Conditions: Liver Cancer
Keywords: adult primary hepatocellular carcinoma localized unresectable adult primary liver cancer advanced adult primary liver cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 78
Healthy volunteers: no

Brief summary:
RATIONALE: Chemoembolization kills tumor cells by blocking the blood flow to the tumor and keeping anticancer drugs near the tumor. Sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. It is not yet known whether chemoembolization is more effective with or without sunitinib malate in treating patients with liver cancer.

PURPOSE: This randomized phase II/III trial is studying the side effects of chemoembolization of the liver and to see how well in works when given together with or without sunitinib malate in treating patients with liver cancer.

Detailed description:
OBJECTIVES:

Primary

* To evaluate unacceptable bleeding or hepatic failure at 10 weeks post-treatment in patients with unresectable hepatocellular carcinoma treated with transarterial chemoembolization in combination with sunitinib malate versus transarterial chemoembolization alone.
* To evaluate the overall survival of these patients.

Secondary

* To evaluate the tumor stabilization rate in these patients.
* To evaluate the safety of this regimen in these patients.
* To evaluate the disease-free survival of these patients.
* To evaluate the relapse-free survival of these patients.
* To evaluate the quality of life of these patients.
* To evaluate the overall survival rate at 2 years of these patients.

OUTLINE: This is a multicenter study.

Pilot: Patients receive oral sunitinib malate once daily on days 1-28. Beginning 7-10 days later, patients undergo 1-3 courses of transarterial chemoembolization (TACE). Treatment repeats every 6 weeks for 1 year.

Randomization: Patients are stratified according to main tumor diameter (\< 5 cm vs ≥ 5 cm), nodular involvement (uninodular vs multinodular), and center. Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive sunitinib malate and TACE as in the pilot phase.
* Arm II: Patients receive oral placebo once daily on days 1-28 and TACE as in the pilot phase.

Quality of life is assessed periodically.

Arms:
arm 1: placebo 3cps/days 4 weeks over 6 during 1 year arm 2: sunitinib (SUTENT®) 37,5 mg/d (3 cps of 12,5 mg) orally 4 weeks over 6 (4 weeks of treatment followed by 2 weeks without treatment) during 1 year

Interventions: intervention 1: sunitinib malate intervention 2: Placebo intervention 3: transarterial chemoembolization
Intervention descriptions: intervention 1: placebo 3cps/days 4 weeks over 6 during 1 year intervention 2: placebo 3cps/days 4 weeks over 6 during 1 year intervention 3: Chimioembolisation

Protocol document:
Prot_000.pdf: 
 
 
 
 
Version 1.0  
 
1
 
 
 
 
 PRODIGE 16 (FFCD 0905) 
 
Randomized phase II/III trial of Transcatheter Arterial 
Chemoembolization plus Sunitinib or placebo in patients with 
hepatocellular carcinoma 
(SATURNE study) 
 
 
A study of the PRODIGE-AFEF Group (FFCD-FNCLCC-AFEF) 
 
 
 
 EudraCT n° :2009-017064-16 
NCT number : NCT01164202 
 
 
REDACTION COMMITTEE: V BOIGE, JC BARBARE, S CATTAN, F BONNETAIN,  
T DE BAERE, M DUCREUX, R GEROLAMI, JD GRANGE, M HEBBAR,  
O ROSMORDUC, JF SEITZ 
 
 
 
Version 1.0 dated 23 January 2012 
 
 
 
 
PROMOTION AND RANDOMISATION 
 
Fédération Francophone de Cancérologie 
 
Digestive (FFCD) 
 
Faculté de Médecine 
 
7, Boulevard Jeanne d’Arc, BP 87900 
 
F-21079 Dijon Cédex, France  
 
Tel: + 33 (0)3 80 66 80 13  
 
Fax: + 33 (0)3 80 38 18 41 
 


 
 
 
 
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TABLE OF CONTENTS 
I. 
RATIONALE .................................................................................................. 8 
II. 
STUDY DESIGN .......................................................................................... 10 
III. 
PROMOTION ............................................................................................... 10 
IV. 
END-POINTS ............................................................................................... 10 
PILOT PHASE STUDY............................................................................................. 10 
INITIAL PHASE II STUDY ........................................................................................ 10 
PHASE III STUDY .................................................................................................... 10 
V. 
INCLUSION CRITERIA ............................................................................... 11 
VI. 
NON-INCLUSION CRITERIA ...................................................................... 11 
VII. 
RANDOMIZATION ...................................................................................... 12 
VIII. 
STRATIFICATIONS ..................................................................................... 12 
IX. 
STUDY TREATMENTS ............................................................................... 12 
X. 
DOSES ADJUSTMENTS ............................................................................ 15 
XI. 
FOLLOW-UP ............................................................................................... 16 
XII. 
RANDOMIZED PILOT AND PHASE II STEP .............................................. 17 
XIV. 
TRANSLATIONAL STUDY ......................................................................... 18 
XV. 
DISCONTINUATION CRITERIA .................................................................. 18 
XVI. 
STATISTICAL METHOD ............................................................................. 19 


