Preoperative Localization Strategies in Primary Hyperparathyroidism

NCT ID: NCT04305561

Last Updated: 2022-04-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 172 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-09-05
• Study Completion Date: 2021-12-31

Brief Summary

The purpose of this project is to examine, in a non-inferiority study, whether the combination of conventional ultrasound and contrast-enhanced ultrasound (CEUS) can replace the radiation-based imaging modalities that are currently used to localize pathological parathyroid glands prior to surgical removal in patients with primary hyperparathyroidism.

This will take the form of a prospective paired cohort study where included patients receive a contrast-enhanced ultrasound examination in addition to the standard preoperative imaging regimen (subtraction scintigraphy with SPECT/CT and conventional ultrasound). Patients act as their own controls as all included patients undergo both CEUS and conventional imaging.

Detailed Description

The human body has four parathyroid glands. These are located in the neck at the backside of the thyroid gland. The four glands produce parathyroid hormone which regulates the amount of calcium in the blood. If one or more of the thyroid glands becomes hyperactive, too much parathyroid hormone is secreted into the blood. This condition is called hyperparathyroidism and results in elevated serum calcium levels. If left untreated, hyperparathyroidism may result in weak bones (osteoporosis), bone fractures, kidney stones and a myriad of unspecific symptoms.

In the vast majority of cases, only one of the four parathyroid glands is responsible for the disease, and the cure is surgical excision of the hyperactive gland. Such a surgery has traditionally involved a dissection of both sides of the neck, allowing the surgeon to visually inspect all four parathyroid glands to determine which gland(s) were hyperactive. Nowadays, if the hyperactive gland can be identified by parathyroid imaging prior to surgery, the surgeon can perform a minimally invasive procedure, focusing on the removal of a single gland. Such a focused procedure minimizes surgical risks and results in a shorter duration of surgery.

The parathyroid imaging regimen currently requires two out-patient visits on two separate days. The patient first visits the Department of Nuclear Medicine where a scan involving two radioactive tracers (a subtraction scintigraphy) and a 3D-examination (a SPECT/CT scan) are performed. The second visit takes place at the department of Head and Neck Surgery, where a head and neck surgeon performs an ultrasound examination of the neck.

The scans at the Department of Nuclear Medicine require the patient to lie completely still for a long time, expose the patient to some degree of radiation, and are relatively expensive. The ultrasound examination is fast and inexpensive, but isn't as sensitive as the scintigraphy (76% versus 70-92%).

Our project attempts to increase the sensitivity of the ultrasound examination by adding on an intravenous contrast agent. The contrast agent stays solely within the blood vessels, where it enhances the ultrasound signal. Contrast-enhanced ultrasound (CEUS) does not expose the patient to radiation, is fast to carry out, and the patient can be informed about the result of the scan immediately.

We hope that by introducing CEUS, we can change the order in which patients are examined prior to surgery, meaning that ultrasound - with or without an added contrast agent - will be the primary parathyroid imaging modality, and that patients will only continue to the Department of Nuclear Medicine if the result of the CEUS examination is uncertain.

Purpose

The purpose of this project is to examine, in a non-inferiority study, whether the combination of conventional ultrasound and contrast-enhanced ultrasound (CEUS) can replace the radiation-based imaging modalities that are currently used to localize pathological parathyroid glands prior to surgical removal in patients with primary hyperparathyroidism.

Method

This will take the form of a prospective paired cohort study where patients receive a contrast-enhanced ultrasound examination in addition to the standard preoperative imaging regimen (subtraction scintigraphy with SPECT/CT and conventional ultrasound). The CEUS examiner will be blinded to the results of the subtraction scintigraphy and SPECT/CT. The surgeon will have access to the results of all the preoperative imaging procedures, including CEUS. Correct localization of a hyperactive parathyroid gland on preoperative imaging is confirmed by a histological examination of the surgical specimen.

Conditions

Primary Hyperparathyroidism

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: SINGLE

Study Groups

Ultrasound + Contrast-enhanced ultrasound

Patients are offered a contrast-enhanced ultrasound (CEUS) examination in addition to conventional imaging. All included patients undergo both CEUS and conventional imaging, enabling them to act as their own controls.

