Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Schlumberger M, Catargi B, Borget I, et al. Strategies of radioiodine ablation in patients with lowrisk thyroid cancer. N Engl J Med 2012;366:

2 PROTOCOL AND STATISTICAL ANALYSIS PLAN TABLE OF CONTENTS Study protocol... Page 2 Amendment n Page 63 Amendment n Page 64 Statistical analysis plan... Page 65 1

3 Medico-Economic Comparison of Strategies of Radioiodine Ablation in Thyroid Cancer Patients: the randomized phase III ESTIMABL study Version N 1.0 and (date) Sponsor: Institut de Cancérologie Gustave Roussy N CSET: 2006/1216 COORDINATING INVESTIGATOR Prof. Martin Schlumberger Institut Gustave Roussy 114 rue Edouard Vaillant Villejuif France SPONSOR Institut Gustave Roussy 114 rue Edouard Vaillant Villejuif France Signature of the Clinical Research Department Director: Date : ESTIMABL was entirely funded by the French Ministry of Health, through the National Institute for Cancer (INCa) in the frame of the STIC 2005 (Soutien aux Technologies Innovantes et Couteuses). 2

4 STUDY CONTACTS Name and Address Telephone / Fax Sponsor Statistician Data manager Pharmacovigilance Institut Gustave Roussy (IGR) 114 Rue Edouard Vaillant F Villejuif Cedex Ellen Benhamou Biostatistic and Epidemiology Department, IGR 114 Rue Edouard Vaillant F Villejuif Cedex Sylviane Iacobelli Biostatistic and Epidemiology Department, IGR 114 Rue Edouard Vaillant F Villejuif Cedex Salim Laghouati UFPV - DRCT Institut Gustave Roussy number tel: fax: benhamou@igr.fr tel: fax: iacobeli@igr.fr tel: fax: phv@igr.fr 3

5 1. Study Rationale Post-operative administration of radioiodine Study Objectives Methodology Eligible patients Inclusion criteria Non-inclusion Criteria Randomization Time of randomization Randomization modalities Main treatment Description of treatments Withdrawal of thyroid hormone treatment RhTSH stimulation Radioiodine administration Evaluation criteria Main criterion: ablation Other criteria Evaluation of toxicities Cost evaluation Quality of life: Short Form-36 and Euroqol-5D (EQ-5D scales (Annex 6) Follow-up During the first 8 months Long-term follow-up Number of patients required for inclusion Statistical analysis Main criterion (thyroid ablation rate) Medico-economic evaluation (cost and quality of life) Analysis of Quality of life Cost data Analysis Cost-utility analysis Serious Adverse Events

6 12.1. Definition Adverse Event (AE) Serious Adverse Event (SAE) Expected Serious Adverse Event Unexpected Serious Adverse Event Intensity criteria Reporting Serious Adverse Events (SAE) Responsibilities of the coordinating Sponsor Independent data monitoring committee Ethical and regulatory aspects Rules and regulations Committee for the Protection of Persons (CPP) Competent Authority Information and Consent of Participants Principal Investigator Responsibilities Data collection Quality assurance Monitoring Monitoring Data ownership / Publication Policy...38 References...39 Annex 1: Patient Information Form...42 Informed Consent Form...49 ESTIMABL research protocol...49 Annex 3: Ultrasound Abnormality Criteria...51 Annex 4: Billewicz Scale...52 Annex 5 : Lachrymal and salivary side effects...53 Annex 6: Quality of life questionnaires...54 Health Survey (SF36) Today s Date:...54 EUROQOL EQ-5D

7 SYNOPSIS OF THE STUDY Medico-Economic Comparison of Strategies of Radioiodine Ablation in Thyroid Cancer Patients : the randomized phase III ESTIMABL study Sponsor Principal investigator Statistician Context Institut Gustave Roussy Martin Schlumberger Ellen Benhamou In France, 3,700 new cases of thyroid cancer are diagnosed each year. Differentiated thyroid carcinoma represents more than 90% of all thyroid cancers; and has a 10-year survival of 90-95%. This favourable prognosis is the result of an effective primary therapy, which consists of a total thyroidectomy followed by radio-iodine ablation with 3.7GBq (100mCi) in case of significant risk of persistent disease. Few centers have investigated the possibility of administering lower activities of 131I (1.1 GBq, 30 mci), in order to limit the potential long-term adverse complications for patients and to improve compliance to radioprotection regulations for family members and medical staff. Radio-iodine ablation requires TSH stimulation, which has been historically achieved by thyroid hormone withdrawal for 3 to 5 weeks. During this period, patients suffer from symptoms of hypothyroidism. Recombinant human TSH (rhtsh, Thyrogen, Genzyme Therapeutics, Cambridge, USA) was approved in Europe in 2006 as an alternative to withdrawal during ablation. It allows patients to remain euthyroid on thyroid hormone therapy, to avoid deterioration of their quality of life and to decrease the number of sick-leave days. Objective The objective is to determine whether a similar rate of successful postoperative thyroid ablation can be obtained 1) in euthyroid patients on thyroid hormone therapy who receive rhtsh and in hypothyroid patients following thyroid hormone withdrawal and 2) in patients treated with a low (1.1 6

8 GBq) or a high (3.7 GBq) 131 I activity. Secondary outcomes are short-term toxicities, hypothyroid symptoms, quality of life and utility, and management costs. Design Centres Randomized phase III trial, designed as an equivalence study in a 2*2 factorial design. Each strategy combines a method of TSH stimulation (either thyroid hormone withdrawal (THW) or rhtsh (Thyrogen, Genzyme)) and an activity of 131 I (either low-activity (1.1 GBq, 30 mci) or high-activity (3.7GBq, 100 mci)). French multicentric study (26 centres) Outcome 1 Main outcome The primary outcome is postoperative thyroid ablation, assessed at 8 ± 2 months after radioiodine ablation with a neck-ultrasonography and a rhtshstimulated serum thyroglobulin (Tg) determination, or a diagnostic 131 I-TBS with 4-5 mci in patients with detectable Tg-antibodies. 2 Secondary outcomes: o1 Rate of hypothyroid symptoms and specific toxicities, and complications o2 Quality of life (SF-36 scale) and utility (EQ-5D scale) Management costs (hospitalization, diagnosis tests and sickleave) Inclusion Criteria 1) Newly diagnosed differentiated papillary or follicular thyroid carcinoma) 2) Total thyroidectomy 30 and 60 days before randomization. 3) L-thyroxine therapy for at least 28 days (or L-triiodothyronine therapy for 14 days) 4) Tumor staged pt1<1cm N1 or Nx, pt1 1cm any N, or pt2 N0. 5) Age 18 years 6) Performance status 0 or 1 7) Written consent to participate. 8) Initial quality of life questionnaire completed before randomization 9) Follow-up period > 3 months 10) Negative pregnancy test for women 7

9 Criteria for non-inclusion Number of patients Treatments compared 1) Partial thyroidectomy 2) L-thyroxine therapy less than 28 days (or L-triiodothyronine therapy < 14 days) 3) Patients with Hurthle cell cancer or aggressive histology 4) Tumor staged pt1<1cm N0, T2 N1 or Nx, T3, T4 or M1 5) Patients for which the use of rhtsh is required for medical reasons 6) Patients with a major concurrent medical disorder (cardiac, renal, liver, respiratory) 7) Patients with other malignancies (exception for in situ cervix uterine cancer, basocellular skin cancer or breast cancer in remission for at least 2 years) 8) Patients with recent history of drugs affecting thyroid function, including iodine containing medications or radiocontrast agents 9) Patients with a recent history of 131 I whole body scan 10) Pregnant women or breast-feeding The trial is designed as an equivalence study in a 2*2 factorial design to answer two questions 1) whether the rate of thyroid ablation with rhtsh is within 10% of the rate obtained with thyroid hormone withdrawal and 2) whether the rate of ablation obtained with the low-activity of 131 I (1.1 GBq) is within 10% of the rate obtained with the 131 I high-activity (3.7 GBq). With a two-sided α=0.05, a 95% power and assuming a successful ablation rate of 80% in patients treated by 3.7 GBq and prepared by thyroid hormone withdrawal, 175 patients per group are required. o1 TSH stimulation 1) by thyroid hormone withdrawal Thyroid hormone withdrawal consists in the discontinuation of L-thyroxine treatment for at least 28 days (or withdrawal of L-triiodothyronine treatment for 14 days), with radioiodine administration when the serum TSH concentration is higher than 30 mui/l. 2) by rhtsh Thyroid hormone therapy is not stopped. If the TSH level is < 5 mui/l, rhtsh (recombinant human thyrotropin, Thyrogen, Genzyme) is administered 8

10 Main Outcome assessment concomitantly with thyroid hormone therapy, 0.9 mg intra-muscularly on two consecutive days, and radioiodine is administered on the day following the second rhtsh injection. o2 Iodine administration Radio-iodine is given orally. A 131 I-total-body scan is performed 72 to 120 hours after the administration of radioiodine with measurement of uptake in the thyroid area using the ROI method. Post-operative ablation is considered complete if both the neck-us is normal and the rhtsh-stimulated Tg is less than or equal to 1 ng/ml (or if the control 131 I-TBS is normal in case of detectable Tg-Ab). Post-operative ablation is considered incomplete if the neck-us is suspicious or if the rhtsh stimulated-tg is greater than 1 ng/ml (or the control 131 I-TBS is abnormal in case of Tg-Ab). Starting Date January 2007 Period of 3 years inclusion Period of 8 months ± 2 months follow-up 9

11 SIGNATURE PAGE Medico-Economic Comparison of Strategies of Radioiodine Ablation in Thyroid Cancer Patients: the randomized phase III ESTIMABL study CSET N : 2006/1216 Investigator center: Version n 1.0 and (date) Department: Name and address of center: I.certify that I have read the protocol entitled Medico- Economic Comparison of Strategies of Radioiodine Ablation in Thyroid Cancer Patients: the randomized phase III ESTIMABL study And I certify to conduct this study in accordance with Good Clinical Practices, the locally applicable regulations and the study Protocol. Date: / / 20 10

