ESTIMABL 2 protocol Final Version 4.0 (December 13 2006) ESTIMABL 2 协议最终版本 4.0（2006 年 12 月 13 日）
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ESTIMABL 2 协议初版与最终版之间的变化摘要
Summary of the changes between initial and final version of
ESTIMABL 2 protocol
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Statistical analysis plan- ESTIMABL2 trial: Initial version 统计分析计划--ESTIMABL2 试验：初始版本
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Statistical analysis plan- ESTIMABL2 trial: Final version 统计分析计划--ESTIMABL2 试验：最终版本
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统计分析计划初稿和定稿之间的改动摘要和原因
Summary and reasons of changes made between the initial
and the final version of the Statistical Analysis plan
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ESTIMABL 2 protocol Initial Version 1.0 (February 06, 2013) 2
ESTIMABL 2 protocol Final Version 4.0 (December 13 2006) 38
"Summary of the changes between initial and final version of
ESTIMABL 2 protocol" 79
Statistical analysis plan- ESTIMABL2 trial: Initial version 82
Statistical analysis plan- ESTIMABL2 trial: Final version 86
"Summary and reasons of changes made between the initial
and the final version of the Statistical Analysis plan" 91| | Page <br> Number |
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| ESTIMABL 2 protocol Initial Version 1.0 (February 06, 2013) | 2 |
| ESTIMABL 2 protocol Final Version 4.0 (December 13 2006) | 38 |
| Summary of the changes between initial and final version of <br> ESTIMABL 2 protocol | 79 |
| Statistical analysis plan- ESTIMABL2 trial: Initial version | 82 |
| Statistical analysis plan- ESTIMABL2 trial: Final version | 86 |
| Summary and reasons of changes made between the initial <br> and the final version of the Statistical Analysis plan | 91 |
Sponsor Protocol N ^(@){ }^{\circ} : IGR 2012/1913 赞助方议定书 N ^(@){ }^{\circ} : IGR 2012/1913
IDRCB N ^(@){ }^{\circ} : 2012-A01569-34
Cancer thyroïdien différencié à faible risque : le traitement ablatif par iode 131 est-il utile? 低风险分化型甲状腺癌：碘 131 消融治疗有用吗？
Differentiated thyroid cancer: is there a need for radioiodine ablation in low risk patients? 分化型甲状腺癌：低风险患者是否需要进行放射性碘消融？
Abbreviated Title of Protocol: ESTIMABL2 协议缩写标题：ESTIMABL2
Version n ^(@)1.1{ }^{\circ} 1.1 - February, 06^("th "),201306^{\text {th }}, 2013 版本 n ^(@)1.1{ }^{\circ} 1.1 - 2 月， 06^("th "),201306^{\text {th }}, 2013
SPONSOR "Institut Gustave Roussy
114, rue Edouard Vaillant
94 805 Villejuif
France" Date : 05/03/2013| SPONSOR | Institut Gustave Roussy <br> 114, rue Edouard Vaillant <br> 94 805 Villejuif <br> France | Date : 05/03/2013 |
| :---: | :---: | :---: |
SIGNATURE PAGE 签名页
Protocol « ESTIMABL 2» 协议 "ESTIMABL 2"IDRCB N ^(0){ }^{0} : 2012-A01569-34Sponsor Protocol N ^(0){ }^{0} : IGR 2012/1913 赞助方议定书 N ^(0){ }^{0} : IGR 2012/1913
Version n 1.1 and (06/02/2013) 版本 n 1.1 和 (06/02/2013)
Investigator center: 调查员中心：
qquad\qquad
Department: 部门：
qquad\qquad
Name and address of center: qquad\qquad 中心名称和地址： qquad\qquad
qquad\qquad certify that I have read the protocol named «ESTIMABL 2" qquad\qquad 证明我已阅读名为 "ESTIMABL 2 "的协议
And I certify to conduct this study in accordance with the the Good Clinical Practice, the local applicable regulation and the study Protocol. 我保证按照《良好临床实践》、当地适用法规和研究协议开展本研究。
Mots clés / Keys words :
Discipline, spécialité (du projet) / Project area: Nuclear Medicine, Thyroid Cancer, Endocrine Oncology
Organe, localisation anatomique de la tumeur / Organ, tumor location: Thyroid
Titre, Prénom & Nom de l'investigateur principal Title, Firstname & Name of PI : Dr Sophie Leboulleux
Fonction et spécialité / Fonction and speciality : Assistant. Nuclear Medicine & Endocrinologist
Service ou département / Unit or department: Nuclear Medicine and Endocrine Oncology
Nom de l'établissement hospitalier / Hospital name : Institut Gustave Roussy
Téléphone / Phone number: 33142114257
Adresse électronique / e-mail : leboulleux@igr.fr| Mots clés / Keys words : | |
| :---: | :---: |
| Discipline, spécialité (du projet) / Project area: | Nuclear Medicine, Thyroid Cancer, Endocrine Oncology |
| Organe, localisation anatomique de la tumeur / Organ, tumor location: | Thyroid |
| Titre, Prénom & Nom de l'investigateur principal Title, Firstname & Name of PI : | Dr Sophie Leboulleux |
| Fonction et spécialité / Fonction and speciality : | Assistant. Nuclear Medicine & Endocrinologist |
| Service ou département / Unit or department: | Nuclear Medicine and Endocrine Oncology |
| Nom de l'établissement hospitalier / Hospital name : | Institut Gustave Roussy |
| Téléphone / Phone number: | 33142114257 |
| Adresse électronique / e-mail : | leboulleux@igr.fr |
STUDY CONTACTS 研究联系人
Name and Address 姓名和地址
Telephone / Fax number 电话/传真号码
Sponsor 赞助商
Institut Gustave Roussy 114 Rue Edouard Vaillant F-94805 Villejuif Cedex 古斯塔夫-鲁西研究所 114 Rue Edouard Vaillant F-94805 Villejuif Cedex
0142114211
Statistician 统计员
Dr Isabelle Borget Institut Gustave Roussy 114 Rue Edouard Vaillant 94805 Villejuif Cedex
Tel :0142 114146 isabelle.borget@igr.fr 电话 :0142 114146 isabelle.borget@igr.fr
ID RCB NUMBER : 2012-A01569-34 ID RCB 编号：2012-A01569-34
VERSION AND DATE: VERSION 1.1 (06/02/2013) 版本和日期：1.1 版（2013 年 2 月 6 日）
STUDY TITLE: 研究题目：
Differentiated thyroid cancer: is there a need for radioiodine ablation in low risk patients? 分化型甲状腺癌：低风险患者是否需要进行放射性碘消融？
A) IDENTIFICATION OF CLINICAL TRIAL
ID RCB NUMBER : 2012-A01569-34
VERSION AND DATE: VERSION 1.1 (06/02/2013)
STUDY TITLE:
Differentiated thyroid cancer: is there a need for radioiodine ablation in low risk patients?| A) IDENTIFICATION OF CLINICAL TRIAL |
| :--- |
| ID RCB NUMBER : 2012-A01569-34 |
| VERSION AND DATE: VERSION 1.1 (06/02/2013) |
| STUDY TITLE: |
| Differentiated thyroid cancer: is there a need for radioiodine ablation in low risk patients? |
NUMBER OF CENTERS:
33| NUMBER OF CENTERS: |
| :---: |
| 33 |
NUMBER OF PATIENTS: 患者人数：
France 法国
33
750
Total "NUMBER OF CENTERS:
33" NUMBER OF PATIENTS:
France 33 750| Total | NUMBER OF CENTERS: <br> 33 | NUMBER OF PATIENTS: |
| :---: | :---: | :---: |
| France | 33 | 750 |
B) IDENTIFICATION OF SPONSOR b) 确定提案国
Institut Gustave Roussy 古斯塔夫-鲁西研究所
114 rue Edouard Vaillant - 94805 VILLEJUIF - FRANCE
Tel : 0142114257 电话：0142114257
Fax: 0142115224 传真：0142115224
C) GENERAL INFORMATION ON STUDY C)学习概况
INDICATION: 指示：
