing lateralising procedures (i.e. investigations to distinguish one from two gland involvement) include computed tomography (CT) or magnetic resonance imaging (MRI). However, these often lack appropriate sensitivity and specificity, while the highly invasive adrenal vein sampling (AVS), in which small catheters are placed into each adrenal vein, is time-consuming, technically demanding, and fails in 20-50% of cases. Such diagnostic challenges have traditionally resulted in less than 300 adrenalectomies per year in the UK for PA (HES data). Therefore, there is an urgent need for an accurate and more widely available method for reliably diagnosing the cause of PA.

To address this, we have adopted a novel diagnostic approach using positron emission tomography-computed tomography (PET-CT) as an alternative to AVS. Currently, this uses metomidate labelled with carbon-11 ([11C]MTO) as a radiotracer, which is taken up preferentially by the adrenal gland, and in particular by adrenal tumours causing PA. However, its utility is limited by a short tracer half-life, which means the scan can only be performed in centres with an on-site cyclotron facility (currently less than 10 NHS sites in the UK). We, therefore, wish to investigate an innovative new tracer with a longer half-life, [18F]CETO, for the lateralisation of PA.

AVS is currently the gold standard for lateralisation in PA. However, it has several limitations, including technical failures and a need to discontinue confounding medications that may interfere with interpretation. These severely limit its availability and utility in routine clinical practice. Our solution to address this has been to use PET coupled with the radiopharmaceutical [11C]metomidate ([11C]MTO) for molecular adrenal imaging. However, [11C]MTO is limited by a short half-life (t1/2 = 20 minutes) therefore restricting this imaging modality to facilities with an on-site cyclotron. [18F]CETO has a longer half-life (t1/2= 110 minutes). It can be distributed to centres 100-150 miles from the primary radiopharmacy site. Preclinical studies have suggested a higher adrenal selectivity with reduced uptake by adjacent organs (e.g. liver, spleen) in comparison to [11C]MTO. Therefore, we anticipate [18F]CETO will offer increased efficacy in PA lateralisation in addition to promoting the creation of a national network for molecular imaging in PA.

The expected dose of [18F]CETO is in the range of 0.2µg to 2µg which is based on data from a validated production method as described in the investigational medicinal product (IMP) dossier. The selected dose is close to the maximum allowed, estimated from dosimetry calculations and taking into account animal in vivo studies. Based on clinical data derived from this study, we will be able to predict what dose should be sufficient to give the required signal to noise ratio, and to be used in future studies. The administration of up to 10µg of the study drug is regarded as safe due to [18F]CETO being a very close analogue to the well-known registered drug Etomidate. The total radiation dose to patients participating in two [18F]CETO PET-CT scans is below 10mSv which is the current standard limit for healthy controls in clinical PET research studies. There is no anticipated clinical benefit for participants in this study. This is a Proof-of-Concept study to investigate the safety and efficacy of [18F]CETO.

This is a Phase 1, single-centre, open-label, micro-dosing study, conducted at Cambridge University Hospitals NHS Foundation Trust. We intend to recruit 11 participants: 5 of these subjects will be healthy controls, and 6 will be patients with PA (three with unilateral disease and three with bilateral disease as lateralised on prior AVS). Recruitment of healthy volunteers and patients will occur concurrently (i.e. it will not be necessary for all healthy volunteers to be recruited before patients will be recruited). The trial duration will be approximately 1 month.

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Main inclusion criteria

Healthy Volunteers
To be included in the trial the participant must:

  • give written informed consent
  • be aged 50 years or over
  • have no underlying medical conditions
  • be able to lie down for at least 2 hours and not be claustrophobic

In addition, all female participants must be:

  • post-menopausal (no menses for 12 months, without an alternative medical cause)

Patients

To be included in the trial the patient must:

  • give written informed consent
  • be aged 40 years or over
  • be able to lie down for at least 2 hours and not be claustrophobic
  • fulfil the following criteria:
    • have a confirmed diagnosis of PA as per Endocrine Society guidelines
      • At least one paired measurement of plasma renin and aldosterone, measured off Spironolactone/Eplerenone within past 12 months, showing ARR above local threshold value.
      • One of the following two criteria:
        • Plasma aldosterone>190pmol/L following saline infusion.
        • Spontaneous hypokalaemia, suppressed plasma renin and plasma aldosterone>550pmol/L.
    • have undergone successful lateralisation of the cause of PA to one or both adrenal glands by adrenal vein sampling (AVS).
    • be willing to have two scans

In addition, all female patients must have a negative (blood) pregnancy test at the screening visit.

Main exclusion criteria

All participants:

  • allergy to radiographic contrast agents
  • allergy or contraindication to synacthen
  • pregnancy, breastfeeding, or the intention to become pregnant during the 6 months following trial participation
  • positive pregnancy test at the screening or baseline visits
  • assessed by the investigator as being unable or unwilling to comply with the requirements of the study protocol.
  • receipt of another IMP as part of a CTIMP
  • prior radiation exposure as part of previous research studies
  • recreational drug use, or substance/alcohol dependency
  • clinically abnormal screening blood tests [including abnormal short synacthen test (SST)].

Additional exclusion criteria for healthy volunteers:

  • women of child-bearing potential (i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy)
  • exposure to radiation during their work
  • received more than 10 mSv of radioactivity in the past 12 months
  • any subject with a history of adrenal disease or who, at the screening visit, reports symptoms, or exhibits physical signs, that could be consistent with previously unsuspected adrenal disease

Additional exclusion criteria for patients:

  • allergy or contraindication to dexamethasone treatment (or lactose intolerant)


Chief investigator

Professor Mark Gurnell

Contact details

Clinical Trials ManagerDr Paula Kareclas

Telephone: 01223 596473 | Email: paula.kareclas@addenbrookes.nhs.uk