12 Medico-Economic Comparison of Strategies of Radioiodine Ablation in Thyroid Cancer Patients: the randomized phase III ESTIMABL study 1. Study Rationale The estimated incidence of thyroid cancer in 2005 in France, was new cases and this cancer is by far the most frequent endocrine cancer. Differentiated histotypes, including papillary and follicular lesions, account for 90% of all thyroid cancers. Treatment includes a total or near total thyroidectomy, and in many cases the post-operative administration of iodine 131. This frequently provides cure and 10-year survival is over 90%. Side effects and potential long-term complications of iodine 131, as well as the concern of professionals and patients for radioprotection led to the administration of lower therapeutic activities in many centers. Both normal and neoplastic thyroid tissue take up radioiodine exclusively after TSH stimulation. This was achieved by prolonged withdrawal of thyroid hormone treatment that induced profound hypothyroidism (Dow). Recombinant human TSH (rhtsh) has been used in routine practice since 2000 for the follow-up of thyroid cancer patients (Haugen, Mazzaferri, Schlumberger). Its use avoids prolonged withdrawal of thyroid hormone treatment and thus any hypothyroidism, maintains quality of life and decreases the number of days of sick leave. In 2005, the European Medicines Agency (EMA) approved rhtsh for the preparation of post-operative treatment with iodine 131 in low-risk thyroid cancer patients. However, rhtsh is expensive, and its routine use in this indication should be supported by a medico-economic analysis. The objectives of the present project are to define for each of the 4 possible therapeutic modalities (either high or low radioiodine 131 activity, preparation with withdrawal or rhtsh): 1. Efficacy, assessed in the short term by the normal thyroid remnant ablation rate, and in the long term by the recurrence rate 2. Long- and short-term complication rates 3. Cost and quality of life. 11

13 The innovative aspect of the study is two-fold: firstly, the evaluation of the use of rhtsh during initial treatment can be conducted in real life conditions, following its recent approval by the EMA in this indication, including a medico-economic evaluation. Secondly, this study will evaluate a new treatment strategy for thyroid cancer patients. Furthermore, this multicenter trial will permit the homogenization of clinical practice in France for thyroid cancer patients, including all technical aspects related to the administration of iodine 131, and thus this study will improve the quality of care of thyroid cancer patients. 2. Post-operative administration of radioiodine 131 Objectives of the post-operative administration of iodine 131 The aims of radioiodine administration after surgery are (Robbins, Schlumberger): 1. Eradication of normal thyroid remnants (ablation, Maxon) that will facilitate subsequent follow-up with serum thyroglobulin (Tg) measurements and in some patients with radioiodine whole body scintigraphy (Eustatia-Rutten, Schlumberger). 2. Destruction of tumor foci in order to decrease the risk of recurrence 3. Availability of a highly sensitive whole body scintigraphy performed 1 to 5 days after the dose, according to the administered activity. The post-operative administration of iodine 131 is thus performed with different aims, according to the patients: 1. In patients with residual disease, the administration of high radioiodine 131 activity (3.7 GBq or more) permits the eradication of both normal thyroid remnants and neoplastic foci. Prolonged withdrawal of thyroid hormone treatment is still preferred, because no study has ever shown that irradiation of neoplastic foci with iodine 131 after rhtsh is as efficient as after prolonged withdrawal. 2. In patients with a low risk of residual disease, the main objective of administering radioiodine 131 is the ablation of normal thyroid remnants. In such patients, some researchers prone the administration of 3.7 GBq of radioiodine 131 or more and others the administration of 1.1 GBq or less. Furthermore, radioiodine 131 that was administered following prolonged withdrawal of thyroid hormone treatment to patients in 12

14 a hypothyroid state can now be administered following rhtsh stimulation in a euthyroid state. In these low-risk patients, the medico-economic evaluation of the various strategies used for the post-operative administration of radioiodine should take into account both the administered activity and the TSH stimulation protocol. In all cases, ablation is controlled at 6-12 months after initial treatment with a thyroglobulin determination after rhtsh stimulation and neck ultrasonography, according to European and US recommendations (Mazzaferri, Schlumberger). Administered radioiodine 131 activity Benefits of low-activity of radioiodine 1. A low activity of radioiodine is associated with a shorter stay in the hospital (1 day) to be compared with the 3-4 days required after the administration of high activity in order to adhere to radioprotection norms. Costs are reduced significantly (together with a lower cost of lower activity), and this is beneficial in terms of quality of life, because the recovery in a dedicated unit, where the patient is isolated, is often badly perceived. 2. Low-activity radioiodine is associated with lower environmental exposure. 3. Low-activity radioiodine is associated with a lower risk of side effects. Following the administration of radioiodine, short-term side effects are frequently observed, such as nausea, vomiting, epigastric pain, loss of taste and smell, inflammation of the salivary glands. In patients with large thyroid remnants, radiation thyroiditis may be observed. These side effects are usually transient. Median-term side effects are observed in 5-10% of patients, and consist in decreased salivary flow, lachrymal problems due to the lachrymal duct stenosis (Mandel, Kloos). In the long term, exposure to high cumulative iodine 131 activity is associated with an increased risk of secondary cancers and leukemias (Rubino). These side effects are related to the irradiation of normal tissues by radioiodine, and the radiation dose is obviously lower with lower activities. Benefits associated with the administration of low-activity iodine 131 should be studied according to its efficacy. A review of the literature does not allow any conclusion regarding the relationship between the administered radioiodine activity and the ablation rate (Sawka). Nine of the 10 cohort studies that included a limited number of patients (<100 patients each) showed 13

15 that lower activities are associated with a lower ablation rate, but the only large study (283 patients) showed similar ablation rates with either low or high activities. Table 1: Randomized studies (% ablation and number of patients) Study 1.1 GBq (30 mci) 1.8 GBq (50 mci) 3.7 GBq (100 mci) Creutzig, % (5/10) 60% (6/10) Johansen, % (21/36) 52% (14/27) Bal, % (17/27) 78% (42/54) 74% (28/38) Sirisalipoch, % (41/63) 89% (67/75) Bal, % (61/73) 82% (63/77) Total 71% (104/146) 75% (146/194) 77% (115/150) The 5 randomized studies published to date are reported in Table 1. A large study based on 565 patients allocated to 5 groups, each patient being treated with an activity ranging from 0.5 to 1.8 GBq (15 to 50 mci). The ablation rate was 83% with 1.1GBq (30mCi), and this rate did not increase with higher activities (Bal). However, due to the limited numbers of patients included in these studies, no conclusion can be drawn, and results may either suggest no difference in efficacy or greater efficacy associated with the administration of a higher activity. It is thus necessary to study the efficacy in terms of the ablation rate on a large number of patients in order to obtain statistically significant results. Preparation for iodine 131administration Until now the preparation for the administration of radioiodine consisted in prolonged withdrawal of thyroid hormone treatment for 4 to 6 weeks after a thyroidectomy. During this interval no treatment was given. When the administration of radioiodine 131 had to be postponed for several weeks or months, treatment with thyroid hormone was given after surgery and then withdrawn for 5 weeks in case of treatment with thyroxine or for 2 weeks in case of treatment with LT3. During prolonged withdrawal, patients experienced severe hypothyroidism. Recombinant human TSH (rhtsh) has been used by the majority of teams since 2000 during the follow-up of thyroid cancer patients 6-12 months after initial treatment. The diagnostic value of serum thyroglobulin determination obtained following either rhtsh stimulation or withdrawal is similar for detecting persistent tumor tissue (Haugen). In this indication, rhtsh avoids 14

16 hypothyroidism, improves quality of life, decreases the duration of sick leave, and its use has been advocated by consensus conferences in Europe and in the US (Mazzaferri, Schlumberger). The use of rhtsh to prepare for the post-operative administration of radioiodine 131 allows the initiation of thyroid hormone treatment soon after surgery without withdrawing it at radioiodine 131 administration, thus avoiding any hypothyroidism and significantly improving quality of life. Furthermore, radioiodine may be administered sooner after surgery and this may decrease the duration of post-operative sick leave. The efficacy of rhtsh preparation in comparison with prolonged withdrawal has been studied in two prospective trials: a randomized trial demonstrated that ablation is obtained in 100% of cases when a 3.7 GBq activity is used, both after withdrawal and rhtsh (Pacini), and this confirmed the results of a previous retrospective study (Robbins). The other prospective study showed that with an activity of 1.1 GBq, the ablation rate was lower with rhtsh than with withdrawal (Pacini), although another retrospective study showed similar efficacy (Barbaro). Dosimetric studies (Luster, Pacini) showed that for a given radioiodine 131 I activity, the radiation dose delivered to the normal thyroid remnants is similar after rhtsh and withdrawal, and that the radiation dose to other organs is significantly lower with rhtsh. However, rhtsh is an expensive drug (around 1000 euros per treatment), and this warrants a medico-economic evaluation. Aims of the study This study will evaluate the medico-economic impact of two preparation methods (withdrawal or rhtsh) and of the administration of two radioiodine 131 activities (1.1 GBq and 3.7 GBq). The literature survey shows that the equivalence in efficacy of these methods in terms of the ablation rate should be demonstrated. We thus describe the study protocol and then the medico-economic evaluation for each of these four methods: evaluation of costs, quality of life, and of complication rates. If ablation rates are similar, these criteria will allow us to determine the optimal ablation method. For the quality of life study, this will be evaluated at randomization, and subsequent evaluations will be compared to this first evaluation. It is not possible to include patients prior to surgery, nor to complete the baseline quality of life questionnaire during withdrawal nor in a randomized manner. 15