Pilot study: 60 patients Main study: 112 patients

Group Type: OTHER

Contrast-enhanced ultrasound

Intervention Type: PROCEDURE

Ultrasound contrast agent: Stabilized sulfur hexafluoride microbubbles (SonoVue®, Bracco).

An 18 G needle will be placed in an antecubital vein and directly attached to a three-way stopcock with an extension tube.

The SonoVue® will be prepared and shaken shortly before injection in accordance with the instructions provided in the product information leaflet.

The patient will be injected with 1.2 ml SonoVue® at a pace of 1-2 ml/s using the 180 degree straight-flow channel of the three-way stopcock, directly followed by a 10 ml bolus of sodium chloride 9 mg/mL (0.9%) injected into the 90 degree channel of the three-way stopcock at a pace of approximately 2 ml/s.

A full examination will typically require one to two injections of 1.2 ml of SonoVue® (one injection per suspected parathyroid adenoma).

Conventional imaging

Dual-tracer 99mTechnetium-pertechnetate/ 99mTechnetium-sestamibi subtraction scintigraphy with single-photon emission computerised tomographic/CT fusion imaging (SPECT/CT) combined with conventional ultrasound.

Pilot study: 60 patients Main study: 112 patients

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Contrast-enhanced ultrasound

Ultrasound contrast agent: Stabilized sulfur hexafluoride microbubbles (SonoVue®, Bracco).

An 18 G needle will be placed in an antecubital vein and directly attached to a three-way stopcock with an extension tube.

The SonoVue® will be prepared and shaken shortly before injection in accordance with the instructions provided in the product information leaflet.

The patient will be injected with 1.2 ml SonoVue® at a pace of 1-2 ml/s using the 180 degree straight-flow channel of the three-way stopcock, directly followed by a 10 ml bolus of sodium chloride 9 mg/mL (0.9%) injected into the 90 degree channel of the three-way stopcock at a pace of approximately 2 ml/s.

A full examination will typically require one to two injections of 1.2 ml of SonoVue® (one injection per suspected parathyroid adenoma).

Intervention Type: PROCEDURE

Eligibility Criteria

Inclusion Criteria

• Patients 18 years and older with primary hyperparathyroidism (defined as an ionized calcium level above the upper reference level and a concomitant parathyroid hormone level in or above the upper third of the reference interval with no other known reason for the hyperparathyroid hypercalcemia) referred to the Department of ORL, Head and Neck Surgery at Odense University Hospital for parathyroidectomy.

Exclusion Criteria

• Allergy to the contrast agent SonoVue®.
• Not legally competent.
• Does not read or speak Danish.
• Other causes of hypercalcemia (e.g. familial hypocalciuric hypercalcemia, pharmacologically or neoplastically induced hypercalcemia, secondary or tertiary hypercalcemia, uncontrolled hyperthyroidism, adrenal insufficiency, granulomatous diseases).
• Persistent or recurrent hyperparathyroidism.
• Previous surgery to the thyroid or the parathyroid glands.
• Current malignancy.
• Breastfeeding.
• Pregnancy.
• Contraindications to the use of SonoVue® (right-to-left shunts, severe pulmonary hypertension (pulmonary pressure >90 mmHg), uncontrolled systemic hypertension, adult respiratory distress syndrome, recent acute coronary syndrome, clinically unstable ischaemic cardiac disease within the last seven days, severe heart rhythm disorders, acute heart failure, or chronic heart failure class III or IV according to the New York Heart Association).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Odense University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Sanne Høxbroe Michaelsen

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Odense University Hospital

Odense C, , Denmark

Countries

Denmark

References

Michaelsen SH, Bay M, Gerke O, Vestergaard S, Graumann O, Nielsen VE, Madsen AR, Bonnema SJ, Godballe C. Evaluation of Surgeon-Performed Ultrasonography With or Without Contrast Enhancement vs Scintigraphy in Patients With Primary Hyperparathyroidism. JAMA Otolaryngol Head Neck Surg. 2023 Jun 1;149(6):531-539. doi: 10.1001/jamaoto.2023.0389.

Reference Type: DERIVED

PMID: 37052913 (View on PubMed)

Other Identifiers

S-20190077

Identifier Type: -

Identifier Source: org_study_id