CETO First in Human Trial (CETO)

• ClinicalTrials.gov Identifier: NCT04529018
• Recruitment Status: Recruiting
• First Posted: August 27, 2020
• Last Update Posted: August 27, 2020
• Sponsor: University of Cambridge
• Collaborator: Cambridge University Hospitals NHS Foundation Trust
• Information provided by (Responsible Party): Professor Mark Gurnell, University of Cambridge

Study Description

Brief Summary:

The study is a Phase 1, single-centre, open label, micro-dosing study. The aim is to investigate an innovative new tracer, [18F]CETO, as a potential alternative to adrenal vein sampling for the lateralisation of primary aldosteronism (PA).

Condition or disease	Intervention/treatment	Phase
Primary Aldosteronism	Combination Product: [18F]CETO	Not Applicable

Detailed Description:

At least one-quarter of the UK adult population has hypertension, 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 difficult to control hypertension. It is challenging to determine whether one adrenal gland is the source of PA (which is potentially curable with surgery) or both glands (which would require long-term drug treatment). Existing lateralising procedures (i.e. investigations to distinguish one from two gland involvement e.g. CT or MRI scan) have significant limitations. Accordingly, most patients must undergo an invasive procedure called adrenal vein sampling (AVS) in which small catheters are placed in each adrenal vein. However, this is time-consuming, technically demanding, and fails in 20-50% of cases. To address this, researchers have adopted a novel approach using PET-CT as an alternative to AVS. Currently, this uses a tracer called metomidate labelled with carbon-11 (11C MTO), 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 half-life, which means the scan can only be performed in centres with a cyclotron facility (currently less than 10 NHS sites). The aim of this study is to investigate the safety of a new tracer with a longer half-life, [18F]CETO, that could be made available for use in many more centres.

The trial objectives are outlined below:

Primary Objective

To evaluate the safety of up to two administrations of [18F]CETO in up to 6 patients with primary aldosteronism and 5 healthy volunteers.

Secondary Objective

• Assess [18F]CETO uptake by the adrenal glands
• Evaluate uptake in bilateral vs unilateral cases of PA following [18F]CETO administration in up to 6 patients.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 11 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Phase I single-centre, open-label, micro-dosing study
• Masking: Single (Outcomes Assessor)
• Masking Description: Scans will be assessed by two independent nuclear medicine physicians, who will be blinded to patient identifiable data when analysing PET-CT scans.
• Primary Purpose: Diagnostic
• Official Title: A 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
• Actual Study Start Date: August 3, 2020
• Estimated Primary Completion Date: November 30, 2020
• Estimated Study Completion Date: November 30, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Healthy Volunteers; A group of 5 healthy volunteers will be tested with the PET radiotracer [18F]CETO to assess safety of tracer administration, and evaluate uptake by the normal adrenal glands.	Combination Product: [18F]CETO; [18F]CETO is a PET radiotracer used to diagnose and visualise the cause(s) of primary aldosteronism; Other Name: CETO
Experimental: Patients with primary aldosteronism; A group of 6 patients with Primary Aldosteronism (3 with unilateral and 3 with bilateral disease) will be tested with up to two administrations of the PET radiotracer [18F]CETO, to assess safety of tracer administration, evaluate the ability of [18F]CETO to distinguish between unilateral and bilateral cases of PA, and determine the effect of Dexamethasone in improving the quality of PET-CT images acquired following administration.	Combination Product: [18F]CETO; [18F]CETO is a PET radiotracer used to diagnose and visualise the cause(s) of primary aldosteronism; Other Name: CETO

Outcome Measures

Primary Outcome Measures :

1. Safety of [18F]CETO administration [ Time Frame: 6 months ]
   The primary outcome measure is the overall safety of [18F]CETO. This will be assessed according to the frequency of adverse events, serious adverse events, clinically significant changes in vital signs, ECG and laboratory parameters.