17 Furthermore, this study will ease the structuring and organization of a network of teams with professionals involved in the care of thyroid cancer patients, and will make it possible to produce consensus guidelines and good clinical practice rules for the quality of care among centers and inside each center. This includes the optimization of the administered radioiodine 131 activity, of the preparation method according to the administered activity, the recovery in specially equipped wards, the whole body scan with quantitation of uptake and the subsequent follow-up protocol. 3. Study Objectives The main objective is to study the equivalence of thyroid ablation rates observed with: 1 One of 2 methods of stimulation (rhtsh or withdrawal) 2 And with one of 2 activities of radioiodine 131 (Low activity: 1.1 GBq or high activity: 3.7 GBq). The trial is an equivalence study using a 2*2 factorial design that will permit the comparison of the two modalities for each treatment and their association. The secondary objectives are to compare among these 4 groups complication rates in the short, medium and long term, treatment costs and quality of life. The study of all these parameters, including that of efficacy (in terms of ablation rates) is necessary for any medico-economic evaluation. 4. Methodology This is a randomized trial that will compare four groups of patients according to the administered activity (low, 1.1 GBq versus high, 3.7 GBq) and the stimulation method used before radioiodine 131 administration (withdrawal versus rhtsh). The trial is an equivalence study using a 2*2 factorial design. Activity of radioiodine 131 Low activity (1.1GBq) High activity (3.7GBq) Stimulation with rhtsh Group 1 Group 2 Stimulation with withdrawal Group 3 Group 4 In each center, a part-time study coordinator will be available and financed by the STIC

18 5. Eligible patients 5.1. Inclusion criteria To be included in the study, patients should meet the following criteria: 1. Patients with a papillary (including the follicular variant) or a follicular thyroid cancer 2. Patients having undergone a total or near total thyroidectomy with or without lymph node dissection, and in whom tumor resection was macroscopically complete 3. Patients having undergone surgery between 1 and 2 months prior to inclusion, and who received thyroid hormone treatment for at least one month. 4. Patients with a low risk of recurrence: pt1 1cm, N1 or pt1>1cm, N0, N1, Nx or pt2, N0. N0 is defined as either the presence of 6 negative lymph nodes at histology, or in cases with < 6 negative lymph nodes at histology following a complete central neck dissection. In cases with multiple micro-cancer foci, when the sum of the diameters of tumor foci is 1cm, whatever the lymph node status. 5. Patients older than 18 years. 6. Patients with a performance status of 0 or Patients who have signed the informed consent form (Annex 1) 8. Patients who filled in the initial Quality of life questionnaires (SF36 & EQ5D). 9. Patients who can be followed up at 3 months, for the completeness of quality of life questionnaires which require the physical presence of the patient. 10. Women of childbearing age should have a negative pregnancy test before any radioiodine administration, and should take a contraceptive method of proven efficacy during the study Non-inclusion Criteria. Patients who will not be included in the trial due to at least one of the following criteria: 1. Patients having undergone less than a total or near total thyroidectomy 2. Patients having undergone surgery more than 2 months before inclusion 3. Patients who had not received treatment with thyroid hormone for at least one month 17

19 4. Patients with a Hürthle cell tumor, or with an aggressive histotype (tall, cylindrical or clear cell, poorly differentiated, or with an anaplastic component), or a diffuse sclerosing variant 5. Patients with a thyroid tumor pt1<1cm, N0 (iodine 131 treatment is not recommended) or T2, N1 or T3, T4 or M1 (patients with a high risk of persistent or recurrent disease who should be treated with high-activity radioiodine following prolonged withdrawal of thyroid hormone treatment) 6. Patients in whom the use of rhtsh is mandatory for medical reasons 7. Patients with a major concurrent medical disorder (cardiac, renal, liver, respiratory) or who are unable to follow the protocol 8. Patients with another malignancy (except for in situ cervix uterine cancer, basocellular skin cancer or breast cancer in remission for at least 2 years) 9. Patients with a recent history of drugs affecting thyroid function, including iodine containing medications or injection of radio-contrast agents 10. Patients with a recent history of 131I whole body scan 11. Pregnant or breast-feeding women 12. Patients who cannot be seen at 3 months because the completeness of the quality of life questionnaire requires the presence of the patient. 13. Participation in another controlled study within 30 days before inclusion in the study. 6. Randomization 6.1. Time of randomization The following information will be requested before randomization: initial inclusion criteria, written signed consent form and initial quality of life questionnaires (SF-36 and EQ-5D). Randomization is performed between 1 to 2 months after the total thyroidectomy and after at least 28 days of L- thyroxine therapy Randomization modalities 18

20 To randomize a patient, the investigator must fill in the randomization form and send it by fax to Sylviane Iacobelli at the Institut Gustave Roussy (fax number: ), who will check that the patient is eligible and that all inclusion criteria are present. Fax the randomization form to: Mrs Sylviane Iacobelli Phone : or BIP Fax: Randomization is performed with the Tenalea program. Patients are randomly allocated to one of the four treatment groups, based on block sizes of 4 or 8, by site, to ensure a balance between the treatment groups at each site. 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 Main treatment Each patient will be randomized to one of the following 4 groups: 1 Group 1 : Stimulation with rhtsh AND low-activity radioiodine (1.1 GBq) 2 Group 2 : Stimulation with rhtsh AND high-activity radioiodine (3.7 GBq) 3 Group 3 : Stimulation with withdrawal AND low-activity radioiodine (1.1 GBq) 4 Group 4 : Stimulation with withdrawal AND high-activity radioiodine (3.7 GBq) 7.1. Description of treatments Withdrawal of thyroid hormone treatment Thyroid hormone treatment is withdrawn for 3 to 4 weeks. Hypothyroidism may be decreased in terms of intensity and of duration by withdrawing LT4 treatment for 5 weeks and by administering LT3 for 3 weeks and then by withdrawing LT3 treatment for 2 weeks. If LT3 has been given since surgery, it will be withdrawn for 2 weeks. In all cases, serum TSH should be measured before radioiodine administration and should be >30 mu/l. 19

21 RhTSH stimulation In case of preparation with rhtsh injections, LT4 treatment at a dose of 2µg/kg body weight or LT3 (1 µg/kg/day) is given for at least 4 weeks, after which the serum TSH level is measured. If serum TSH is < 5 µu/ml, rhtsh (0.9 mg intramuscularly) is administered on 2 consecutive days and radioiodine 131 is given on the day after the second injection. If serum TSH is > 5 µu/ml, thyroid hormone treatment is maintained for two additional weeks after which serum TSH is again determined Radioiodine administration Radioiodine 131 is administered per os during recovery in a ward specifically equipped for radioactive treatments. Before radioiodine 131 administration 1. The absence of pregnancy is ascertained in all women of childbearing age, by performing a pregnancy test before the administration of radioiodine 2. The absence of iodine contamination is sought by interview and if in doubt by measuring iodine in a urinary sample. 3. The patient receives complete oral and written information on radioprotection. Abundant hydration and laxative treatment is administered during recovery. A whole body scan is performed before discharging the patient from the hospital either 1 or 2 days after the administration of 1.1 GBq, or 3 or 4 days after the administration of 3.7 GBq. Activity present in the thyroid bed will be quantified with the ROI method, according to a protocol established by the Department of Medical Physics at the IGR (Annex 2). In all cases, the dose rate at 1 meter is measured before discharging the patient from hospital. 20

22 Study parameters at ablation: Radioiodine uptake in thyroid remnants is quantified during the whole body scan performed after radioiodine 131 administration. The radiation dose rate at 1 meter is measured before discharging the patient from hospital. The serum thyroglobulin (Tg) level is measured on the day of radioiodine administration in case of withdrawal, together with serum TSH determination and in case of rhtsh injection, on the day after the second injection. Serum Tg determination and anti-tg antibody determination will be performed in each center and a serum aliquot will be kept at -80 for central determination at the end o f the study with a standardized method (Biopathology Department, IGR). These parameters will be used to interpret the ablation rate in each group of patients. In the rhtsh groups, L-T4 treatment will be maintained unchanged during and after hospitalization. In the withdrawal groups, L-T4 treatment will be initiated on the day when whole body scintigraphy is performed, usually at a daily starting dose of 2 µg/kg of body weight. In all cases, serum TSH will be verified 3 months later. 8. Evaluation criteria 8.1. Main criterion: ablation Ablation will be ascertained at 8 months (+/- 2 months) after surgery and is defined according to the European and US consensus as: An undetectable serum Tg level (<1ng/mL) after rhtsh stimulation (one intramuscular injection of 0.9 mg, for 2 consecutive days and a serum Tg determination 3 days after the second injection of rhtsh). If serum Tg is then detectable (> 1ng/mL), and in the absence of any abnormality on neck ultrasonography, another rhtsh stimulation will be performed 6 months later to check whether serum Tg is then undetectable. Serum Tg and anti-tg antibody determinations will be performed in each center and a serum aliquot will be kept at -80 for central dete rmination at the end of the study with a standardized method (Biopathology Department, IGR). And by the absence of abnormalities at neck ultrasonography. In case of abnormalities at ultrasonography (Annex 3), a fine needle aspiration biopsy will be performed and treatment will be decided according to its results. 21

23 In the presence of serum anti-tg antibodies or of an abnormal recovery test at 8 months, a whole body scan with radioiodine 131 (4-5 mci Iodine 131) will be performed at 8 months following rhtsh injections together with a neck ultrasonography examination Other criteria The medico-economic evaluation aims to compare the cost and quality of life of patients between the 4 strategies Evaluation of toxicities 1) Hypothyroid symptoms by the Billewicz scale (Annex 4) The Billewicz scale is administered by the investigator during the following visits: o o o o At randomization (baseline) (Q0) At the beginning of the hospitalization for radioiodine ablation (Q1) 3 months after radioiodine ablation (1 st control after RAI) (Q3) 8 months after radioiodine ablation, when the main endpoint (ablation) is evaluated (Q4) 2) Side effects induced by radioiodine ablation (Annex 5) A specific questionnaire is used to assess the time of onset and the intensity of lachrymal or salivary disorders, as well as other disorders induced by 131 I administration (sickness and vomiting, epigastric pain, loss of taste or smell). This specific scale is administered by the investigator during the following visits: o o o o At randomization (baseline) (Q0) At the end of the hospitalization for radioiodine ablation (Q1) 3 months after radioiodine ablation (1 st control after RAI) (Q3) 8 months after radioiodine ablation, when the main endpoint (ablation) is evaluated (Q4) Cost evaluation 22

