Hypothesis
We hypothesize that, for intermediate-risk thyroid papillary carcinoma patients with no structural or functional metastases and ps-Tg 1–20 ng/ml, the 3-year disease-free survival of low-dose 131I (1.1 GBq) may not be lower than that of high-dose 131I (3.7 GBq).
Primary objective
Our main objective is to compare the 3-years disease-free survival between low-dose 131I (1.1 GBq) and high-dose 131I (3.7 GBq) in intermediate-risk thyroid papillary carcinoma patients with no structural or functional metastases and ps-Tg 1–20 ng/ml.
Secondary objectives
The study will evaluate the efficacy, safety and health economics of low dose 131I (1.1 GBq).
Trial design
This is a prospective, single-center, randomized, double-blinded (patient and researcher) parallel controlled, non-inferiority study. The trial is conducted at the Nuclear Medicine Department, Zhujiang Hospital of Southern Medical University. The follow-up period is 3 years. The study has been registered at ClinicalTrials.gov (ID: NCT04354324). Figure 1 shows an overview of the trial.
Sample size
Eligible patients will be randomly assigned to low-dose (1.1 GBq)/intervention group and high-dose (3.7 GBq)/control group with a 1:1 ratio. According to literature reports and pre-clinical data [6–8], the disease-free survival of the control group is 92%, non-inferiority cut-off value is δ = 7%. A total of 254 subjects are generated from α = 0. 025 (one-sided test), Power = 0.8, proportion = 0.5 (control group) and lost rate = 10% (two groups) by PASS 12.0 software (NCSS, US).
Population
Subjects admitted to our department for 131I therapy are recruited by the research staff by means of propaganda, science popularization and so on. Eligible subjects who agree to participate in the study will have to sign a written informed consent that has been approved by the Ethics Committee before any screening process or evaluation. A total of 254 patients with PTC will be enrolled in the study from April 2020 to June 2024 at the department of Nuclear Medicine, Zhujiang Hospital of Southern Medical University.
Inclusion criteria
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Patients with histological confirmation of intermediate-risk PTC according to 2015 ATA Management Guidelines [5];
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DTC patients who underwent total or near-total thyroidectomy according to 2015 ATA guidelines;
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The level of serum ps-Tg at least 28 days after surgery is 1–20 ng/ml without or withdraw levothyroxine for 3 weeks at least;
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Age is ≥ 16 years old;
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Patients who volunteer to participate in the study and sign informed consent.
Exclusion criteria
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Image, for example ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI) or 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and so on, indicates the presence of metastases;
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131I whole body scan indicating the presence of metastases outside the thyroid bed;
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Patients with positive Tg antibody (TgAb) (≥ 115 Ku/L);
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Patients who have other coexisting serious diseases or other factors that may affect the outcome of ablation;
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Pregnant or breastfeeding women, or with birth planning within six months.
Randomization
A simple randomization method is used in this study. A statistician uses SPSS 20.0 software (IBM, Armonk, NY) to generate 254 random numbers, which are then randomly divided into groups A and B in a 1:1 ratio to form a random distribution table. The statistician determines the dosage (1.1GBq or 3.7GBq) of group A and group B in advance, and retains the random distribution scheme in the form of a document, which is sealed and stored.
Sealed envelope method is used to realize grouping concealment. The statistician responsible for the grouping concealment distributes the results in 254 light-tight envelopes to the researchers. The researchers open the envelopes in the order of enrollment, according to the allocation scheme in the envelopes, and determine the group of patients (group A or group B), so as to avoid the possibility of selectively deciding whether a certain study object should be included in the enrollment of patients because the researchers know the whole grouping order in advance.
Blinding
The randomization will be performed using a code list created by the statisticians of Zhujiang Hospital of Southern Medical University. The trial staff will not know the arm of allocation (double-blind study). Technician in our department will prepare treatment kits assigning them the identification codes following the randomization lists. Only if necessary, for the safety of patients, the single kit code will be open by the investigators during the study period.
Interventions
The test group and the control group will receive oral administration of 1.1 GBq and 3.7 GBq, respectively, once on an empty stomach. The interventions in this trial are one-time interventions. The researchers will stand by to see if the patients finish the drink while they take the medicine. The test drug and control drug are prepared (the radioactive activity is measured with instruments) by technician who are unblinded. The outer packing and volume of the two groups are the same, but the dosage forms are different, and the packing will be marked as A or B. Therefore, the products of the two groups cannot be distinguished with the naked eyes but measuring instruments. After the randomization is completed, drugs are distributed to participants according to their group number (A or B).
Research process
The research process is divided into three phases: screening stage, treatment stage and following stage. Combined medications and adverse events record will be collected at every stage. Time schedule of the study is shown in Table 1.
Table 1
Schedule of the study process.
