1. Protocol Summary Summary of Trial Design. IoN

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1 1. Protocol Summary 1.1. Summary of Trial Design Title: Short Title/acronym: IoN Is ablative radioiodine Necessary for low risk differentiated thyroid cancer patients IoN EUDRACT no: Sponsor name & reference: Funder name & reference: ISRCTN no: Design: Overall aim: Primary endpoint: Secondary endpoints: Target accrual: Inclusion & exclusion criteria: University College London (UCL/10/0299) Cancer Research UK ISRCTN Multicentre randomised phase II/III trial Phase II: to examine feasibility of recruitment. Phase III: to determine whether the 5-year disease-free survival rate among patients who do not have routine Radioactive iodine (RAI) ablation is non-inferior to those who do. Phase II: monthly patient accrual rates Phase III: 5-year disease-free survival based on: 1) histologically confirmed structural loco-regional recurrent or residual disease 2) distant recurrence Phase III: Cause Specific mortality Loco-regional recurrence Distant and biochemical recurrence Interventions for recurrence Additional investigations for recurrence Quality of Life Adverse events Incidence of second primary tumours Cost effectiveness of each treatment arm Phase III: minimum of 454 patients Refer to sections 5.1 (Thyroid surgery) and 5.2 (Recommended surgery) for guidance and definition around surgery and inclusion into IoN TNM eligibility should be assessed against TNM 7 th edition Inclusion R0 total thyroidectomy (in one or two stages, no residual Page 9 of 74

2 disease present; Rx at the discretion of the MDT) within the last 6 months Negative pregnancy test in women of child bearing potential Aged 16 or over WHO performance status 0 2, self-caring Histological confirmation of differentiated thyroid carcinoma: MDT decision for inclusion based on overall clinico-pathological assessment Papillary thyroid cancer o Non aggressive histological features (small foci of aggressive histology allowed at the discretion of the MDT) o pt1a(m): all individual foci 1cm o pt1b and pt1b(m): >1-2cm o pt2 and pt2(m): >2-4cm o pt3 and pt3(m): >4cm o pt3 R0 : any size with minimal extrathyroidal extension recommended by the MDT o pn0 o pn1a o pnx o Encapsulated Follicular Variant of Papillary Thyroid Cancer (EFVPTC) with capsular invasion only Follicular thyroid cancer/hürthle cell cancer o minimally invasive with capsular invasion only (or up to four foci of possible invasion of intra - capsular vessels at the discretion of the MDT only) o pt1b: >1-4cm intrathyroidal o pt3 R0: (up to 4cm only) with minimal extrathyroidal extension recommended by the MDT N.B. Multifocal tumours ( 2 foci) of all histological types should be designated with (m), and the size of the largest focus determines the classification (as described in the TNM 7th edition). For example, if there are two foci, one 0.8cm and the other 3cm, the classification is based on the 3cm focus; i.e. pt2(m). Exclusion pt1a - Papillary and Follicular carcinoma which is unifocal and 1cm in size <4cm Encapsulated Follicular Variant of Papillary Thyroid Cancer (EFVPTC) with no capsular invasion Anaplastic or medullary carcinoma R1/R2 Thyroidectomy Page 10 of 74

3 Patients with: o pn1b o M1 Aggressive Papillary thyroid cancer with any of the following features: o Widely invasive o Poorly differentiated o Anaplastic o Tall cell o Columnar cell o Diffuse sclerosing variants Follicular thyroid cancer/hürthle cell cancer with any of the following features: o Anaplastic o Widely invasive o Poorly differentiated o Tumours greater than 4cm pt4 or macroscopic and microscopic tumour invasion of locoregional tissues or structures Women who are breast feeding Patients who have CT performed with iv contrast less than 2-3 months before ablation Previous treatment for thyroid cancer (except surgery) Previous malignancies with limited life expectancy or likely to interfere with the patient s ability to be able to comply with treatment and/or follow-up at least for 5 years Dysphagia, oesophageal stricture, active gastritis, gastric erosions, peptic ulcer, suspected reduced gastrointestinal motility MDT decision against ablation or suitability for trial in the light of severe co-morbid condition/s Planned number of sites: Target countries: Treatment summary: 30+ United Kingdom Patients with low risk DTC who meet the eligibility criteria are randomised to: Radioactive iodine (RAI) ablation, or No Radioactive iodine (No-RAI) ablation Following surgery: Initial neck ultrasound (no earlier than 8 weeks post-surgery) rhtsh/hormone withdrawal Local Tg assay and bloods sent for central Beckman Tg Page 11 of 74

4 Anticipated duration of recruitment: Duration of patient follow-up: Definition of end of trial: assay No Radioactive iodine (No-RAI) ablation (arm 2): No Radioactive iodine TSH suppression therapy (< 0.1 miu/l) for the duration of the trial Radioactive iodine (RAI) ablation (arm 1): RAI ablation using Sodium [131 I] Iodide, 1.1 GBq Post ablation scan as per standard practice TSH suppression therapy (< 0.1 miu/l) for the duration of the trial Both arms: Confirmation of Optimal TSH suppression (<0.1) 2 months later 6-9 months after ablation (Arm 1)/stimulated Tg (Arm 2): o rhtsh/hormone withdrawal stimulated Tg, neck ultrasound Follow-up for 5 years o In the first year neck ultrasound and Tg assay on TSH suppression therapy (local and central Beckman assay) at 6 and 12 months o For following 4 years Tg assay on TSH suppression therapy (local and central Beckman assay) every 6 months and neck ultrasound every 12 months Phase II: 1-3 years Phase III: 3-5 years (including Phase II) All patients will be followed for five years (timed from the 6-9 month visit) with protocol-prescribed visits, then as per routine practice. 11 years after randomisation of the last patient onto the trial Page 12 of 74

5 1.2. Trial Schema RAI Ablation (n=285) Low-risk Differentiated Thyroid Cancer Total Thyroidectomy (1 or 2 stage) pre-rand assessments RANDOMISE 1:1 Key THW=Thyroid Hormone Withdrawal; rhtsh=recombinant human Thyroid Stimulating Hormone; TSHST=Thyroid Stimulating Hormone suppression therapy; TFTs=Thyroid Function Tests; AE=Adverse Events No-RAI Ablation (n=285) Initial neck Ultrasound (US) ( 8 wks post surgery) Initial neck Ultrasound (US) ( 8 wks post surgery) rhtsh (days 1&2) or THW* Low iodine diet 2wks pre-ablation Pregnancy test Blood for initial stimulated Tg Post ablation scan ABLATION rhtsh (days 1&2) or THW** Blood for initial stimulated Tg *Resume TSHST 2 days after ablation 2m after initial stimulated Tg ADJUST T4 to TSH <0.1 miu/l **Resume TSHST same day 6-9m after initial stimulated Tg rhtsh (days 1&2) or THW** Blood for local stimulated Tg **Resume TSHST same day Follow up - ALL PATIENTS Year 1 every 6 months Years 2-5 every 6 months Years 2-5 every 12 months After 5 Years Follow up as per local practice Please refer to the protocol for detailed information on treatment and assessments. At any time point, additional tests are allowed at the clinician s discretion. Page 13 of 74