24 Costs will be evaluated from the societal perspective. The main resources likely to differ between strategies are the following: o o o rhtsh, with an estimated cost of for 2 injections, Medical costs for radioiodine administration: the hospital stay is expected to be shorter in the low activity groups than in the high activity groups. The cost of 131 I is also dependent on the activity administered (1.1GBq: 116 euros ; 3.7GBq : 237 euros). Moreover, the use of rhtsh may reduce the hospital stay for radioiodine ablation, because iodine is eliminated faster in a euthyroid than in a hypothyroid state. Admission and discharge dates will be collected, by care unit. Sick leave: the length of sick leave in active patients is expected to be shortened in patients prepared with rhtsh, as compared to that in patients prepared by thyroid hormone withdrawal. The sick leave period will be collected during two periods of time: During the TSH stimulation period, between randomization (Q0) and the beginning of hospitalization for radioiodine ablation (Q1), During the 8 months following radioiodine ablation, with an evaluation planned at 6 weeks (using a notebook completed at home by the patient), at 3 and 8 months following radioiodine ablation. The following other medical resources to be collected: The number of TSH determinations performed between randomization and the evaluation at 8 months, as these numbers may differ according to the TSH stimulation method used. Transportation costs, as patients prepared by withdrawal are expected to use medical transportation more frequently than patients prepared with rhtsh Symptomatic treatments administered for side effects (laxatives, corticosteroids) will not be collected as they are rarely used and these treatments are not expensive. However; treatment administered in case of severe adverse events will be collected (hospitalizations, drugs, diagnostic examinations). Medical costs associated with an incomplete ablation after an abnormal work-up at 8 months, including hospitalization and another treatment with radioiodine. 23

25 All items necessary for the estimation of these costs will be included in the clinical Case Report Form (CRF) Quality of life: Short Form-36 and Euroqol-5D (EQ-5D scales (Annex 6) The SF-36 and the Euroqol-5D scales are validated generic scales used to estimate patient quality of life and utility (Brazier, Van Agt). They are used together as they are complementary. The SF-36 scale is used to describe the component and the dimensions of quality of life that are affected by the TSH stimulation method or radioiodine activity. The EQ-ED is used to obtain a utility index which allows one to calculate the time spent in this specific state in the cost-utility evaluation. 1) The self-administered SF-36 scale The SF-36 is suitable for self-administration. The SF-36 is a multi-purpose, short-form health survey with only 36 questions. It yields an 8-scale profile: physical functioning, physical condition, bodily pain, general health, vitality, social functioning, emotional status, mental health, as well as psychometrically-based physical and mental health summary measures. It can be administered in 5-10 minutes with a high degree of acceptability. The version used in the present study is the acute (1-week) recall version, whereas the standard version has a recall period of one month. Authorization to use the questionnaire will be requested from the authors of the Scale ( 24

26 2) The EQ-5D questionnaire The EQ-5D is a standardized tool used to estimate the utility index required for the calculation of the cost-effectiveness ratio. It is a self-administrated questionnaire whose completion time is less than 5 minutes. The first page of the EQ-5D system comprises the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: no problems, some problems, extreme problems. The respondent is asked to indicate his/her health state by ticking the box corresponding to the most appropriate statement in each of the 5 dimensions. An EQ-5D health state is then converted to a single summary index, called the utility index, by applying a formula that essentially attaches weights to each of the levels in each dimension. This formula is based on the valuation of EQ-5D health states of samples from the general population. At present, there is no valuation based on the French general population. The utility index obtained from a European population will be used (Greiner) The second page, the respondent can self-rate health on a vertical, visual analog scale where the extremities are labeled Best imaginable health state and Worst imaginable health state. This information can be used as a quantitative measure of health status as appraised by the individual respondents. An authorization to use the questionnaire will be requested from the authors of the Scale ( 3) Hypothesis 1 Impact on the stimulation method : The impact of the stimulation method on quality of life is the deterioration of quality of life in patients stimulated by withdrawal, whereas it remains stable in patients receiving rhtsh. This hypothesis is based on the results of a recent study which compared the quality of life (assessed with the SF-36 scale) of the two stimulation methods in patients whose follow-up surveillance program included a whole body scan or thyroglobulin 25

27 determination (Schroeder). As the impact of treatment on quality of life is short, few evaluation times are required. 2 Impact of radioiodine activity : It is difficult to put forward an a priori hypothesis of the effect of radioiodine activity on quality of life. Low radioiodine activity may allow a more rapid return to the initial quality of life score. However, this effect is probably moderate in intensity and duration. 3 In case of incomplete ablation at 8 months In case of incomplete ablation at 8 months, a work-up combining a serum rhtshstimulated thyroglobulin determination and a neck ultrasound examination will be performed 6 months later. In case of abnormalities, a second radioiodine treatment can be administered. The hypothesis is that this second treatment is pointless for the patient. 4) Time of evaluation of quality of life For each patient, 7 evaluations using the EQ-5D scale and 4 evaluations using the SF-36 scale are planned: Q0: at randomization (baseline) : SF-36 + EQ-5D Initial assessment of quality of life. The scale will be administered by the clinician investigator. Condition required for randomization. Q1: at admission for radioiodine ablation: SF-36 + EQ-5D Estimation of the deterioration of quality of life caused by the stimulation method. The scale will be administered on the first day of hospitalization by the clinician investigator. Q2 (Q2S2, Q2S4, Q2S6) : during the 6 weeks following radioiodine ablation : Assessment of QoL during the recovery period (existence of a prolonged effect of the stimulation method which is a measure of the effect of the 131 iodine activity used). A logbook will be given to the patient so that he/she can complete the EQ-5D scale every 15 days (S2, S4, S6) and the SF-36 exclusively at 6 weeks: o o o Q2S2 : 2 weeks after hospitalization for radioiodine ablation : EQ-5D Q2S4 : 4 weeks after hospitalization for radioiodine ablation : EQ-5D Q2S6 : 6 weeks after hospitalization for radioiodine ablation : EQ-5D + SF36 26

28 Q3: 3 months after radioiodine ablation : SF-36 + EQ-5D Evaluate a possible longer-term impact of the strategies on QoL. Q4: 8 months after radioiodine ablation : SF-36 + EQ-5D 9. Follow-up Patients will be followed up annually over 10 years, according to the standard recommendations concerning surveillance During the first 8 months The main and secondary endpoints will be analyzed once all the patients have had a follow-up examination at 8 months, all the questionnaires have been obtained and the database has been cleaned Long-term follow-up The local and distant recurrence rate, as well as the complication rate will be evaluated annually during the first 3 years following randomization, and then every 2 years over the next 4 years. Monitoring will include an annual serum Tg determination under L-thyroxine therapy, and at 4 years (± 6 months) after the first follow-up examination, a neck ultrasound examination and a serum Tg determination after stimulation with rhtsh. Progression will be documented by a clinical examination, a neck ultrasound examination, a 131 I whole body-scan, CT, MRI, PET-FDG, Tg determination, cytology or histology. 10. Number of patients required for inclusion This is an equivalence trial using a 2-by-2 factorial design, whose hypotheses are the following: 27

29 the rate of thyroid ablation is equivalent using the two TSH stimulation methods (rhtsh and thyroid hormone withdrawal) the rate of thyroid ablation is equivalent using the two radioiodine activities (1.1 and 3.7 GBq) Equivalence of the two 131 I activities [low-activity 131 I (1.1 GBq) and high-activity 131 I (3.7 GBq) will be demonstrated if the rate of complete ablation achieved with the two activities does not differ by more than 10 %. Likewise, equivalence of the two stimulation methods (rhtsh and thyroid hormone withdrawal) will be demonstrated if the rate of ablation observed does not differ by more than 10 %. With a two-sided α=0.05, 80% power and assuming an ablation rate of 80% in patients treated with 3.7 GBq or with thyroid hormone withdrawal, 175 patients per group are required. This number of patients is sufficient to answer the medico-economic question. The main criterion for the cost-effectiveness evaluation will be the difference in the utility index between strategies. 136 patients per strategy are required to detect a difference of 0.1 in the utility index at radioiodine ablation, with a one-sided α=0.05, 95% power and a standard deviation=0.25. Given the number of participating centers and their recruitment capacity, patient inclusion should be achieved in one year, and data collection over 2 years. This time estimation may be re-evaluated if recruitment is longer than expected. Data quality control will be initiated during the investigator meetings (3 meetings/year over 2 years). 11. Statistical analysis No patient exclusion will be accepted in the intent-to-treat analysis. Erroneously included patients or patients who will not adhere to the study protocol will be taken into account in their randomization group, based on the intent-to-treat principle. In order to limit the number of patients lost follow-up, the clinician investigator in each center will contact the patients for follow-up visits. 28

30 11.1. Main criterion (thyroid ablation rate) The main endpoint will be analyzed 8 months after inclusion of the last patient, once all the questionnaires have been collected and the database has been cleaned, using the classic methodology used for a 2-by-2 factorial design, including: Comparison of the 2 radioiodine activities Comparison of the two TSH stimulation methods Interaction between radioiodine activity and the TSH stimulation method For the first step of the analysis, the comparative tests will only concern the main endpoint Medico-economic evaluation (cost and quality of life) At the end of the first stage, the analysis will concern secondary endpoints, including quality of life and costs. The economic study aims to compare the costs and quality of life between the 4 strategies, in order to define the optimal strategy, based on a cost-utility criterion Analysis of Quality of life The mean scores of the SF-36 and EQ-5D scales (physical component summary, psychological component summary, utility index and visual analog scale from EQ-5D) will be compared between the 4 strategies using the nonparametric Kruskall-Wallis test, at each evaluation. A mean utility index and its 95% interval confidence will be calculated for each strategy. The data will be analyzed taking into account missing data. For missing items in the SF-36 questionnaire, recommendations extracted from the SF-36 scoring manual will be applied (Ware). Conversely, the utility index can be obtained only if all the items have been completed. 29