Stage
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Selection
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Treatment
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Follow-up
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Sequence
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1
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2
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3
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4
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5
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6
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7
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8
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9
|
10
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Time (m, month)
|
-1week
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0
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1m
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3m
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6m
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12m
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18m
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24m
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30m
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36m
|
Basic information collection
|
|
|
|
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|
|
|
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Signed informed consent
|
√
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|
|
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|
|
|
|
|
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Inclusion and exclusion criteria
|
√
|
|
|
|
|
|
|
|
|
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Demographic characteristics
|
√
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|
|
|
|
|
|
|
|
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Medical and treatment history
|
√
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|
|
|
|
|
|
|
|
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Combined disease and medication
|
√
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√
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√
|
√
|
√
|
√
|
√
|
√
|
√
|
√
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Physical examination
|
√
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√
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√
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√
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√
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√
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√
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√
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√
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√
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Effectiveness observation index
|
|
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|
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|
|
|
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Neck ultrasound
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√
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√
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√
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√
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√
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√
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√
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√
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√
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Thyroid function testsa
|
√
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√
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√
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√
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√
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√
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√
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√
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√
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√
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Tg
|
√
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√
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√
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√
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√
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√
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√
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√
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√
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√
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TgAb
|
√
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√
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√
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√
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√
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√
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√
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√
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√
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√
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Neck and chest CT
|
√
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|
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√
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|
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√
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131I whole-body scan
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√
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√
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It will be performed in 6–12 months after the initial treatment for patients who does not achieve excellent response.
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Optional examination
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Neck MRI
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If the neck ultrasound indicates suspicious lymph nodes, but the diagnosis cannot be confirmed
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18FDG-PET/CT
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sTg ≥ 10 ng/ml in 6–12 months after the initial treatment.
|
Disease-free Survival (primary)
|
√
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√
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√
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√
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√
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√
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√
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√
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√
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√
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Successful remnant ablation
|
√
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√
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√
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√
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√
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√
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√
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√
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√
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√
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Curative effect
|
√
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√
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√
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√
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√
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√
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√
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√
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√
|
√
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Progression-free survival
|
√
|
√
|
√
|
√
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√
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√
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√
|
√
|
√
|
√
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Safety index
|
|
|
|
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|
|
|
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|
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Gastrointestinal side effect
|
|
√
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√
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√
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√
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√
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√
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√
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√
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√
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Radiation thyroiditis
|
|
√
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√
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√
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√
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√
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√
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√
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√
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√
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Salivary adenitis
|
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√
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√
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√
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√
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√
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√
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√
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√
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√
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Hematopoietic system adverse reactions
|
|
√
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√
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√
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√
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√
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√
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√
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√
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√
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Reproductive system
|
|
√
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√
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√
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√
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√
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√
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√
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√
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√
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Secondary cancer
|
|
√
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√
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√
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√
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√
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√
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√
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√
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√
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Adverse event
|
|
√
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√
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√
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√
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√
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√
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√
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√
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√
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Health Economics Evaluation Index
|
|
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|
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Hospital isolation date
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|
√
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Hospital costs
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|
√
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Others
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Random grouping
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|
√
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|
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CT: computed tomography; MRI: magnetic resonance imaging; 18F-FDG PET/CT: 18F-fluorodeoxyglucose positron emission tomography/computed tomography. |
a. Thyroid function tests including FT3, FT4 and thyroid stimulating hormone (TSH). |
Outcomes
Primary outcome
The primary outcome is disease-free survival, defined as the percentage of patients who achieve excellent responses during the 3-year follow-up period.
Secondary outcomes
The secondary outcomes include:
1. Effectiveness evaluation indexes [5]:
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Successful remnant ablation: subjects evaluated at 6–12 months after the initiation of treatment meet one of the following two conditions: (a) absence radioactive iodine uptake in the thyroid bed according to a diagnostic 131I whole-body scan; (b) serum stimulated Tg is < 1 ng/ml or suppressed Tg is < 0.2 ng/ml.
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Efficacy: judged by response-to-therapy categories (see Table 2).
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Progression-free survival: subjects who meet any one of the following conditions are seen as progression survival: (a) Functional or structural metastases appear during follow-up; (b) when sTg > 1 ng/ml or suppressed Tg > 0.2 ng/ml, the serum Tg level increases by more than 25% compared to the previous; (c) TgAb was negative at the time of enrollment, and it is positive and persistently elevates during follow-up. The others are defined as progression-free survival.
2. Safety indexes: the incidence of short-term and long-term adverse reactions after 131I treatment (Time points to distinguish short-term and long-term is 3 months), including gastrointestinal side effect, radiation thyroiditis, salivary adenitis, myelosuppression, secondary cancer, etc. (see Table 3).
3. Health economics evaluation indexes: average hospital isolation day and the cost of hospitalization when patients receive treatment. The hospital isolation day is determined by the radiation dose in the patient's body, and the national discharge standard must be met when discharged (400 MBq or 25 µSv/h).
Table 2
Stratification of efficacy.
Excellent response
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Biochemical incomplete response
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Structural incomplete response
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Indeterminate response
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Negative image; met one of the following: 1) Suppressed Tg < 0.2 ng/mla; 2) sTg < 1 ng/mla.
|
Negative image; meet one of the following: 1) suppressed Tg ≥ 1 ng/mla; 2) sTg ≥ 10 ng/mla; 3) TgAb persistently elevated during follow-up.