Patients with low risk differentiated thyroid cancer 低风险分化型甲状腺癌患者
METHODOLOGY: 方法：
Open-label randomized phase III trial, using a non-inferiority comparison design. After randomization, patients will receive either post-operative radioiodine ablation with an activity of 1.1GBq(30mCi)1.1 \mathrm{GBq}(30 \mathrm{mCi}) after stimulation by rhTSH, and then be followed-up (ablation group) or be followed-up (without postoperative radioiodine ablation) (follow-up group). 开放标签随机 III 期试验，采用非劣效性比较设计。随机分组后，患者将在术后接受放射性碘消融，在rhTSH的刺激下使活性达到 1.1GBq(30mCi)1.1 \mathrm{GBq}(30 \mathrm{mCi}) ，然后进行随访（消融组）或随访（不进行术后放射性碘消融）（随访组）。
PRIMARY OBJECTIVE: 主要目标：
To assess the non-inferiority of the proportion of patients without tumor-related event evaluated at three years after total thyroidectomy in the absence of radioiodine ablation (follow-up group) compared to the ablation group, in patients with low-risk differentiated thyroid cancer treated with total thyroidectomy with or without lymph node dissection (pT1am N0 or Nx, pT1b N0 or Nx). 目的：评估低风险分化型甲状腺癌患者在接受甲状腺全切除术并进行或不进行淋巴结清扫术（pT1am N0或Nx，pT1b N0或Nx）治疗后三年，在未进行放射性碘消融的情况下，评估无肿瘤相关事件发生的患者比例（随访组）与消融组相比的非劣效性。
SECONDARY OBJECTIVES: 次要目标：
To compare the two strategies in terms of: 从以下方面对两种战略进行比较
Salivary and lachrymal toxicities 唾液和泪液毒性
Patient’s quality of life, anxiety and fear of recurrence 患者的生活质量、焦虑和对复发的恐惧
Rate of patients without event at 5 years following thyroidectomy 甲状腺切除术后 5 年未发生事件的患者比例
Rate of patients without event at 3 and 5 years after thyroidectomy, according to the initial lymph node status 根据最初的淋巴结状态，甲状腺切除术后 3 年和 5 年无事件发生的患者比例
Recurrence rate (histologically proven) at three years following thyroidectomy 甲状腺切除术后三年的复发率（组织学证实
Future of patients experiencing en event. 经历 en 事件的病人的未来。
Costs of treatment and follow-up 治疗和后续费用
Rate of patients without event at 3 and 5 years after thyroidectomy, according to tumoral molecular characterization 根据肿瘤分子特征，甲状腺切除术后 3 年和 5 年未发生事件的患者比例
INCLUSION CRITERIA: 纳入标准：
Patients with differentiated thyroid cancer (papillary, follicular or with Hurthle cells) in the absence of aggressive histological subtypes (poorly differentiated, tall-clear-cylindric cell, diffuse sclerosing or with an anaplastic component) 分化型甲状腺癌患者（乳头状、滤泡状或伴有 Hurthle 细胞），且不伴有侵袭性组织学亚型（分化不良、高大透明细胞、弥漫硬化或伴有无性细胞）。
Patients having undergone a total thyroidectomy with complete (R0) tumor resection, with or without lymph node neck dissection 接受过甲状腺全切除术，肿瘤完全切除（R0），并进行或未进行颈部淋巴结清扫的患者
Surgery performed 2 to 4 months before inclusion 纳入前 2 至 4 个月进行过手术
Patients with low risk of recurrence: pT1amN0 or pT1amNx with a sum of the size of the lesions above 1 cm and equal to or less than 2 cm , or pT1bN0 or pT1bNx (TNM 2010 classification). (Patients with less than 6 lymph nodes in the neck dissection will be classified as Nx) 低复发风险患者：pT1amN0 或 pT1amNx，病灶大小之和大于 1 厘米且等于或小于 2 厘米，或 pT1bN0 或 pT1bNx（TNM 2010 分类）。(颈部清扫淋巴结少于 6 个的患者将被归类为 Nx）。
Post-operative neck ultrasound (performed 2 to 4 months after surgery) showing the absence of abnormalities in the lateral lymph node compartments, or if abnormalities, no lymph nodes with abnormal cytology and/or thyroglobulin concentration in the aspirate fluid > 10ng//mL>10 \mathrm{ng} / \mathrm{mL} 术后颈部超声波检查（术后 2 至 4 个月）显示侧淋巴结区无异常，如果有异常，则淋巴结细胞学无异常和/或抽吸液中无甲状腺球蛋白浓度 > 10ng//mL>10 \mathrm{ng} / \mathrm{mL} 。
Age >= 18\geq 18 years 年龄 >= 18\geq 18 岁
Performance status of 0 or 1 性能状态为 0 或 1
Patients who signed the informed consent 签署知情同意书的患者
Patients who can be followed-up annually during 5 years in order to assess the objectives of the study 可在 5 年内每年对患者进行随访，以评估研究的目标
Women of childbearing age should have a negative pregnancy test before any radioiodine administration 育龄妇女在使用任何放射性碘之前应进行阴性妊娠试验
Both patients with or without thyroglobulin antibodies are eligible 有或没有甲状腺球蛋白抗体的患者均符合条件
NON INCLUSION CRITERIA: 非纳入标准：
Patients having undergone less than a total thyroidectomy 未完成甲状腺全切除术的患者
Patients with aggressive histotype (poorly differentiated, tall-clear-cylindric cell, diffuse sclerosing, or with an anaplastic component) 侵袭性组织型患者（分化不良、高大透明细胞、弥漫性硬化或伴有无弹性成分）
Patients having undergone surgery less than 2 months or more than 4 months before inclusion 入选前 2 个月以内或 4 个月以上接受过手术的患者
Patients with cancer classified as pT1a unifocal (in which ablation is not necessary), or pT1N1, pT2, pT3, pT4 or N1 (who have a higher risk of recurrence) (classification TNM 2010) 癌症分类为 pT1a 单灶（无需消融）或 pT1N1、pT2、pT3、pT4 或 N1（复发风险较高）的患者（2010 年 TNM 分类）。
Patient with known distant metastasis 已知有远处转移的患者
Abnormal post-operative neck ultrasound of the lateral lymph node compartments 术后颈部侧淋巴结超声检查异常
Patients with another malignancy not in remission for at least 2 years (except for in situ cervix uterine cancer, basocellular skin cancer) 患有其他恶性肿瘤且病情未缓解至少 2 年的患者（原位子宫颈癌和基底细胞皮肤癌除外）。
Patients with a recent history of drugs affecting thyroid function, including injection of radiocontrast agents during the last 8 weeks. 近期服用过影响甲状腺功能药物的患者，包括在过去 8 周内注射过放射性造影剂的患者。
Patients previously treated with radioactive iodine or who previously underwent a whole body scan with radioactive iodine 曾接受过放射性碘治疗或曾接受过放射性碘全身扫描的患者
Pregnant or breast feeding women 孕妇或哺乳期妇女
Subject with any kind of disorder that may compromise his/her ability to give written informed consent and/or to comply with study procedures 受试者患有任何可能影响其作出书面知情同意和/或遵守研究程序的能力的疾病
PRIMARY AND SECONDARY EVALUATION CRITERIA: 主要和次要评估标准：
Primary criterion: 主要标准：
The primary criterion is the rate of patients without event during the 3 years following surgery. An event is defined by (composite criterion): 主要标准是术后 3 年内无事件发生的患者比例。事件的定义是（综合标准）：
At initial treatment, for patients randomized in the ablation group, the presence on the whole body scan of focus of radioiodine uptake outside the thyroid bed needing further treatment. 在初始治疗时，对于随机分入消融组的患者，如果全身扫描结果显示甲状腺床外有放射性碘摄取灶，则需要进一步治疗。
During follow up, in both groups, by the administration of an activity of 1131 >= 1,1GBq(30mCi)1131 \geq 1,1 \mathrm{GBq}(30 \mathrm{mCi}) or by surgery because of: 在随访过程中，两组患者都服用了 1131 >= 1,1GBq(30mCi)1131 \geq 1,1 \mathrm{GBq}(30 \mathrm{mCi}) 活性物质，或因以下原因接受了手术治疗：
abnormal lymph node on neck ultrasound with an abnormal cytology and/or a thyroglobulin ( Tg ) concentration in the aspirate fluid > 10ng//mL>10 \mathrm{ng} / \mathrm{mL} 颈部超声检查发现淋巴结异常，且细胞学检查结果异常和/或抽吸液中甲状腺球蛋白（Tg）浓度 > 10ng//mL>10 \mathrm{ng} / \mathrm{mL} 。