31 Cost data Analysis The mean management cost per patient and per strategy will be calculated after valuation of resources consumed (mainly the cost of rhtsh, hospitalization for radioiodine ablation and sick leave). The differences in costs between strategies will be compared using the Kruskall-Wallis test. A 95% confidence interval will be calculated Cost-utility analysis The reference strategy is withdrawal to prepare for ablation and the administration of a high activity of radioiodine which correspond to current practice. The type of medicoeconomic analysis will depend on the efficacy results and on quality of life. Each of the 3 alternative strategies will be compared to the reference strategy. A priori, there are three possibilities: 1) The strategies are not equivalent in terms of efficacy : if the difference in the thyroid ablation rate at 8 months between the reference strategy and an alternative strategy is more than 10%. This means that the number of follow-up tests (after rhtsh stimulation) and of second radioiodine 131 ablations will be higher for the less effective strategy, inducing additional costs and disutility (measured by the EQ-5D) for this strategy. A cost-utility evaluation will be performed after the second radioiodine treatment. 2) The strategies are equivalent in terms of efficacy: thyroid ablation rates at 8 months do not differ by more than 10% between the strategies. In this case, quality of life will be used to compare the strategies. If a strategy is associated with higher quality of life scores (utility score difference > 0.1), two cases are possible: if the alternative strategy is less expensive, it is then dominant (less expensive and more efficient). If it is more expensive, an incremental cost-utility ratio will be calculated, expressed in qualityadjusted life months (qalm). A 95% confidence interval and an acceptability curve will be estimated by the nonparametric bootstrap method. 30

32 3) If these strategies are equivalent in terms of efficacy (ablation) and in terms of quality of life (EQ-5D), a cost minimization study will be performed. The dominant strategy will be the least expensive one. 12. Serious Adverse Events Definition Adverse Event (AE) An Adverse Event (AE) is any new untoward medical occurrence or worsening of a preexisting medical condition in a patient or clinical investigation subject administered an investigational (medicinal) product. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory findings for example), symptoms, or disease transiently associated with the use of a medical product, whether or not a causal relationship (i.e. related/unrelated) with the treatment is suspected Serious Adverse Event (SAE) A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: - is fatal (results in death) - is life-threatening - requires or prolongs in-patient hospitalization - results in persistent or significant disability / incapacity - gives rise to a congenital anomaly / birth defect - is medically significant (defined as any clinical event or laboratory result that may not be immediately life-threatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the subject or may require an intervention (e.g. medical, surgical) to prevent one of the other serious outcomes listed in the definition above. Examples of such events include but are not limited to, allergic broncho-spasm requiring intensive treatment in an emergency room or at home, blood dyscrasia or convulsions that do not result in inpatient hospitalization, development of drug dependency or drug abuse, transmission of an infectious agent. 31

33 Although overdose and cancer are not always serious according to regulatory definitions, these events should be reported on a SAE report form and expedited to the sponsor. A SAE considered potentially related to a study drug qualifies as a Serious Adverse Drug Reaction (SADR). Events exclusively related to a tumor relapse/progression or the treatment of a tumor relapse/progressions are not considered as SAE. The following are not considered as serious adverse events (SAE): - A visit to the emergency room or other hospital department for less than 24 hours that does not result in admission (unless considered an important medical event or a lifethreatening event) - Outpatient or same-day or ambulatory procedures - Observation or short-stay units - Hospitalization due to diagnostic procedures or standard supportive care (e.g. implant of central venous catheter) - Pre-planned hospitalization for a condition which existed at the start of study drug and which did not worsen during the course of study drug treatment - Admission on social grounds (e.g., subject has no place to sleep; hospice facilities) - Administrative admission (e.g., for yearly physical examinations) - Protocol-specified admission during a clinical trial (e.g. for a procedure required by the study protocol or for clinical research) - Optional admission not associated with a precipitating clinical AE (e.g. for elective cosmetic surgery) Expected Serious Adverse Event An expected SAE is an event already mentioned in the most recent version of the investigator brochure or in the summary of product characteristics, for drugs with a market authorization Unexpected Serious Adverse Event An unexpected SAE is an event not mentioned or different in nature, intensity and/or, evolution from that found in the investigator brochure or in the summary of product characteristics, for drugs with a market authorization. 32

34 Intensity criteria Intensity criteria must not be confused with severity criteria, which serve as guidelines to define declaration obligations. The intensity of events will be estimated according to the NCI-CTCAE classification, version 4.0 (toxicity score grade 1 to 5). The intensity of adverse events not listed in this classification will be evaluated according to the following terms: 1 Mild (grade 1): does not affect the patient's usual daily activity 2 Moderate (grade 2): perturbs the patient's usual daily activity 3 Severe (grade 3): prevents the patient from carrying out his usual daily activities 4 Very Severe (grade 4): necessitates intensive care or is life threatening 5 Death (grade 5) Reporting Serious Adverse Events (SAE) Any SAE which occurs or comes to the attention of the investigator at any time during the study since consent is given and within 30 days after the last administration of study drugs, independent of the circumstances or suspected cause, must be reported immediately, within 24 hours of knowledge (at latest on the next working day) by fax via a SAE report form to: Pharmacovigilance unit Fax : +33 (0) Phone : 33 (0) (9 a.m. - 6 p.m. from Monday to Friday, except on bank holidays) phv@igr.fr All late Serious Adverse Events (occurring after this period of 30 days) considered to be reasonably related to the study treatment(s) or the research should be declared (no time limit). Information collected on the SAE form is crucial for case assessment. For this reason diligence in collecting as much verifiable and reliable information is needed: both, quality and timeliness are key factors. If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its individual symptoms. The following 33

35 information should be captured for all SAEs: onset, duration, intensity, severity, relationship to study drugs, action taken and treatment required. The investigator should also attach the following to the SAE report form, wherever possible: 1 A copy of the summary of hospitalization or prolongation of hospitalization 2 A copy of the post-mortem report 3 A copy of all laboratory examinations and the dates on which these examinations were carried out, including relevant negative results, as well as normal laboratory ranges. 4 All other documents he/she considers useful and relevant. All these documents will remain anonymous. Further information can be requested (by fax, telephone or when visiting) by the monitor and/or the safety manager. Follow-up information The investigator is responsible for the appropriate medical follow-up of patients until resolution or stabilization of the adverse event or until the patient's death. This may mean that follow-up should continue once the patient has left the trial. Follow-up information about a previously reported SAE should be reported by the investigator to the Pharmacovigilance Unit within 48 hours of receiving it (on the SAE report form, by ticking the box marked Follow-up N ). The investigator should also transmit the final report at the time of resolution or stabilization of the SAE. He/She retains the documents concerning the supposed adverse event so that previously transmitted information can be completed if necessary Responsibilities of the coordinating Sponsor The Pharmacovigilance Unit at IGR will assess the SAE in terms of seriousness, severity (NCI- CTCAE v4.0), relationship to the study drugs and expectedness chapters). All SAEs will be coded using medra. Suspected Unexpected Serious Adverse Reactions (SUSARs) 34

36 To comply with regulatory requirements, the coordinating sponsor will notify all national sponsors of all SAEs that are related to the investigational medicinal product and unexpected (i.e. not previously described in the investigator brochure or in the Summary of Product Characteristics). In the European Union, an event meeting these criteria is termed a suspected Unexpected Serious Adverse Reaction (SUSAR). In case of a SUSAR, a CIOMS-1 form will be sent by the IGR Pharmacovigilance Unit to each national sponsor within 72 hours. Each national sponsor is responsible for the declaration to the National Ethics Committee (if required according to local regulations) and to the national competent authority. All SUSAR reports and all reports involving expected SADR that are fatal will additionally be forwarded to all study investigators and to the Independent Data Monitoring Committee. The study offices involved are responsible for informing the Ethics Review Board(s) concerned as well as the respective investigators. The reporting procedure has to comply with national legislation. Annual safety report The IGR Pharmacovigilance Unit will issue once a year throughout the clinical trial, or upon request, the annual safety report (ASR) of the study, in accordance with the detailed guidelines from the European Commission concerning the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use of April 2006 and the applicable revisions thereof. The pharmacovigilance unit will send a copy of the ASR to national sponsors. 13. Independent data monitoring committee A trial monitoring committee (IDMC = Independent Data Monitoring Committee) will be set up to monitor patient safety, to ensure the trial is conducted in an ethical manner, to evaluate the risk/benefit ratio of the trial and to ensure an independent review of the scientific results during and at the end of the trial. This committee will play an advisory role with respect to the Promoter 35

37 upon whom it is incumbent to make the final decision to implement recommendations proposed by the committee. 14. Ethical and regulatory aspects Rules and regulations The clinical trial is conducted in conformity with: - Ethical principles of the Helsinki Declaration of 1964, revised in Edinburgh in 2000, - Good Clinical Practices as defined by the International Harmonization Conference (ICH E6, 17/07/96), - The European Directive (2001/20/EC) on the performance of clinical trials, - The European Directive (2001/20/EC and 2005/28/EC) - The Informatics and Liberties Law (n 78-17) of J anuary 6, 1978 modified by Law n of August 6, 2004 relative to the protection of physical persons with respect to the treatment of personal information. - Law n of March 4, 2002 relative to pati ents rights and to the quality of the healthcare system, Committee for the Protection of Persons (CPP) Competent Authority This protocol was submitted to the Ethics Committee/IRB/CPP which gave its approval under number on July 10 th, This protocol has also been approved by the Competent Authority. Institut Gustave Roussy has taken out a legal liability insurance policy (N XXXX). A final report on the trial will be written at the latest, 1 year after the end of the trial (defined as the time of the main analysis) and sent to the competent authority and to the Ethics Committee/IRB/CPP. Institut Gustave Roussy will maintain records of essential trial documentation in the Sponsor file for a minimum duration of 15 years after the end of the trial. 36

