Mortality Benefit of Ultrasound for Thyroid Nodules Identified With PET Imaging: Non-Inferiority Emulated Target Trial

Mortality Benefit of Ultrasound for Incidental Thyroid Nodules Identified With PET Imaging: A Non-Inferiority Emulated Target Trial

The investigators hypothesize that all-cause mortality in patients with an incidental thyroid nodule on PET-CT who did not have thyroid ultrasound (the exposure) within 3 months of the PET-CT is non-inferior within a 5% margin to those who have thyroid ultrasound at 7-years. That is, among patients with an incidental thyroid nodule on PET-CT, mortality is no more than 5% larger (in absolute difference) for those who do not have thyroid ultrasound compared to those who do. The investigators will also report mortality differences at landmark timeframes of 1-year, 3-years, 5-years, and 10-years. To estimate group differences in mortality, the investigators will conduct a non-inferiority emulated target trial utilizing clone-censor weighting to address potential immortal time bias introduced by the 3-month grace period. The investigators will adjust for demographic, potential confounder, and mortality risk adjustor factors. The investigators will stratify analyses based on baseline disease severity (estimated 5-year relative survival risk) and disease status (progression, lymph node involvement, other sites of metastases). All subjects will be accrued from the Mass General Brigham healthcare system, which includes two academic medical centers, a specialty head and neck hospital, and multiple community hospitals and numerous community clinics.

Study Overview

• Status: Active, not recruiting
• Conditions: Thyroid Cancer; Thyroid Nodule (Benign); Thyroid Nodule (Diagnosis)
• Intervention / Treatment: Diagnostic test: Thyroid Ultrasound

Detailed Description

Study Hypothesis: The investigators hypothesize that all-cause mortality in patients with an incidental thyroid nodule on PET-CT who did not have thyroid ultrasound within 3 months is no worse than 5% lower than those who did have ultrasound.

Outcome Measures:

Primary Outcome: All-cause mortality. Secondary Outcomes: Numbers of thyroid cancer diagnoses, thyroid ultrasounds, thyroid biopsies, and thyroid surgeries Exploratory Outcomes: Types of thyroid cancer diagnoses

Study Population: All patients age 18-years and older with incidental thyroid nodule on PET-CT performed between 1/1/2015 and 12/31/2021.

Sites/Facilities: Mass General Brigham healthcare system including Massachusetts General Hospital, Brigham and Women's Hospital, Mass Eye and Ear, and associated community sites.

Exposure: Thyroid ultrasound evaluation within 3-months of PET-CT.

• Study Type: Observational
• Enrollment (Estimated): 5000

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Patients who had a PET-CT at Mass General Brigham 1/1/2015 to 12/31/2021

Description

Inclusion Criteria:

1. Age >=18
2. Thyroid nodule on PET-CT performed 1/1/2015 to 12/31/2021
3. At least one clinical note in the EHR from the 36-month window prior to the PET

Exclusion Criteria:

1. Thyroid ultrasound listed in the medical record in the prior 3 years
2. Documented history of prior thyroid cancer diagnosis

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients with thyroid nodule on PET	Diagnostic test: Thyroid Ultrasound; Thyroid ultrasound performed within 3 months of PET to characterize a thyroid nodule identified on the PET

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
All-Cause Mortality	7 Years

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of Thyroid Cancer Diagnoses	7 Years
Number of Thyroid Ultrasound Examinations	7 Years
Number of Thyroid Biopsies	7 Years
Number of Thyroid Surgeries	7 Years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Types of Thyroid Cancers	Exploratory	7 Years

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Harvard School of Public Health (HSPH); Agency for Healthcare Research and Quality (AHRQ)

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2025
• Primary Completion (Actual): November 30, 2025
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: November 20, 2025
• First Submitted That Met QC Criteria: November 20, 2025
• First Posted (Actual): December 1, 2025

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 17, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Pathologic Processes; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Thyroid Diseases; Pathological Conditions, Signs and Symptoms; Thyroid Nodule; Disease; Thyroid Neoplasms
• Other Study ID Numbers: 2024P002073-1; R18HS029839 (U.S. AHRQ Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All deidentified data used in the study analysis.
• IPD Sharing Time Frame: Study protocol with study analysis plan submitted at time of clinicaltrials.gov registration. IPD and analytic code will be shared upon manuscript publication.
• IPD Sharing Access Criteria: General public via the Harvard Dataverse repository.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No