and/or abnormal mass in the thyroid bed with an abnormal cytology 和/或甲状腺床有异常肿块且细胞学检查异常
and/or surgical resection of thyroid cancer 和/或甲状腺癌手术切除
and/or an elevated Tg level in the absence of anti-Tg antibodies (TgAb) defined according to Figure 1 和/或在没有抗 Tg 抗体（TgAb）的情况下 Tg 水平升高，定义见图 1
and/or the appearance of anti-Tg antibodies (Ab)(\mathrm{Ab}) above the upper limit of the normal range for the kit used, persisting on 2 measurements performed with the same kit at an interval of time of at least 6 months 和/或出现抗绒毛膜促性腺激素抗体 (Ab)(\mathrm{Ab}) ，超过所用试剂盒正常范围的上限，且在使用同一试剂盒进行的两次测量中持续出现，间隔时间至少 6 个月
and/or the increase of TgAb of more than 50%50 \% on 2 measurements performed with the same kit with an interval of time of at least 6 months. 和/或使用同一试剂盒进行的 2 次测量中，TgAb 的增加超过 50%50 \% ，且间隔时间至少 6 个月。
Figure1: Definition of elevated Tg level in the absence of Tg antibodies ( TgAb ) 图 1：无 Tg 抗体（TgAb）时 Tg 水平升高的定义
If none of these events occurred during the 3 years following total thyroidectomy, a patient will be considered without event. Conversely, a patient will be considered to have an event if at least one of these events occurred during the 3 years following total thyroidectomy. All patients have to be followed during 3 years (lost to follow-up not allowed). 如果患者在甲状腺全切除术后 3 年内未发生上述任何事件，则视为未发生事件。反之，如果患者在甲状腺全切除术后的 3 年内至少发生过一次上述事件，则视为发生过事件。所有患者都必须接受 3 年随访（不允许失去随访）。
SECONDARY CRITERIA 次级标准
Lachrymal and Salivary Glands Toxicities will be evaluated by a specific questionnaire at baseline, 3 months, one year, and 3 years 泪腺和唾液腺毒性将在基线、3 个月、1 年和 3 年时通过特定问卷进行评估
Impact on patients quality of life, anxiety and recurrence fear will respectively be evaluated with the SF-36, STAI, IES, fear or cancer recurrence questionnaires at inclusion, 3 months after inclusion, 1 and 3 years post-operatively 将分别在入组、入组后 3 个月、术后 1 年和 3 年使用 SF-36、STAI、IES、恐惧或癌症复发问卷评估对患者生活质量、焦虑和复发恐惧的影响
Rate of patients without event at 5 years following thyroidectomy 甲状腺切除术后 5 年未发生事件的患者比例
Rate of events three and five years after thyroidectomy, adjusted on the initial lymph node status 甲状腺切除术后三年和五年的事件发生率，根据最初的淋巴结状态进行调整
Recurrence rate (histologically proven) at three years following thyroidectomy, and then at 5 years. 甲状腺切除术后三年和五年的复发率（经组织学证实）。
Rate of cure after an event 事件发生后的治愈率
Cost of treatment and follow-up 治疗和后续费用
Rate of events three and five years after thyroidectomy, adjusted on tumoral molecular characterization 根据肿瘤分子特征调整甲状腺切除术后三年和五年的事件发生率
D) DESCRIPTION OF STUDY TREATMENTS- EXPERIMENTAL PLAN d) 研究处理说明--实验计划
Patients will be randomly assigned to receive either 1311 after stimulation by rhTSH and follow-up (ablation group) or to be followed-up (follow-up group), with stratification on the site and initial lymph node status (NO or Nx). 患者将被随机分配到在接受 rhTSH 刺激和随访后接受 1311 治疗（消融组）或接受随访（随访组），并根据淋巴结部位和初始淋巴结状态（NO 或 Nx）进行分层。
Patients randomized in the ablation group 消融组随机患者
rhTSH stimulation rhTSH 刺激
After surgery and start of LT4 treatment, intramuscular injections of rhTSH ( 0.9 mg ) are performed on two consecutive days on LT4 treatment 手术和 LT4 治疗开始后，在 LT4 治疗的连续两天进行 rhTSH 肌肉注射（0.9 毫克）。
Administration of 1.1 GBq of I131 施用 1.1 GBq 的 I131
1131 is given orally 24 hours after the second injection of rhTSH. A whole body scan (WBS) is performed 2 to 5 days after the administration or 1131 with determination of the neck uptake according to a standardized protocol. 在第二次注射 rhTSH 24 小时后口服 1131。在注射或服用 1131 2 至 5 天后进行全身扫描 (WBS)，并根据标准化方案测定颈部摄取量。
Follow-up consists in: 后续行动包括：
10 (+/- 2 months) after surgery: a neck ultrasound and a serum Tg measurement after rhTSH stimulation 术后 10 个月（+/- 2 个月）：在 rhTSH 刺激后进行颈部超声检查和血清 Tg 测量
2 years (+/- 2 months) after surgery: a serum Tg measurement under LT4 treatment (Tg/LT4) 术后 2 年（+/- 2 个月）：在 LT4 治疗下测量血清 Tg（Tg/LT4）
3 years (+/- 2 months) after surgery: a neck ultrasound and a serum Tg/LT4 术后 3 年（+/- 2 个月）：颈部超声波和血清 Tg/LT4
4 years (+/- 2 months) after surgery: a serum Tg/LT4 术后 4 年（+/- 2 个月）：血清 Tg/LT4
5 years (+/- 2 months) after surgery: a neck ultrasound and a serum Tg/LT4 术后 5 年（+/- 2 个月）：颈部超声检查和血清 Tg/LT4
Patients randomized in the follow up group 随访组的随机患者
Neither radioiodine nor rhTSH is administered postoperatively. Patients will undergo the same followup procedures as patients randomized to the ablation group, except that at 10 months after surgery, Tg will be measured under LT4 treatment and not after rhTSH stimulation. 术后既不使用放射性碘，也不使用 rhTSH。除了术后 10 个月将在 LT4 治疗下而非 rhTSH 刺激后测量 Tg 外，患者将接受与消融组患者相同的随访程序。
In both groups, the aim of LT4 treatment is to maintain the serum TSH level between 0.3 and < 1mU//L<1 \mathrm{mU} / \mathrm{L}. 在这两组患者中，LT4治疗的目的是将血清促甲状腺激素水平维持在0.3和 < 1mU//L<1 \mathrm{mU} / \mathrm{L} 之间。
For both groups, an aliquot of serum aliquot at randomisation, 10 months and 3 years after surgery will be kept for Tg central measurement at the end of the study. 两组患者在随机分组、术后 10 个月和术后 3 年时，都将保留等量的血清样本，以便在研究结束时进行 Tg 中心测定。
For both groups, a central review of neck ultrasounds with doubtful images will be performed within 15 days in order to guide the indication of fine needle aspiration biopsy. 对于这两组患者，将在 15 天内对有疑问的颈部超声图像进行集中复查，以指导细针穿刺活检的指征。
All patients will be followed during 5 years (including patients experiencing an event in order to assess the future of patients after treatment. 将对所有患者进行为期 5 年的随访（包括发生事件的患者，以评估患者治疗后的前景）。
TREATMENT DURATION: 7 days 疗程： 7 天
E) SAMPLE SIZE DETERMINATION e) 确定样本量
This is a non-inferiority trial, with the hypothesis that rate of patients without event at 3 years in the follow-up group is non-inferior to that in ablation group. Non-inferiority will be demonstrated if the rate of patients without event at 3 years does not differ by more than Delta L=-5%\Delta L=-5 \%. The estimated rate of patients without event is 95%95 \% in the group of patients treated with 30 mCi and rhTSH. Demonstration of non-inferiority at a significance level of 0.05 (one-sided) with a power of 90%90 \% required a sample size of 652 subjects ( 326 per group). Therefore, we selected a sample size of 750 subjects, considering that 15%15 \% of patients will have anti-Tg antibodies and who will not be evaluable. 这是一项非劣效性试验，假设随访组患者 3 年后未发生事件的比率不低于消融组。如果 3 年无事件发生的患者比率相差不超过 Delta L=-5%\Delta L=-5 \% ，则证明非劣效性。在接受 30 mCi 和 rhTSH 治疗的患者组中，无事件发生的患者比率估计为 95%95 \% 。在显著性水平为 0.05（单侧）、功率为 90%90 \% 的情况下，证明非劣效性需要 652 例受试者（每组 326 例）的样本量。因此，考虑到 15%15 \% 的患者会有抗 Tg 抗体，无法进行评估，我们选择了 750 例受试者作为样本量。