38 14.3. Information and Consent of Participants Prior to the conduct of any procedure linked to biomedical research, any person wishing to participate in a research study gives his/her free, informed and written consent. This consent is obtained once the participant has been informed by the investigator during a consultation and after the person has been given sufficient time to think it over. Having read the information notice, the patient must date and sign the consent form if he/she accepts to participate. This consent form must also be signed by the investigator. The original consent form must be kept in the study file by the investigator and the study participant should receive a copy Principal Investigator Responsibilities The principal investigator of each establishment concerned promises to conduct the clinical trial in conformity with the protocol which has been approved by the CPP and the competent authority. The principal investigator should not modify any aspect of the protocol without prior written permission from the Sponsor nor without the approval of the proposed modifications by the Ethics Committee/IRB/CPP and the competent authority. The Principal Investigator is responsible for: - providing the Sponsor with his/her CV as well as that of co-investigators, -identifying members of his/her team participating in the trial and defining their responsibilities, - recruiting patients after receiving the Sponsor s approval, Each investigator is responsible for: - personally obtaining the informed consent form which has been dated and signed by the participant in the research, prior to any specific trial selection procedure, - regularly completing the case report form (CRF) for each patient included in the trial and ensuring that the Clinical Research Assistant (CRA) mandated by the Sponsor has direct access to source documents in order to validate information on the CRF, - Dating, correcting and signing the corrections on the CRF for each patient included in the trial, - accepting regular visits from a CRA and possibly visits from auditors mandated by the Sponsor or inspectors from the regulatory authorities. 37

39 All documentation concerning the trial (protocol, consent form, case report form, investigator file, etc ), as well as the original documents (laboratory results, imaging studies, medical consultation reports, clinical examination reports, etc.) is considered confidential and should be kept in a safe place. The Principal Investigator should keep data as well as a list of patientidentifying data for at least 15 years after the end of the study. 15. Data collection Specify the characteristics of the CRF (paper and electronic, design ), calendar and the method used to collect and transmit data. 16. Quality assurance Monitoring In order to guarantee the authenticity and the credibility of the data in conformity with good clinical practices, the Sponsor has installed a quality assurance system which includes: - Trial management in accordance with the procedures at the Institut Gustave Roussy, - Quality control of data at the investigating site by the Clinical Research Assistant (CRA), - Possible auditing of investigating centers, Monitoring Quality control on the site will be ensured by the CRA. The CRA must check that the investigator s file exists and that it is updated. The CRA must verify the consent forms, that subjects fulfill eligibility criteria, the validity of evaluation criteria and treatment toxicity with the help of source documents (and other aspects to be specified and adapted according to the study). The CRA will check drug accountability and ensure that the drug accountability forms are validated and signed by the in-house pharmacist before any request for destruction. 17. Data ownership / Publication Policy The investigator promises, on his/her behalf as well as that of all the persons involved in the conduct of the trial, to guarantee the confidentiality of all the information provided by the Institut Gustave Roussy until the publication of the results of the trial. All publications, abstracts or presentations including the results of the trial require prior approval of the Sponsor (Institut Gustave Roussy). 38

40 References 1. Bal CS, Kumar A, Pant GS. Radioiodine dose for remnant ablation in differentiated thyroid carcinoma: a randomized clinical trial in 509 patients. J Clin Endocrinol Metab 2004; 89: Barbaro D, Boni G, Meucci G, et al. Radioiodine treatment with 30 mci after recombinant human TSH stimulation in thyroid cancer: effectiveness for postsurgical remnants ablation and possible role of iodine content in L-thyroxine in the outcome of ablation. J Clin Endocrinol Metab 2003; 88: Eustatia-Rutten CFA, Smit JWA, Romijn JA, et al. Diagnostic value of serum thyroglobulin measurements in the follow-up of differentiated thyroid carcinoma, a structured meta-analysis. Clin Endocrinol 2004; 61: Dow KH, Ferrell BR, Anello C. Quality-of-life changes in patients with thyroid cancer after withdrawal of thyroid hormone therapy. Thyroid 1997; 7: Haugen BR, Pacini F, Reiners C, Schlumberger M, Ladenson PW, Sherman SI et al. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999; 84: Kloos RT, Duvuuri V, Jhiang SM, Cahill KV, Foster JA, Burns JA. Nasolacrimal drainage system obstruction from radioactive iodine therapy for thyroid carcinoma. J Clin Endocrinol Metab 87: , Luster M, Sherman SI, Skarulis MC, Reynolds JR, Lassmann M, Hänscheid H, et al. Comparison of radioiodine biokinetics following the administration of recombinant human thyroid stimulating hormone and after thyroid hormone withdrawal in thyroid carcinoma. Eur J Nucl Med Mol Imaging 2003; 30: Mandel SJ, Mandel L. Radioactive iodine and the salivary glands. Thyroid 2003; 13: Maxon HR, Smith HS. Radioiodine-131 in the diagnosis and treatment of metastatic well differentiated thyroid cancer. Endocrinol Metab Clin N Am 1990; 19: Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001; 86:

41 11. Mazzaferri EL, Robbins RJ, Spencer CA, Braverman LE, Pacini F, Wartofsky L et al. A consensus report of the role of serum thyroglobulin as a monitoring method for low- risk patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 2003; 88: Pacini F, Molinaro E, Castagna MG, Lippi F, Ceccarelli C, Agate L, et al. Ablation of thyroid residues with 30 mci 131I : a comparison in thyroid cancer patients prepared with recombinant human TSH or thyroid hormone withdrawal. J Clin Endocrinol Metab 2002; 87: Pacini F, Ladenson PW, Schlumberger M, et al. Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international, randomized, controlled study J Clin Endocrinol Metab 2006; 91: Pacini F, Schlumberger M, Harmer C, et al. Post-surgical use of radioiodine ( 131 I) in patients with papillary and follicular thyroid cancer and the issue of remnant ablation. A consensus report. Eur J Endocrinol 2005 ; 153 : Robbins RJ, Larson SM, Sinha N, Shaha A, Divgi C, Pentlow KS, et al. A retrospective review of the effectiveness of recombinant human TSH as a preparation for radioiodine thyroid remnant ablation. J Nucl Med 2002 ; 43 : Robbins RJ, Schlumberger MJ. The evolving role of 131 I for the treatment of differentiated thyroid carcinoma. J Nucl Med, 2005; 46: 28S-37S 17. Rubino C, De Vathaire F, Dottorini ME, Hall P, Schvartz C, Couette JE, Dondon MG, Abbas MT, Langlois C, Schlumberger M. Second primary malignancies in thyroid cancer patients. Br J Cancer 2003; 89: Sawka AM, Thephamongkhol K, Brouwers M, Thabane L, Browman G, Gerstein HC. A systemic review and metaanalysis of the effectiveness of radioactive iodine remnant ablation for well-differentiated thyroid cancer. J Clin Endocrinol Metab, 2004; 89: Schlumberger M, Berg G, Cohen O, Duntas L, Jamar F, Jarzab B, et al. Follow-up of lowrisk patients with differentiated thyroid carcinoma : a European perspective. Eur J Endocrinol 2004; 50: Schlumberger M. Papillary and follicular thyroid carcinoma. N Engl J Med 1998; 338:

42 21. Wartofsky L, Sherman SI, Gopal J, Schlumberger M, Hay ID. The use of radioactive iodine in patients with papillary and follicular thyroid cancer. J Clin Endocrinol Metab 1998; 83: Brazier J, Jones N, Kind P. Testing the validity of the Euroqol and comparing it with the SF-36 health survey questionnaire. Quality Life Research 1993; 2: Van Agt HM, Essink-Bot ML, Krabbe PF, Bonsel GJ. Test-retest reliability of health state valuations collected with the EuroQol questionnaire. Social Science Medicine 1994; 39: Greiner W, Weijnen T, Nieuwenhuizen M et al. A single European currency for EQ-5D health states. Results from a six-country study. Eur J Health Econ. 2003;4: Schroeder PR, Haugen BR, Pacini F et al. A Comparison of Short-term Changes in Health-related Quality of Life in Thyroid Carcinoma Patients Undergoing Diagnostic Evaluation with rhtsh Compared to Thyroid Hormone Withdrawal. J Clin Endocrinol Metab ; Roset M, Badia X, Mayo NE. Sample size calculations in studies using the Euroqol 5D. Quality of Life Research 1999; 8: Craig J, McEwan P, Peters JR et al. The routine collation of health outcomes data from hospital treated subjects in the health outcomes data repository (HODAR): descriptive analysis from the first 20,000 subjects. Value in Health 2005; 8 (5): Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 health survey. Manual and interpretation guide. Boston, MA: The Health Institute, New England Medical Center;

43 Annex 1: Patient Information Form PATIENT INFORMATION FORM Complete title of the clinical trial: Medico-Economic Comparison of Strategies of Radioiodine Ablation in Thyroid Cancer Patients: the randomized phase III ESTIMABL study Mrs., Miss, Mr, Your doctor is proposing to you to participate in a medical research protocol called ESTIMABL that is sponsored by the Institut Gustave Roussy (IGR). You are being invited to take part in a research study. Your participation must be based on an entirely voluntary decision. We invite you to read this Information Sheet and to take sufficient time for reflection before you give your written informed consent. Your doctor will discuss with you details of your treatment and answer any question you may have related to the trial or your disease before giving your consent, and all along your treatment. Even after you have given your written informed consent you will remain free to stop your participation at any time and without giving any justification. This decision will not affect your relationships with your doctor and the medical team and you will be offered the most appropriate treatment replacement insuring that the quality of the medical cares is not altered. We thank you in advance for your collaboration. 1. What is the Objective of the study? The ablation consists in the administration of a post-operative treatment by 131 radioactive iodine. It is given as a complement to the surgical treatment, to destroy remaining normal thyroid cells. Its main interest is to facilitate long term follow-up. The objective of the study is to compare the efficacy of four post-operative strategies for your thyroid cancer, and to evaluate the economic impact of these strategies. The 4 strategies combine two TSH stimulation methods (either thyroid hormone withdrawal or rhtsh) and two radioiodine activities (1.1 GBq (30 mci) or 3.7 GBq (100 mci)). The study will be carried out in 42