Secondary Outcome Measures :

1. [18F]CETO uptake by the the adrenal glands. [ Time Frame: 6 months ]
   [18F]CETO uptake by the adrenal glands will be assessed by measurement of Standardized Uptake Values (SUV) over the left and right adrenal glands. All assessments will be performed by a dedicated blinded reviewer.
2. To evaluate uptake in bilateral versus unilateral cases of PA following [18F]CETO administration in up to 6 patients. [ Time Frame: 6 months ]
   Evaluation of adrenal uptake of [18F]CETO in bilateral versus unilateral cases of PA will be performed by comparing SUV values of both adrenal glands in three patients with each subtype of PA (using a dedicated blinded reviewer).

Eligibility Criteria

• Ages Eligible for Study: 40 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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.

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.

Additional exclusion criteria for healthy volunteers:

• women of child-bearing potential (i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile)
• 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)

Contacts and Locations

Contacts

Contact: Martin Thomas, PhD; 01223 254 920; martin.thomas@addenbrookes.nhs.uk

Contact: Russell Senanayake, MRCP, MSc; 01223 348 739; russell.senanayake@nhs.net

Locations

United Kingdom

Addenbrooke' Hospital; Recruiting

Cambridge, Cambridgeshire, United Kingdom, CB20QQ

Contact: Mark Gurnell, FRCP, PhD 01223 348739 mg299@medschl.cam.ac.uk

Contact: Martin Thomas, PhD 01223 254 920 martin.thomas@addenbrookes.nhs.uk

Sub-Investigator: Russell Senanayake, MRCP, MSc

Sub-Investigator: Waiel Bashari, MRCP, MSc

Sub-Investigator: James MacFarlane, MRCP

Sponsors and Collaborators

University of Cambridge

Cambridge University Hospitals NHS Foundation Trust

Investigators

• Principal Investigator: Mark Gurnell, PhD, FRCP; University of Cambridge

More Information

Publications:

Burton TJ, Mackenzie IS, Balan K, Koo B, Bird N, Soloviev DV, Azizan EA, Aigbirhio F, Gurnell M, Brown MJ. Evaluation of the sensitivity and specificity of (11)C-metomidate positron emission tomography (PET)-CT for lateralizing aldosterone secretion by Conn's adenomas. J Clin Endocrinol Metab. 2012 Jan;97(1):100-9. doi: 10.1210/jc.2011-1537. Epub 2011 Nov 23.

Hahner S, Stuermer A, Kreissl M, Reiners C, Fassnacht M, Haenscheid H, Beuschlein F, Zink M, Lang K, Allolio B, Schirbel A. [123 I]Iodometomidate for molecular imaging of adrenocortical cytochrome P450 family 11B enzymes. J Clin Endocrinol Metab. 2008 Jun;93(6):2358-65. doi: 10.1210/jc.2008-0050. Epub 2008 Apr 8.

Bergström M, Juhlin C, Bonasera TA, Sundin A, Rastad J, Akerström G, Långström B. PET imaging of adrenal cortical tumors with the 11beta-hydroxylase tracer 11C-metomidate. J Nucl Med. 2000 Feb;41(2):275-82.

• Responsible Party: Professor Mark Gurnell, Professor in Clinical Endocrinology and Honorary Consultant, University of Cambridge
• ClinicalTrials.gov Identifier: NCT04529018
• Other Study ID Numbers: CETO-FIH; 2018-004851-18 ( EudraCT Number ); ISRCTN16159564 ( Other Identifier: ISRCTN registry )
• First Posted: August 27, 2020
• Last Update Posted: August 27, 2020
• Last Verified: August 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Professor Mark Gurnell, University of Cambridge:

Adrenal; Conn's; Endocrine; Aldosterone

Additional relevant MeSH terms:

Hyperaldosteronism; Adrenocortical Hyperfunction; Adrenal Gland Diseases; Endocrine System Diseases