F) DURATION OF STUDY f) 学习期限
INCLUSION PERIOD: 2.5 years 纳入期：2.5 年
TREATMENT PERIOD: 5 days 疗程： 5 天
FOLLOW-UP PERIOD: 5 years 跟踪期：5 年
OVERALL DURATION OF STUDY: 7.5 years 总学制： 7.5 年
SOMMAIRE / TABLE OF CONTENT 目录
I. INTRODUCTION AND RATIONALE OF THE STUDY … 10 I.
II. STUDY OBECTIVE … 11 II.研究活动...... 11
II.1. Primary Objective … 11 II.1.主要目标...... 11
II.2. Secondary Objective … 11 II.2.
III. METHODOLOGY … 12 III.方法...... 12
IV. SELECTION OF PATIENTS … 12 IV.
IV.1. Inclusion criteria … 12 IV.1.纳入标准...... 12
IV.2. EXCLUSION CRITERIA … 12 IV.2.排除标准...... 12
V. TREATMENTS … 13
V.1. Randomization … 13 V.1.随机化 ... 13
V.1.1. Time of randomization … 13 V.1.1.随机化时间...... 13
V.1.2. Randomization modalities … 13 V.1.2.
V.2. Description of treatments … 13 V.2.
V.2.1. Patients randomized in the ablation group … 13 V.2.1.消融组随机患者...... 13
V.2.2. Patients randomized in the follow up group … 14 V.2.2.随访组的随机患者...... 14
VI. EVALUATION CRITERIA … 14 VI.
VI.1. Primary criterion … 14 VI.1.
VI.1.1. Tg central measurement … 15 VI.1.1.Tg 中心测量...... 15
VI.1.2. Neck ultrasound … 15 VI.1.2.颈部超声波 ... 15
VI.1.3. Post ablation whole body scan … 15 VI.1.3.
VI.2. Secondary criteria … 16
VI.2.1. Salivary and Lachrymal toxicities … 16 VI.2.1.
VI.2.2. Impact on patient’s quality of life, anxiety and recurrence fear … 16 VI.2.2.
VI.2.3. Rate of events five years after thyroidectomy … 17 VI.2.3.
VI.2.4. Rate of events three and five years after thyroidectomy adjusted on the lymph node status … 17 VI.2.4.
VI.2.5. Recurrence rate (histologically proven) at three and five years after thyroidectomy … 17 VI.2.5.
VI.2.6. Management and follow-up cost … 17 VI.2.6.
VI.2.7.Rate of events three and five years after thyroidectomy adjusted on the tumoral molecular characterization … 18 VI.2.7.根据肿瘤分子特征调整甲状腺切除术后三年和五年的事件发生率..............
VII. DETERMINATION OF SAMPLE SIZE AND STATISTICAL ANALYSIS … 18 VII.
VII.1. Determination of sample size … 18 VII.1.
VII.1.1. Statistical analysis … 18 VII.1.1.统计分析
VIII. SERIOUS ADVERSE EVENTS … 19 VIII.严重不良事件......
VIII.1. Definition … 19 VIII.1.定义...... 19
VIII.2. Recording and Reporting / Action to be taken in the case of a SAE … 20 VIII.2.
VIII.3. Follow-up … 21 VIII.3.后续行动...... 21
VIII.4. Information given to investigators, ethics committee and regulatory authorities … 21 VIII.4.
IX. STUDY DISCONTINUATION … 21 IX.
X. ETHICAL AND REGULATORY ASPECTS … 22
X.1. Rules and regulations … 22 X.1.规则和条例.......
X.2. Committee for the Protection of Persons (CPP) - Competent Authority … 22 X.2.
X.3. Information and Consent of Participants … 22 X.3.
X.4. Principal Investigator Responsibilities … 22 X.4.