44 26 centers in France. The length of inclusion is expected to be one year, but it may be prolonged. TSH (Thyrotrophin-stimulating hormone) is an hormone secreted by the pituitary gland (the pituitary gland is an endocrine gland located under the brain), which regulates the endocrine function of the thyroid gland: it increases radioiodine 131 uptake, the production of Thyroglobulin (Tg) and of Thyroxine (the thyroid hormone) by the thyroid cells. Stimulation by TSH is required to obtain radioiodine 131 uptake by the thyroid gland, and is thus an essential condition before the administration of radioiodine 131 treatment. TSH secretion by the pituitary gland may be decreased by thyroxine treatment. An elevated serum TSH level can be obtained either after prolonged withdrawal of thyroxine treatment (during 3 to 5 weeks, responsible for of hypothyroidism symptoms) or by injections of recombinant human TSH, which is performed during the thyroxine treatment (and thus which does not induce any hypothyroidism). Recombinant human TSH (rhtsh) is a drug administered by intramuscular injection over 2 consecutive days, and it has the same activity as physiological TSH. It has been used in several thousands of patients, demonstrating its efficacy and its good tolerance. Thyroglobulin (Tg) is a protein exclusively produced by the thyroid cells. After the destruction of the thyroid gland, its serum level must be undetectable. If serum Tg is detected, some thyroid cells, either normal or neoplastic have to be sought for. Stimulation by rhtsh improves its detection. The becquerel (symbol Bq) is a radioactivity unit. One Bq is defined as one nucleus disintegration per second. Giga Becquerel (GBq) is a multiple of Bq. The correspondence with the old radioactivity unit is the following 1.1 GBq = 30 mci ; 3.7 GBq = 100 mci (millicurie). This study uses a low (1.1 GBq) or a high radioiodine activity (3.7 GBq). 2. What is the methodology? 43

45 This is a comparative study, in which the treatment will be determined by randomization after initial surgery, among the following 4 strategies: o o o o Thyroid hormone withdrawal + low iodine radioactivity (1.1 GBq) Thyroid hormone withdrawal + high radioiodine activity (3.7 GBq) rhtsh + low iodine activity (1.1 GBq) rhtsh + high radioiodine activity (3.7 GBq) The studied parameters are the following : o The efficacy will be assessed at 8 months in terms of thyroid ablation, by a neck ultrasound examination and the serum Tg level at 3 days after the second injection of rhtsh. The recurrence rate will also be evaluated. o The rate of short- and long-term complications, linked to the TSH stimulation method (hypothyroidism symptoms due to withdrawal or side effects induced by rhtsh) or to 131 radioiodine activity (nausea, loss of taste or smell, salivary or lachrymal disorders) will be measured. o The medico-economic evaluation will take into account the patient s quality of life and the cost of each strategy. Quality of life will be assessed by 2 questionnaires. The first one comprises 36 questions (SF36, Short Form 36) and requires 5 to 10 minutes to be completed. The second is the EQ5D scale; it comprises 5 questions and takes less than 5 minutes to be completed. You will be asked to complete them before your treatment and then on 4 occasions during the 3 months following hospitalization. o A complementary document specifying the dates of the questionnaires will be given to you at the beginning of the study. In addition, the calculation of the cost required parameters either available at the hospital (treatment, length of hospitalization) or parameters which depend on you (sick leave, transport). In order to guarantee the collection of these data, it will be necessary to indicate them in the complementary document. The investigator will help you to collect these data. Whatever the treatment allocated, the quality of care and the follow-up of your disease will be the same. 3. What are the predictable risks? 44

46 In case of prolonged thyroid hormone withdrawal, hypothyroidism is observed but its intensity differs among patients. In case of rhtsh injection, no hypothyroidism is expected, but rhtsh may cause asthenia, headache, or nausea during the hours following the administration of the drug; these symptoms occur in less than 10% of patients, are mild and transient. The intramuscular injection may also cause pain at the injection point and, very rarely, complications (hematoma, infection). 4. What will be the duration of your participation? Length of treatment: 8 months Length of follow-up: 10 years 5. What is your treatment and medical follow-up schedule? After initial surgery, one of the following 4 strategies will be allocated by randomization: o o o o Thyroid hormone withdrawal + low iodine radioactivity (1.1 GBq) Thyroid hormone withdrawal + high radioiodine activity (3.7 GBq) rhtsh + low radioiodine activity (1.1 GBq) rhtsh + high radioiodine activity (3.7 GBq) In case of withdrawal, the thyroxine treatment will be discontinued during 1 month, and the TSH level will be measured to control that it is higher than 30µU/mL. In case of rhtsh, the thyroxine treatment will be continued over 1 month, until the serum TSH level decreases to <5µU/mL, otherwise the thyroxine treatment will be continued for 1 or 2 additional weeks. You will be hospitalized for the radioiodine treatment. A clinical and a biological check-up will be performed at 3 months, and then at 8 months (+/- 2 months). This protocol is in agreement with the follow-up recommendations for patients treated by 131 I. 6. What is the impact of treatment on your quality of life? 45

47 We would like to improve our knowledge of the impact of treatment on your daily and professional activities. In order to do so, your doctor (or a nurse) will ask you a series of questions related to your quality of life and your sick leave, if applicable. These questions will be asked twice before your treatment: during this consultation and at admission in the hospital for radioiodine ablation. After leaving the hospital, a notebook comprising quality of life questionnaires will be given to you. We thank you for accepting to complete these questionnaires every 15 days during 6 weeks, (15, 30 and 45 days after leaving the hospital), and to acknowledge your sick leave dates that occurred during this period. Approximately three and eight months after your treatment, you will be asked the same questions again by your doctor or a nurse. 7. What are the other possible treatments? In case you do not accept to participate in the trial, the standard treatment consisting in the administration of an elevated radioiodine activity (3.7 GBq) will be given to you after thyroid hormone withdrawal. 8. What standard of care can be expected once the trial is over? At the 8 month (+-2 month) follow-up check-up (end of the study), the management of your disease will be performed in accordance to the standards of care recommended by guidelines, whatever the treatment: If the check-up is normal, a yearly follow-up will consist on thyroxine treatment, in a clinical examination, and eventually a neck ultrasonography (US) and serum Tg and TSH determinations. A neck US and rhtsh-stimulated Tg determination will be performed 4 years after the first check-up. If the check-up is suspicious: another check-up after rhtsh stimulation will be carried out 6 to 12 months later; if the Tg level or the neck US remains suspicious, another radioiodine treatment 46

48 may be administered. If your participation is interrupted, you will be proposed to continue with the same type of treatment. 9. What are your rights as a patient participating in this trial? You have the right to withdraw from the study at any time and without providing any justification. This will have no consequence on your subsequent treatment and on the quality of the medical care you will receive. Your relationship with your doctor will not be affected and, if you wish, you will be followed up by the same medical team. The sponsor of this trial is the Institut Gustave Roussy (IGR), referred to as IGR in this document and located in 114 rue Edouard Vaillant cedex France, and is responsible for this trial and its operational management. IGR has taken all the measures in accordance with the law for the protection of persons involved in biomedical research (Huriet Law n of De cember 20th, 1988 modified by the Public Health Law n of August 9th, 2004). IGR must guarantee fair compensation for undue injury caused to a person who is willingly undergoing biomedical research. In conformity with the law, IGR has subscribed a biomedical research insurance with the company SHAM France (Lyon). The modalities of this protocol have been submitted for approval to the Competent Authority (Agence Française de Sécurité Sanitaire des Produits de Santé-Afssaps) which has approved this trial and to the Ethics Committee whose mission is to verify the scientific relevance of the trial and the conditions required for the protection of your rights. The Ethics Committee has given a favorable opinion. Your medical file will remain confidential and will be accessed only under the responsibility of the physician in charge of your treatment as well as the health authorities and the persons mandated by the sponsor and bound by professional confidentiality. Your doctor will keep your identity confidential. Your personal medical data will be processed automatically and anonymously in conformity with the law n of August 6th, 2004 relative to the protection of persons and their computerized personal data files and modifying the law n of January 6th, 1978 on informatics and freedom. Furthermore, at your request and according to the law, n of March 4th, 2002 relative to patient rights, the co-investigator physician will inform you of the overall results of the trial. 47

49 10. Who should you contact in case of problems and/or questions? In case of problems, adverse events during the trial or questions, please contact the following persons: Your contact persons during the clinical trial (title, name, first name, address & phone N ) : Details of the physician in charge of the patient

50 Informed Consent Form ESTIMABL research protocol Title of the study: Medico-Economic Comparison of Strategies of Radioiodine Ablation in Thyroid Cancer Patients: the randomized phase III ESTIMABL study I, the undersigned, hereby declare that, Name:... First name :... I have read the information note (pages 1 to 7) on the research protocol mentioned above. I was able to ask all the questions I wished and received appropriate answers. I was given ample time for reflection between the information I received and the time of my decision to participate in this trial. Having considered the information communicated to me : Tick off the appropriate box according to your will (YES/NO) YES NO 1) I freely and willingly accept to participate in the biomedical research study (a)(b) of the ESTIMABL clinical trial (a)(b) 3) I accept that the blood samples taken during the study may be analyzed exclusively for therapeutic or scientific purposes. (c) 4) I give my consent for the future use of the blood samples exclusively for therapeutic or scientific purposes, except if I express my refusal in writing while I am alive. (c) (a) Law n of 12/20/1998, referred to as the Huriet-Sérusclat law, relative to the protection of persons willingly undergoing biomedical research, modified by the Public Health law n of 08/09/2004. (b) Law n of 08/06/2004 relative to the protections of persons with respect to the computerized treatment of personal data and modifying the Informatics and Freedom law n of 01/06/1978 relative to the processing of data files and individual freedom. 49