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Evidence of structural or functional disease from image (suspicious lymph nodes on ultrasound); any level of Tg and TgAb.
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Negative image; suppressed Tg detectable, but < 1 ng/ml; meet any one of following: 1) sTg detectable, but < 10 ng/ml; 2) TgAb stable or declining.
|
Tg: thyroglobulin; sTg: stimulated thyroglobulin; TgAb: anti-thyroglobulin antibody. |
a. When TgAb is negative. |
Table 3
Adverse reactions after 131I treatment.
Adverse Reactions
|
Details
|
Gastrointestinal side effect
|
Nausea, vomit, abdominal distension, constipation, decreased appetite, etc.
|
Radiation thyroiditis
|
Swelling and pain in the thyroid area, swallowing pain, dysphagia, etc.
|
Salivary adenitis
|
Pain and swelling of the salivary, dry mouth, taste alteration, dental caries, etc.
|
Hematopoietic system adverse reactions
|
Myelosuppression includes leukopenia, thrombocytopenia, erythrocytopenia, aplastic anemia
|
Reproductive system
|
Infertility, irregular menses, abortion, stillborn
|
Secondary cancer
|
Various secondary tumors
|
Adverse event reporting and harms
It was reported in the literature that the incidence of adverse reactions was high when 131I dose exceeded 18.5–22.2 GBq. In this study, low and high doses of 131I (1.1 GBq and 3.7 GBq) are given in one time to treat differentiated thyroid cancer, which are relatively low and safe. The most common adverse reactions after 131I treatment, such as acute gastrointestinal reactions, radioactive thyroiditis and salivary adenitis, can be alleviated after general observation or symptomatic treatment. All adverse events reported by participants or detected by physicians will be recorded in the case report form (CRF), and all serious adverse events will be reported to the Ethics Review Committee.
Retention
A coordinator will be assigned to each subject responsible for a CRF to ensure adequate recording of every participant’s data. When the participant withdraws from the trial, record the reasons for withdrawal. Subjects will enjoy the following rights:
(1) Enjoy a free thyroid function test once a year;
(2) During the study, Emission Computed Tomography (ECT), bone density, thyroid iodine uptake test and urine iodine tests shall be free of charge according to the needs of the disease (the required drug fees will not be within the free range, only the cost of drugs will be charged);
(3) Provide free internal radiation monitoring for individuals;
(4) Free lifelong thyroid cancer consultation;
(5) Enjoy priority medical services.
Data collection
1. Establishment of standard operating procedures
Prior to the start of the trial, the investigator and sponsor / Contract Research Organization (CRO) will discuss the formulation of standard operating procedures for clinical trials, in order to unify the operation methods, judgment standards and record forms during the trial process, so that researchers will strictly implement the protocol.
2. Training of researchers
Prior to the start of the trial, the main investigators and monitors of each center will organize training for all medical staff participating in the trial, including clinical trial protocols, clinical trial manuals, standard operating procedures, special precautions, etc.
3. Ensure the reliability and accuracy of the instrument
The various instruments, equipment, actuals, standards, etc. used in various inspection items in clinical trials should have strict quality standards and ensure that they work under normal conditions.
Statistical analysis
SAS9.4 statistical software is used for statistical analysis. All statistical inferences are performed by two-sided test. The statistically significant test level is set to 0.05, and the confidence interval of the parameters is estimated to be 95% confidence interval. Use the parametric method as much as possible. When the data do not meet the conditions of the parameter method, it can be analyzed by the conversion method. If still not satisfied, consider using a non-parametric method.
A descriptive analysis of baseline data (including demographic indicators, etc.) will be performed. As for abnormal data, analysis of causes will be carried out to exclude objective and subjective reasons.
The integrity of the data is monitored in real time. If the patient is found not to be followed up in time, he will be notified by phone and the data will be filled in time. Withdrawal subjects do not fill in the data. The missing values are replaced by sequence averages.
Confidentiality
In order to protect and respect the privacy of the participants, unless necessary, the names of them will not be used directly, but anonymous numbering. Prior consent is required for the use of a tape recorder, camera, etc. When the researcher needs to use the medical records or relevant documents, he/she shall obtain the prior consent of the relevant authorities and shall not use them without authorization. When the research results are published, the identity of the research subjects shall not be implied, and the rights and interests of them shall not be affected.
Dissemination plans
The results of the trial will be published in medical journals and presented at conferences. Identification information about subjects will be kept confidential.
Ethics approval
Written approval has been obtained from the Medical Ethics Committee of Zhujiang Hospital of Southern Medical University, China (approval number 2019-KY-050-02). Written, informed consent to participate will be obtained from all participants. Any modifications (eg, changes to eligibility criteria, outcomes, analyses) to the protocol will require a formal amendment to the protocol. The amendment will be submitted to the Ethics Committee for approval. In the event of any discomfort or new changes in the subject's condition or any unforeseen circumstances, whether drug-related or not, the subject should be notified promptly to the physician, who will make a judgment and medical treatment. If the study is determined to be related to the damage, we will bear the cost of treatment or give corresponding financial compensation to the subject in accordance with relevant regulations of China.