XI. DATA COLLECTION … 23 XI.
XII. QUALITY ASSURANCE - MONITORING … 24 XII.
XIII. DATA OWNERSHIP / PUBLICATION POLICY … 24 XIII.
XIV. REFERENCES … 25 XIV.
ANNEXE 1: QUESTIONNAIRE DE TOXICITE SALIVAIRE ET LACRYMALE … 27
ANNEXE 2: QUESTIONNAIRE SUR LA SANTE : SF-36 POUR SITUATION AIGUE … 28 附录 2：健康调查表：急性期 SF-36
ANNEXE 3: QUESTIONNAIRE D’ANXIETE STAI … 31
ANNEXE 4 : QUESTIONNAIRE IES-R … 32
ANNEXE 5: INVENTAIRE DE LA PEUR DE LA RECIDIVE DU CANCER … 33
ANNEXE 6: ECHOGRAPHIE CERVICALE … 35 附件 6：宫颈超声...... 35
I. INTRODUCTION AND RATIONALE OF THE STUDY I.研究的导言和基本原理
Differentiated thyroid cancer (DTC) is the most frequent endocrine cancer. Its increasing incidence is now estimated to be 7000 cases per year in France(1, 2). This increasing incidence is predominantly due to the increased detection of small cancers, with low risk of recurrence(3, 4). 分化型甲状腺癌（DTC）是最常见的内分泌癌症。据估计，目前法国每年的发病率为7000例（1, 2）。发病率上升的主要原因是发现的小癌增多，复发风险低（3, 4）。
Initial treatment of DTC includes a total thyroidectomy followed in many cases by the administration of radioactive iodine. Most patients are cured after the initial treatment, with recurrence occurring in < 5<5 to 15%15 \% of cases according to prognostic factors. The 10-year disease specific overall survival is over 90%. DTC的初始治疗包括甲状腺全切除术，在许多病例中，随后会使用放射性碘。大多数患者在初次治疗后都能痊愈，根据预后因素， < 5<5 到 15%15 \% 的病例中会出现复发。10年疾病特异性总生存率超过90%。
Post-operative radioactive iodine administration (or postoperative ablation) is given to eradicate the postsurgical thyroid remnant, which is the small amount of residual normal thyroid tissue remaining after a total thyroidectomy. The main goal of radioiodine ablation is to facilitate the early detection of recurrence based on serum thyroglobulin (Tg) measurement. Additionally, it facilitates initial staging by identifying previously undiagnosed disease based on the whole body scan (WBS) performed 2 to 5 days after the administration of radioiodine. Finally, it also treats remaining malignant disease, when present. After initial treatment, follow-up of these patients is based on the serum thyroglobulin (Tg) determination, a specific marker for thyroid tissue, and neck ultrasound. 术后放射性碘给药（或术后消融）是为了消除术后甲状腺残留物，即甲状腺全切除术后残留的少量正常甲状腺组织。放射性碘消融的主要目的是根据血清甲状腺球蛋白（Tg）的测量结果，及早发现复发。此外，根据放射性碘用药后 2 到 5 天进行的全身扫描（WBS），还能发现之前未诊断出的疾病，从而有助于初步分期。最后，它还能治疗剩余的恶性疾病。初次治疗后，这些患者的随访主要基于甲状腺组织的特异性标志物--血清甲状腺球蛋白（Tg）的测定和颈部超声波检查。
In patients with a unifocal DTC less than 1 cm and in the absence of lymph node metastases (pT1aN0), the risk of recurrence is very low and it is currently not recommended to perform radioiodine ablation(5, 6). In patients with a tumor between 1 and 2 cm without known lymph node metastases ( pT1b\mathrm{pT1b}, N0 or Nx ) or in multifocal tumor of less than 1 cm without known lymph node metastases (pT1am, N0 or Nx), who are considered at low risk of recurrence, the benefit of radioiodine on overall survival and on recurrence free survival has not been demonstrated(7-10). The current management of these low risk DTC patients is evolving towards the use of lower activities of radioactive iodine and the use of recombinant human TSH rather than thyroid hormone withdrawal that induces hypothyroidism and its related symptoms. 对于单灶 DTC 小于 1 厘米且无淋巴结转移（pT1aN0）的患者，复发风险非常低，目前不建议进行放射性碘消融（5, 6）。对于肿瘤在 1 至 2 厘米之间且无淋巴结转移（ pT1b\mathrm{pT1b} ，N0 或 Nx）或肿瘤小于 1 厘米且无淋巴结转移的多灶性肿瘤（pT1am，N0 或 Nx）的低复发风险患者，放射性碘对总生存期和无复发生存期的益处尚未得到证实（7-10）。目前对这些低风险 DTC 患者的治疗正朝着使用较低放射性碘活度和使用重组人 TSH 的方向发展，而不是使用会诱发甲状腺功能减退及其相关症状的甲状腺激素停药。
A recent French multicentric phase III trial (financed by the French Ministry of Health, through the National Institute for Cancer (INCa)) included, between 2007 and 2010, 752 patients with low risk DTC. It showed that the rates of complete ablation of thyroid remnants were comparable with: 1) an activity of 1.1GBq(30mCi)1.1 \mathrm{GBq}(30 \mathrm{mCi}) of radioiodine or an activity of 3.7GBq(100mCi)3.7 \mathrm{GBq}(100 \mathrm{mCi}) and 2)) using a stimulation by recombinant human TSH or a stimulation with prolonged thyroid hormone withdrawal(11). These results are concordant with a similar study conducted in the UK including 450 patients(12). 最近，法国开展了一项多中心 III 期试验（由法国卫生部通过国家癌症研究所（INCa）资助），在 2007 年至 2010 年期间，共纳入了 752 名低危 DTC 患者。试验结果表明，甲状腺残留物完全消融率与以下条件相当：1）放射性碘活性 1.1GBq(30mCi)1.1 \mathrm{GBq}(30 \mathrm{mCi}) 或活性 3.7GBq(100mCi)3.7 \mathrm{GBq}(100 \mathrm{mCi}) ；2）使用重组人促甲状腺激素刺激或长期停用甲状腺激素刺激的 )) (11)。这些结果与在英国进行的一项包括450名患者的类似研究相吻合（12）。
In addition to a comparable efficacy for complete ablation, the benefits of ablation with a low activity of radioactive iodine following rhTSH administration versus high activities of radioactive iodine following thyroid hormone withdrawal include improvement in patients’ quality of life, shorter hospitalization stay, lower irradiation to the body and the environment, lower salivary and lachrymal side effects, avoidance of the symptoms of hypothyroidism, shorter sick leave periods and finally lower cost(13-20). 除了完全消融的疗效相当外，在使用 rhTSH 后使用低活度放射性碘进行消融与在停用甲状腺激素后使用高活度放射性碘进行消融的好处还包括：改善患者的生活质量、缩短住院时间、降低对身体和环境的辐射、降低唾液和泪腺副作用、避免甲减症状、缩短病假时间以及最终降低成本（13-20）。
Recent studies have showed that between 23 and 59%59 \% of patients have a stimulated Tg level that is undetectable (under 1ng//mL1 \mathrm{ng} / \mathrm{mL} ) postoperatively, a major criteria of successful ablation(21-24). Furthermore, among the patients with an undetectable postoperative stimulated Tg level, the risk of abnormal WBS was 0%0 \% in one study and 3%3 \% in another study, but abnormal WBS was only found in patients with initial neck lymph node metastases ( pN1\mathrm{pN1} )(21, 24). The benefits of postoperative radioactive iodine ablation in these patients are thus a matter a debate(25). 最近的研究表明，23 到 59%59 \% 的患者术后检测不到刺激 Tg 水平（ 1ng//mL1 \mathrm{ng} / \mathrm{mL} 以下），这是消融成功的一个主要标准（21-24）。此外，在术后检测不到刺激性 Tg 水平的患者中，一项研究发现 WBS 异常的风险为 0%0 \% ，另一项研究发现为 3%3 \% ，但只有最初有颈部淋巴结转移的患者才会出现 WBS 异常（ pN1\mathrm{pN1} ）(21, 24)。因此，术后放射性碘消融对这些患者的益处还存在争议（25）。
In the context of less aggressive treatment, our hypothesis is that radioiodine ablation may be avoided in patients with small thyroid cancer with no lymph node involvement (classified as pT1m or pT1b,N0\mathrm{pT1b}, \mathrm{~N} 0 or Nx ). In other terms, it means that the proportion of patients without event during the 3 years following surgery is not decreased if patients are only followed-up (without receiving radioiodine ablation), as compared to patients treated post-operatively with radioiodine and then followed-up. Avoiding radioiodine treatment avoids radio-induced toxicities, improve patient’s quality of life, and decrease management costs. Conversely, the absence of radioiodine ablation may increase patient’s anxiety in terms of risk of recurrence, because the risk of having persistent disease will not be excluded by a post ablation WBS. This 3 year follow-up period of time was chosen, because in retrospective series, over 80%80 \% of all events occurred during that time. 我们的假设是，对于没有淋巴结受累的小甲状腺癌患者（分类为pT1m或 pT1b,N0\mathrm{pT1b}, \mathrm{~N} 0 或Nx），可以避免进行放射性碘消融。换句话说，与术后接受放射性碘治疗并随访的患者相比，如果只对患者进行随访（不接受放射性碘消融治疗），术后三年内未发生事件的患者比例不会降低。避免接受放射性碘治疗可以避免放射性碘引起的毒性反应，提高患者的生活质量，降低管理成本。相反，不进行放射性碘消融可能会增加患者对复发风险的焦虑，因为消融后的 WBS 无法排除疾病持续存在的风险。之所以选择 3 年的随访期，是因为在回顾性系列研究中，超过 80%80 \% 的所有事件都发生在这段时间内。