51 (c) Law n of 08/06/2004 relative to bioethics. I have been informed that the specimen samples taken within the context of this study will be kept and I give my consent for their future use, exclusively for medical or scientific purposes, even after my death. I accept that the medical data recorded during this trial may be collected and computerized in accordance with the law of August 6th, 2004 relative to the protection of persons and the processing of personal data. I am also aware that I have the right to refuse the computerized treatment of my personal data. Moreover, I can exert my right to access and correct these data Dr... To be completed by the patient To be completed by the doctor Name and Surname Name and Surname Signature : Signature : Date : Date : 50

52 Annex 3: Ultrasound Abnormality Criteria Name : First Name : Date of birth : Inclusion Number : Center Number : NECK ULTRASOUND WORKSHEET Ultrasound before radioiodine Dr: Date o Right thyroid bed : empty remnant suspicious for tumor tissue o Left thyroid bed : empty remnant suspicious for tumor tissue o Lymph node right lateral : absence physio suspicious If suspicious : Ratio L/S<2 Microcalcif cystic component o Absence of hilum Hypervascularization o Lymph node left lateral : absence physio suspicious If suspicious : Ratio L/S<2 Microcalcif cystic component o Absence of hilum Hypervascularization o Lymph node central : absence physio suspicious If suspicious : Ratio L/S<2 Microcalcif cystic component o Absence of hilum Hypervascularization Conclusion: Normal US Suspicious appearance (lymph node & /or thyroid bed) Intermediate Ultrasound 8 months after radioiodine Dr: Date o Right thyroid bed : empty remnant suspicious for tumor tissue o Left thyroid bed : empty remnant suspicious for tumor tissue o Lymph node right lateral : absence physio suspicious If suspicious : Ratio L/S<2 Microcalcif cystic component o Absence of hilum Hypervascularization o Lymph node left lateral : absence physio suspicious If suspicious : Ratio L/S***<2 Microcalcif cystic component o Absence of hilum Hypervascularization o Lymph node central : absence physio suspicious If suspicious : Ratio L/S<2 Microcalcif cystic component Absence of hilum Hypervascularization Conclusion: Normal US Suspicious appearance (lymph node & /or compartment) Intermediate 51

53 Annex 4: Billewicz Scale Hypothyroidism symptoms Billewicz Scale Symptom : Diminished sweating Absent Doubtful Present Dry skin Absent Doubtful Present Cold intolerance Absent Doubtful Present Weight increase Absent Doubtful Present Constipation Absent Doubtful Present Hoarseness Absent Doubtful Present Paresthesia Absent Doubtful Present Deafness Absent Doubtful Present Slow movements Absent Doubtful Present Coarse skin Absent Doubtful Present Cold skin Absent Doubtful Present Periorbital puffiness Absent Doubtful Present Slow pulse heart Absent Doubtful Present 52

54 Annex 5 : Lachrymal and salivary side effects 1 During the last 2 weeks, did you have salivary disorders? Yes No (if no question 4) 2 If yes, these disorders were: 1 Mild 2 Moderate 3 Severe 3 During the 2 last weeks, did salivary disorders bother me? None A little A lot Extremely During meals After meals All the time 4 During the last 2 weeks, did you have lachrymal disorders? Yes No 5 If yes, were these disorders: 4 Mild 5 Moderate 6 Severe 53

55 Annex 6: Quality of life questionnaires Health Survey (SF36) Today s Date: This survey asks for your own views concerning your health status. This information will help keeping track on how you feel and how well you are able to do your usual activities. Please answer these questions by check marking your choice. Please select only one choice for each item. 1- In general, would you say your health status is? 1. Excellent 2. Very good 3. Good 4. Fair 5. Poor 2- Compared to ONE YEAR AGO, how would you rate your current health status in general? 1. MUCH BETTER than one year ago. 2. Somewhat BETTER than one year ago. 3. About the SAME as one year ago. 4. Somewhat WORSE than one year ago. 5. MUCH WORSE than one year ago. 54

56 3- The following items are about activities you might do during a typical day. Does your health status now limit your activities? If so, how much? Activities 1. Yes, Limited A Lot 2. Yes, Limited A Little 3. No, Not Limited At All a) Vigorous activities, such as running, lifting heavy objects, participating in strenuous sports? b) Moderate activities, such as moving a table, pushing a vacuum cleaner, bowling, or playing golf? 1. Yes, limited a lot 2. Yes, limited a little 3. No, not limited at all 1. Yes, 2. Yes, 3. No, not limited a lot limited a little limited at all c) Lifting or carrying groceries? 1. Yes, limited a lot d) Climbing several flights of stairs? 1. Yes, limited a lot e) Climbing one flight of stairs? 1. Yes, limited a lot f) Bending, kneeling or stooping? 1. Yes, limited a lot g) Walking more than a mile? 1. Yes, limited a lot h) Walking several blocks? 1. Yes, limited a lot i) Walking one block? 1. Yes, limited a lot j) Bathing or dressing yourself? 1. Yes, limited a lot 2. Yes, limited a little 2. Yes, limited a little 2. Yes, limited a little 2. Yes, limited a little 2. Yes, limited a little 2. Yes, limited a little 2. Yes, limited a little 2. Yes, limited a little 3. No, not limited at all 3. No, not limited at all 3. No, not limited at all 3. No, not limited at all 3. No, not limited at all 3. No, not limited at all 3. No, not limited at all 3. No, not limited at all 4- During the past 4 weeks, have you had any of the following problems with your work or other regular activities as a result of your physical health status? Yes No a) Cut down on the amount of time you spent on work or 1. yes 2. No other activities? b) Accomplished less than you would like? 1. yes 2. No c) Were limited in the kind of work or other activities? 1. yes 2. No 55

57 d) Had difficulty performing the work or other activities (for example it took extra effort)? 1. yes 2. No 5. During the past 4 weeks, have you had any of the following problems with your work or other regular daily activities as a result of any emotional problems (such as feeling depressed or anxious)? Yes No a) Cut down on the amount of time you spent on work or 1. yes 2. No other activities? b) Accomplished less than you would like? 1. yes 2. No c) Didn t do work or other activities as carefully as usual? 1. yes 2. No 6. During the past 4 weeks, to what extent has your physical health status or emotional problems interfered with your normal social activities with family, friends, neighbors, or groups? 1. Not at all 2. Slightly 3. Moderately 4. Quite a bit 5. Extremely 7. How much bodily pain have you had during the past 4 weeks? 1. None 2. Very mild 3. Mild 4. Moderate 5. Severe 6. Very severe 8. During the past 4 weeks, how much did pain interfere with your normal work (including both work outside the home and housework)? 1. Not at all 2. A little bit 3. Moderately 4. Quite a bit 5. Extremely 56

58 9. These questions are about how you feel and how things have been with you during the past 4 weeks. For each question, please give the one answer that comes closest to the way you have been feeling. How much of the time during the past 4 weeks 1. All of 2. Most 3. A good 4. Some 5. A little 6. None of the time of the bit of the of the of the time the time time time time a) Did you feel full of pep? 1. All 2. Most 3. A good 4. Some 5. A little 6. None of the time of the time bit of the time of the time of the time the time b) Have you been very 1. All 2. Most 3. A good 4. Some 5. A little 6. None of nervous? the time of the time bit of the time of the time of the time the time c) Have you felt so down in 1. All 2. Most 3. A good 4. Some 5. A little 6. None of the dumps that nothing could the time of the time bit of the time of the time of the time the time cheer you up? d) Have you felt calm and 1. All 2. Most 3. A good 4. Some 5. A little 6. None of peaceful? the time of the time bit of the time of the time of the time the time e) Did you have a lot of 1. All 2. Most 3. A good 4. Some 5. A little 6. None of energy? the time of the time bit of the time of the time of the time the time f) Have you felt downhearted 1. All 2. Most 3. A good 4. Some 5. A little 6. None of and blue? the time of the time bit of the time of the time of the time the time g) Do you feel worn out? 1. All 2. Most 3. A good 4. Some 5. A little 6. None of the time of the time bit of the time of the time of the time the time h) Have you been happy? 1. All 2. Most 3. A good 4. Some 5. A little 6. None of the time of the time bit of the time of the time of the time the time i) Did you feel tired? 1. All 2. Most 3. A good 4. Some 5. A little 6. None of the time of the time bit of the time of the time of the time the time 10. During the past 4 weeks, how much of the time has your physical health or emotional problems interfered with your social activities (like visiting with friends, relatives, etc.)? 57

59 1. All the time 2. Most of the time. 3. Some of the time 4. A little of the time. 5. None of the time. 11. How TRUE or FALSE is each of the following statements for you? Definitely true Mostly true Don t know Mostly false Definitely false a) I seem to get sick a little easier than other people Definitely true Mostly true Don t know Mostly false Definitely false b) I am as healthy as anybody I know Definitely true Mostly true Don t know Mostly false Definitely false c) I expect my health to get worse Definitely true Mostly true Don t know Mostly false Definitely false d) My health is excellent Definitely true Mostly true Don t know Mostly false Definitely false 58

60 EUROQOL EQ-5D By placing a tick in one box in each group below, please indicate which statements best describe your own health status today. Mobility I have no problems in walking around I have some problems in walking around I am confined to bed Self-Care I have no problems with self-care I have some problems washing or dressing myself I am unable to wash or dress myself Usual Activities (e.g. work, study, housework, family or leisure activities) I have no problems with performing my usual activities I have some problems with performing my usual activities I am unable to perform my usual activities Pain/Discomfort I have no pain or discomfort I have moderate pain or discomfort I have extreme pain or discomfort Anxiety/Depression I am not anxious or depressed I am moderately anxious or depressed I am extremely anxious or depressed 59

61 Best Imaginable health status 60

62 To help people say how good or bad a health status is, we have drawn a scale (rather like a thermometer) on which the best status you can imagine is marked 100 and the worst status you can imagine is marked 0. We would like you to indicate on this scale how good or bad your own health status is today, in your opinion. Please do this by drawing a line from the box below to whichever point on the scale that indicates how good or bad your health status is today. 61