The objective of our project is to test the hypothesis that 3 -years after surgery the rate of low risk patients without tumor related event in the absence of postoperative radioiodine ablation is similar to that of patients who had radioiodine ablation with an activity of 1.1GBq(30mCi)1.1 \mathrm{GBq}(30 \mathrm{mCi}) of 1131 given after a preparation with rhTSH. Low risk patients are defined as pT1amN0, pT1amNx, pT1bN0 or pT1bNx patients with normal postoperative neck ultrasound. We will also compare both strategies in term of adverse events, especially salivary and lachrymal toxicities and impact on patients’ quality of life and anxiety. Furthermore, because of the ongoing debate on the impact of prophylactic neck lymph node dissection in DTC, the rate of patient without event 3-years after surgery, according their initial lymph node status ( N 0 or Nx ) will also be compared(5). We will also take into account the tumoral molecular characterization (including BRAF(V600E) status) because of its impact on prognosis(26). Finally, due to costs related to rhTSH and hospitalisation in a nuclear medicine facility, the two strategies will be compared in terms of cost. The French centers involved in this multicentric study have experience in academic prospective studies, with two large studies performed since 2001 (THYRDIAG and ESTIMABL which respectively enrolled 950 and 752 patients) published in three original articles(11, 27, 28). Furthermore, the coordinating centre, headed by Pr\operatorname{Pr} M. Schlumberger, is a cancer centre with 250 new cases of thyroid cancer per year and over 4000 patients with thyroid cancer seen every year. It is also the centre coordinating the rare cancer TUTHYREF network, for “Refractory thyroid Cancer” supported by the French Institut National du Cancer. Most centres associated to this project have already widely collaborated: 19 of the 33 centres participating in the present study were involved in the THYRDIAG study, 21 were involved in the ESTIMABL study and all are enrolled in the TUTHYREF network. This allows us to propose this project of recruiting 750 patients within 2.5 years. It will also help to homogenize and will probably improve the quality of care of DTC patients in France. 我们项目的目的是验证一个假设，即术后3年未进行放射性碘消融的低危患者中未发生肿瘤相关事件的比例与在使用rhTSH制剂后进行活性为 1.1GBq(30mCi)1.1 \mathrm{GBq}(30 \mathrm{mCi}) 为1131的放射性碘消融的患者中发生肿瘤相关事件的比例相似。低风险患者是指术后颈部超声检查正常的 pT1amN0、pT1amNx、pT1bN0 或 pT1bNx 患者。我们还将比较两种策略的不良反应，尤其是唾液和泪液毒性反应，以及对患者生活质量和焦虑的影响。此外，由于目前对预防性颈部淋巴结清扫术对 DTC 的影响仍有争议，我们还将根据患者的初始淋巴结状态（N 0 或 Nx），比较术后 3 年无事件发生的比例（5）。我们还将考虑肿瘤分子特征（包括 BRAF(V600E) 状态），因为它对预后有影响（26）。最后，由于rhTSH和在核医学机构住院的相关费用，我们将对两种策略的成本进行比较。参与这项多中心研究的法国中心在学术前瞻性研究方面经验丰富，自2001年以来已进行了两项大型研究（THYRDIAG和ESTIMABL，分别纳入了950名和752名患者），并发表了三篇原创文章（11、27、28）。此外，由 Pr\operatorname{Pr} M. Schlumberger领导的协调中心是一个癌症中心，每年新增甲状腺癌病例250例，每年接诊4000多名甲状腺癌患者。该中心还是法国国家癌症研究所支持的 "难治性甲状腺癌 "罕见癌症TUTHYREF网络的协调中心。 与本项目相关的大多数中心已经开展了广泛合作：参与本研究的 33 个中心中有 19 个参与了 THYRDIAG 研究，21 个参与了 ESTIMABL 研究，所有中心都加入了 TUTHYREF 网络。这使我们能够提出在 2.5 年内招募 750 名患者的计划。这也将有助于实现同质化，并有可能提高法国 DTC 患者的治疗质量。
II. STUDY OBECTIVE II.研究目标
II.1. Primary Objective II.1.主要目标
This is a randomized phase III trial in patients with low-risk differentiated thyroid cancer treated with total thyroidectomy with or without lymph node dissection (pT1am N0 or Nx, pT1b N0 or Nx). 这是一项随机III期试验，针对低风险分化型甲状腺癌患者，采用全甲状腺切除术，同时进行或不进行淋巴结清扫（pT1am N0或Nx，pT1b N0或Nx）。
The main objective of the study is to assess the non-inferiority of the rate of patients without event evaluated at three years after thyroidectomy in the absence of radioiodine ablation (where patients are followed up only) compared to a postoperative ablation with an activity of 1.1GBq(30mCi)1.1 \mathrm{GBq}(30 \mathrm{mCi}) of 1131 given after rhTSH injections and follow-up. 该研究的主要目的是评估在甲状腺切除术后三年，在未进行放射性碘消融（仅对患者进行随访）的情况下，与在注射 rhTSH 并进行随访后进行活性为 1.1GBq(30mCi)1.1 \mathrm{GBq}(30 \mathrm{mCi}) 1131 的术后消融相比，无事件发生的患者比率是否具有优越性。
II.2. Secondary Objective II.2.次要目标
The secondary objectives are to compare the two strategies in terms of: 次要目标是从以下方面对这两种战略进行比较：
Salivary and lachrymal toxicities 唾液和泪液毒性
Patient’s quality of life, anxiety and recurrence fear 患者的生活质量、焦虑和对复发的恐惧
Rate of patients without event at 5 years following thyroidectomy 甲状腺切除术后 5 年未发生事件的患者比例
Rate of patients without events 3 and 5 years after thyroidectomy, according to the initial lymph node status (NO vs Nx) 根据最初的淋巴结状态（NO vs Nx），甲状腺切除术后 3 年和 5 年未发生事件的患者比例
Recurrence rate (histologically proven) at three years following thyroidectomy, and then at 5 years. 甲状腺切除术后三年和五年的复发率（经组织学证实）。
Future of patients experiencing an event within the 5 years of thyroidectomy 甲状腺切除术后 5 年内发生事件的患者比例
Costs of treatment and follow-up 治疗和后续费用
Rate of patients without events 3 and 5 years after thyroidectomy, according to tumoral molecular characterization 根据肿瘤分子特征，甲状腺切除术后 3 年和 5 年未发生事件的患者比例
III. METHODOLOGY III.方法论
This is an open-label randomized phase III trial, using a non-inferiority comparison design. Patients will be randomly assigned to receive either a post-operative radioiodine ablation with an activity of 1.1 GBq ( 30 mCi ) after stimulation by rhTSH, and then be followed-up (ablation group) or to be followedup (without post-operative radioiodine ablation) (follow-up group). Randomization is stratified on the site and initial lymph node status (N0/Nx). 这是一项开放标签随机 III 期试验，采用非劣效性比较设计。患者将被随机分配到接受术后放射性碘消融（rhTSH 刺激后活性为 1.1 GBq ( 30 mCi)），然后接受随访（消融组）或随访（无术后放射性碘消融）（随访组）。随机分组的依据是手术部位和初始淋巴结状态（N0/Nx）。
IV. SELECTION OF PATIENTS IV.患者的选择
IV.1. Inclusion criteria IV.1.纳入标准
Patients with differentiated thyroid cancer (papillary, follicular or with Hurthle cells) in the absence of aggressive histological subtypes (poorly differentiated, tall-clear-cylindric cell, diffuse sclerosing or with an anaplastic component) 分化型甲状腺癌患者（乳头状、滤泡状或伴有 Hurthle 细胞），且不伴有侵袭性组织学亚型（分化不良、高大透明细胞、弥漫硬化或伴有无性细胞）。
Patients having undergone a total thyroidectomy with complete (R0) tumor resection, with or without lymph neck node dissection 接受过甲状腺全切除术，肿瘤完全切除（R0），并进行或未进行颈部淋巴结清扫的患者
Total thyroidectomy performed 2 to 4 months before inclusion 在纳入前 2 至 4 个月进行全甲状腺切除术
Patients with low risk of recurrence: pT1amN0\mathrm{pT1amN0} or pT1amNx\mathrm{pT1amNx} with a sum of the size of the lesions above 1 cm and equal to or less than 2 cm , or pT1bN0\mathrm{pT1bN0} or pT1bNx\mathrm{pT1bNx} (tumor size: 1-2cm) (TNM 2010 classification). (Patients with less than 6 lymph nodes in the neck dissection will be classified as Nx). 复发风险低的患者： pT1amN0\mathrm{pT1amN0} 或 pT1amNx\mathrm{pT1amNx} ，病灶大小之和大于 1 厘米且等于或小于 2 厘米，或 pT1bN0\mathrm{pT1bN0} 或 pT1bNx\mathrm{pT1bNx} （肿瘤大小：1-2 厘米）（TNM 2010 分类）。(颈部清扫淋巴结少于 6 个的患者将被归类为 Nx）。
Post-operative neck ultrasound (performed 2 to 4 months after surgery) showing the absence of abnormalities in the lateral lymph node compartments, or if abnormalities, no lymph node with abnormal cytology and/or thyroglobulin in the aspirate fluid > 10ng//mL>10 \mathrm{ng} / \mathrm{mL} 术后颈部超声波检查（术后 2 至 4 个月）显示侧淋巴结区无异常，如果有异常，则淋巴结抽吸液中无异常细胞学和/或甲状腺球蛋白 > 10ng//mL>10 \mathrm{ng} / \mathrm{mL} .
Age >= 18\geq 18 years 年龄 >= 18\geq 18 岁
Performance status of 0 or 1 性能状态为 0 或 1
Patients who signed the informed consent 签署知情同意书的患者
Patients who can be followed-up annually during 5 years in order to assess the objectives of the study 可在 5 年内每年对患者进行随访，以评估研究的目标
Women of childbearing age should have a negative pregnancy test before any radioiodine administration 育龄妇女在使用任何放射性碘之前应进行阴性妊娠试验
Both patients with or without thyroglobulin antibodies are eligible 有或没有甲状腺球蛋白抗体的患者均符合条件
IV.2. Exclusion criteria IV.2.排除标准
Patients having undergone less than a total thyroidectomy 未完成甲状腺全切除术的患者
Patients with aggressive histotype (poorly differentiated, tall-clear or cylindric cell, diffuse sclerosing, or with an anaplastic component) 侵袭性组织型患者（分化不良、高大透明细胞或圆柱形细胞、弥漫性硬化或伴有无弹性成分）
Patients having undergone surgery less than 2 months or more than 4 months before inclusion 入选前 2 个月以内或 4 个月以上接受过手术的患者
Patients with cancer classified as pT1a unifocal (in which ablation is useless), or pT1N1, pT2, pT3, pT4 or N1 (who have a higher risk of recurrence) (classification TNM 2010) 癌症分类为 pT1a 单灶（消融无用）或 pT1N1、pT2、pT3、pT4 或 N1（复发风险较高）的患者（2010 年 TNM 分类）。
Patient with known distant metastasis 已知有远处转移的患者
Abnormal post-operative neck ultrasound of the lateral lymph node compartments 术后颈部侧淋巴结超声检查异常
Patients with another malignancy (except for in situ cervix uterine cancer, basocellular skin cancer or breast cancer in remission for at least 2 years) 患有其他恶性肿瘤的患者（原位子宫颈癌、基底细胞皮肤癌或缓解至少 2 年的乳腺癌除外）
Patients with a recent history of drugs affecting thyroid function, including iodine containing medications or injection of radio-contrast agents 近期服用过影响甲状腺功能的药物（包括含碘药物或注射放射造影剂）的患者
Patients previously treated with radioactive iodine or who previously underwent a whole body scan with radioactive iodine 曾接受过放射性碘治疗或曾接受过放射性碘全身扫描的患者
Pregnancy or breast feeding women 孕妇或哺乳期妇女
Subjects with any disorder that may compromise his/her ability to give written informed consent and/or to comply with study procedures 受试者患有任何可能影响其做出书面知情同意和/或遵守研究程序的能力的疾病
V. TREATMENTS V.治疗
Patients will be randomly assigned to receive either a post-operative radioiodine ablation with an activity of 1.1GBq(30mCi)1.1 \mathrm{GBq}(30 \mathrm{mCi}) after stimulation by rhTSH, and then be followed-up (ablation group) or to be followed-up without post-operative radioiodine ablation (follow-up group) 患者将被随机分配到接受术后放射性碘消融术（rhTSH 刺激后活性为 1.1GBq(30mCi)1.1 \mathrm{GBq}(30 \mathrm{mCi}) ），然后接受随访（消融术组）或不接受术后放射性碘消融术（随访组）。
V.1. Randomization V.1.随机化
V.1.1. Time of randomization V.1.1.随机化时间
The following information will be requested before randomization: 随机化之前将要求提供以下信息：
Initial inclusion criteria, 初步纳入标准、
Written signed consent form, 书面签署同意书、
Post-operative neck ultrasound showing the absence of abnormality in the lateral lymph node compartments, 术后颈部超声显示侧淋巴结区无异常、
Quality of life questionnaires (SF-36, Spielberger trait anxiety inventory (STAI), IES, fear of cancer recurrence). 生活质量问卷（SF-36、Spielberger 特质焦虑量表（STAI）、IES、癌症复发恐惧）。
v.1.2. Randomization modalities v.1.2.随机化模式
Randomization will be performed between 2 to 4 months after total thyroidectomy. 随机化将在甲状腺全切除术后 2 到 4 个月之间进行。
To randomize a patient, the investigator must fill in the randomization form and send it by fax to the data-manager at the Institut Gustave Roussy (fax number: 0142115207 or BIP 01421149 00), who will check that the patient is eligible and that all inclusion criteria are met. 要对患者进行随机分配，研究人员必须填写随机分配表并传真给古斯塔夫-鲁西研究所的数据管理人员（传真号码：0142115207 或 BIP 01421149 00）。
Randomization is performed with the Tenalea program. Patients are randomly allocated to one of the two treatment groups, based on block, by site (to ensure a balance between the treatment groups at each site) and will be stratified on site and tumor lymph node status (N0 or Nx). 采用 Tenalea 程序进行随机分配。患者将根据区块、部位（确保每个部位治疗组之间的平衡）随机分配到两个治疗组中的一个，并根据部位和肿瘤淋巴结状态（N0 或 Nx）进行分层。
After randomization, a form will be returned to the investigational center to provide the identification number of the patient in the trial and the treatment group. Confirmation will be sent by fax and/or email. 随机化后，将向研究中心发回一份表格，提供试验中患者的身份编号和治疗组别。确认函将通过传真和/或电子邮件发送。
V.2. Description of treatments V.2.疗程说明
Each patient will be randomized to one of the following 2 groups: 每位患者将被随机分为以下两组：
Ablation group: radioiodine ablation with an activity of 1.1 GBq ( 30 mCi ) after stimulation by rhTSH, and then follow-up during 5 years, 消融组：在接受 rhTSH 刺激后进行 1.1 GBq（30 mCi）放射性碘消融，然后进行为期 5 年的随访、
Follow-up Group: post-operative follow-up during 5 years (without post-operative radioiodine ablation). 随访组：术后随访 5 年（无术后放射性碘消融）。
V.2.1. Patients randomized in the ablation group V.2.1.消融组随机患者
rhTSH stimulation : Between 2 and 4 months after surgery and start of LT4 treatment, intramuscular injections of rhTSH (0.9mg)(0.9 \mathrm{mg}) are performed on two consecutive days on LT4 treatment. rhTSH 刺激：手术后 2 至 4 个月，LT4 治疗开始后，在 LT4 治疗期间连续两天肌肉注射 rhTSH (0.9mg)(0.9 \mathrm{mg}) 。
Administration of 1.1 GBq of I131: I131 is given orally 24 hours after the second injection of rhTSH. A whole body scan (WBS) is performed 2 to 5 days after the administration of I131, and uptake in the neck is quantified according to a standardized procedure. Activity present in the thyroid bed will be quantified with the ROI method, according to the protocol established by the Department of Medical Physics at the IGR, previously used in the ESTIMABL study. 注射 1.1 GBq 的 I131：在第二次注射 rhTSH 24 小时后口服 I131。注射 I131 2 至 5 天后进行全身扫描（WBS），按照标准化程序量化颈部的摄取量。甲状腺床的活性将根据 IGR 医学物理系制定的方案，采用 ROI 方法进行量化，该方案曾在 ESTIMABL 研究中使用过。
Follow-up consists in: 后续行动包括：
10 (+/- 2) months after surgery: a neck ultrasound and a serum Tg measurement after rhTSH stimulation 术后 10 (+/- 2) 个月：rhTSH 刺激后进行颈部超声检查和血清 Tg 测量
2 years (+/- 2 months) after surgery: a serum Tg measurement on LT4 treatment (Tg/LT4) 术后 2 年（+/- 2 个月）：LT4 治疗期间的血清 Tg 测量（Tg/LT4）
3 years (+/- 2 months) after surgery: a neck ultrasound and a serum Tg/LT4 术后 3 年（+/- 2 个月）：颈部超声波和血清 Tg/LT4
4 years (+/- 2 months) after surgery: a serum Tg/LT4 术后 4 年（+/- 2 个月）：血清 Tg/LT4
5 years (+/- 2 months) after surgery: a neck ultrasound and a serum Tg/LT4 术后 5 年（+/- 2 个月）：颈部超声检查和血清 Tg/LT4
V.2.2. Patients randomized in the follow up group V.2.2.随访组的随机患者
Neither radioiodine nor rhTSH is administered post-operatively. Patients will undergo the same follow-up procedures as patients randomized in the ablation group, except that at 10 months after surgery, Tg is measured under LT4 treatment and not after rhTSH stimulation. 术后既不使用放射性碘，也不使用 rhTSH。患者将接受与消融组随机患者相同的随访程序，但术后 10 个月时，Tg 将在 LT4 治疗下测量，而不是在 rhTSH 刺激后测量。
In both groups, the aim of LT4 treatment is to maintain the serum TSH level between 0.3 and 1mU//L1 \mathrm{mU} / \mathrm{L}. 在这两组中，LT4治疗的目的是将血清促甲状腺激素水平维持在0.3和 1mU//L1 \mathrm{mU} / \mathrm{L} 之间。
VI. EVALUATION CRITERIA VI.评估标准
VI.1. Primary criterion VI.1.首要标准
The primary criterion is the rate of patients without event during the 3 years following surgery. An event is defined by (composite criterion): 主要标准是术后 3 年内无事件发生的患者比例。事件的定义是（综合标准）：
At initial treatment, for patients randomized in the ablation group, the presence on the WBS of focus of radioiodine uptake outside the thyroid bed needing further treatment. 在初始治疗时，对于随机抽取的消融组患者，如果在 WBS 上发现甲状腺床以外的放射性碘摄取灶，则需要进一步治疗。
During follow up, for patients in both groups, administration of an activity of I131 >= 1.1GBq\geq 1.1 \mathrm{GBq} ( 30 mCi ) or surgery for: 在随访期间，两组患者都要接受 I131 >= 1.1GBq\geq 1.1 \mathrm{GBq} (30 mCi) 或手术治疗：
abnormal lymph node on neck ultrasound with an abnormal cytology and/or a thyroglobulin ( Tg ) level in the aspirate fluid > 10ng//mL>10 \mathrm{ng} / \mathrm{mL} 颈部超声检查发现淋巴结异常，且细胞学检查结果异常和/或抽吸液中甲状腺球蛋白（Tg）水平 > 10ng//mL>10 \mathrm{ng} / \mathrm{mL} 。
and/or an abnormal mass in the thyroid bed with an abnormal cytology 和/或甲状腺床出现异常肿块且细胞学检查异常
and/or an elevated Tg level in the absence of anti-Tg antibodies (TgAb) defined according to Figure 1 和/或在没有抗 Tg 抗体（TgAb）的情况下 Tg 水平升高，定义见图 1
and/or the appearance of anti-Tg antibodies (Ab) above the upper limit of the normal range for the kit used, persisting on 2 measurements performed with the same kit at an interval of time of at least 6 months 和/或出现超过所用试剂盒正常范围上限的抗绒毛膜促性腺激素抗体 (Ab)，且在使用同一试剂盒进行的两次测量中持续出现，间隔时间至少 6 个月
and/or the increase of TgAb by more than 50%50 \% on 2 measurements performed with the same kit at an interval of time of at least 6 months. 和/或在至少 6 个月的时间间隔内，使用同一试剂盒进行的 2 次测量中，TgAb 的增加超过 50%50 \% 。
If none of these events occurred during the 3 years following total thyroidectomy, a patient will be considered without event. Conversely, a patient will be considered to have an event if at least one of these events occurred during the 3 years following total thyroidectomy. The proportion of patients without event will be calculated as a percentage in each group, without considering the time at which the event occurs. Patients included in the “ablation group” may have event diagnosed on WBS, whereas patients included in the follow-up group will not (WBS not performed). We made the hypothesis that event in the follow-up group will occur within the 3 years following thyroidectomy. The analysis will be performed when all patients will have 3 years of follow-up, and no lost of follow-up will be tolerated. In the absence of censored datas, the rate of patients without event at 3 years can be calculated as a proportion. Therefore, we will not take into account the moment of the detection of the event, but only the cumulative rate of events during the 3 years following surgery. 如果患者在甲状腺全切除术后 3 年内未发生上述任何事件，则视为未发生事件。反之，如果患者在甲状腺全切除术后 3 年内至少发生过一次上述事件，则视为发生过事件。无事件患者的比例将以每组的百分比计算，不考虑事件发生的时间。纳入 "消融组 "的患者可能会在 WBS 诊断出事件，而纳入随访组的患者则不会（未进行 WBS）。我们的假设是，随访组中的事件将在甲状腺切除术后 3 年内发生。分析将在所有患者都接受 3 年随访且不能容忍随访中断的情况下进行。在没有删减数据的情况下，3 年内未发生事件的患者比例可以按比例计算。因此，我们将不考虑事件的发现时间，而只考虑术后 3 年内事件的累积率。
Both patients with or without anti-thyroglobulin antibodies are eligible for the present study. The question raised in the present study and its therapeutic implications are also applicable to patients with anti-Tg antibodies, and it is important that the results of the present study be tested for these patients (external validity). However, patients with Tg antibodies cannot be considered as evaluable for the main criterion (the serum Tg level is not evaluable). Thus, patients with Tg antibodies will be included, but they will not be considered as evaluable in the main analysis. Analysis of the main criteria will be performed separately in patients with and without Tg antibodies. If the proportion of patient will not be different between the 2 subgroups, then an analysis based on the global population will be performed. 有或没有抗甲状腺球蛋白抗体的患者均可参与本研究。本研究提出的问题及其治疗意义也适用于有抗 Tg 抗体的患者，因此本研究的结果必须经过这些患者的检验（外部有效性）。然而，有 Tg 抗体的患者不能被视为主要标准的可评估对象（血清 Tg 水平不可评估）。因此，有 Tg 抗体的患者也会被纳入，但在主要分析中不会被视为可评估的患者。对有和没有 Tg 抗体的患者将分别进行主要标准分析。如果两个亚组患者的比例没有差异，则将根据总体人群进行分析。
Figure1: Definition of elevated Tg level in the absence of Tg antibodies ( TgAb ) 图 1：无 Tg 抗体（TgAb）时 Tg 水平升高的定义
The cut-off values for Tg levels differ between the two arms because: (1) lower Tg/LT4 levels in the ablation group are expected, as compared to the follow-up group (2) Tg levels after rhTSH stimulation (