 
 
 
 
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DURING THIS 
STAGE, 
PATIENTS WILL NOT BE RANDOMIZED AND WILL ALL RECEIVE SUNITINIB. 
AFTER A TOTAL OF 10 CHEMOEMBOLIZATION SESSIONS, INCLUSIONS WILL 
BE DISCONTINUED AND TOLERANCE RESULTS WILL BE REVIEWED BY A 
COMMITTEE OF INDEPENDENT EXPERTS. ......................................................... 19 
PATIENTS INCLUDED IN THIS PILOT PHASE WILL BE PARTICULARLY 
MONITORED FOR THE PURPOSE OF DETECTING TWO POTENTIAL 
COMPLICATIONS ASSOCIATED WITH THE COMBINATION OF SUNITINIB-
CHEMOEMBOLIZATION: SEVERE BLEEDING AND LIVER FAILURE. THE 
OBSERVED RATE OF BLEEDING OR LIVER FAILURE AFTER 
CHEMOEMBOLIZATION IS IN THE ORDER OF 10 TO 15% IN RECENT STUDIES 
. ONE OR TWO TOXICITIES ARE EXPECTED AMONG THE 10 
CHEMOEMBOLIZATION SESSIONS. IF 4 OR MORE TOXICITIES OCCUR, THEN 
THE TOXICITY OF THE SUNITINIB-CHEMOEMBOLIZATION COMBINATION IS 
CONSIDERED UNACCEPTABLE AND THE TRIAL IS DISCONTINUED. IF 3 OR 
FEWER TOXICITIES OCCUR, THE TOXICITY IS CONSIDERED ACCEPTABLE 
AND THE TRIAL IS CONTINUED IN PHASE II WITH RANDOMIZATION. 
PATIENTS INCLUDED IN THE PILOT PHASE WILL NOT BE INCLUDED IN THE 
FINAL ANALYSIS OF THE SATURN TRIAL. ......................................................... 19 
THE RESULTS OF THE PILOT PHASE WILL BE SENT TO AFFSAPS FOR 
INFORMATION. ....................................................................................................... 19 
USING FLEMING ONE STEP DESIGN WITH THE FOLLOWING HYPOTHESES: 19 
H0: AN OCCURRENCE RATE OF BLEEDING OR LIVER FAILURE 1 WEEK 
AFTER LAST ADMINISTRATION OF THE TACE-SUNITINIB COMBINATION OF 
30 % IS UNACCEPTABLE ...................................................................................... 20 
H1: AN OCCURRENCE RATE OF BLEEDING OR LIVER FAILURE 1 WEEK 
AFTER LAST ADMINISTRATION OF THE TACE-SUNITINIB COMBINATION OF 
15% IS EXPECTED .................................................................................................. 20 
IT WOULD BE REQUIRED TO INCLUDE 35 PATIENTS IN EACH ARM. .............. 20 
AMONG THE 35 PATIENTS IN THE SUNITINIB ARM: .......................................... 20 
IF WE OBSERVED 8 OR MORE THAN 8 PATIENTS (22.9 %) WITH SEVERE 
BLEEDING OR LIVER FAILURE 1 WEEK AFTER LAST ADMINISTRATION OF 
THE TACE-SUNITINIB, THE TOXICITY RATE IS NOT STATISTICALLY 
DIFFERENT FROM 30%. THIS TREATMENT WOULD BE DECLARED 
UNACCEPTABLE AND INCLUSIONS WILL NOT BE PURSUED FOR PHASE III 
TRIAL. 20 


 
 
 
 
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IF WE 
OBSERVED 
7 OR LESS THAN 7 PATIENTS (20 %) WITH SEVERE BLEEDING OR LIVER 
FAILURE 1 WEEK AFTER LAST ADMINISTRATION OF THE TACE-SUNITINIB, 
THE TOXICITY RATE IS STATISTICALLY DIFFERENT FROM 30 %. THIS 
TREATMENT WOULD BE DECLARED PROMISING AND INCLUSION WILL BE 
PURSUED FOR PHASE III, ..................................................................................... 20 
CALCULATED POWER IS 85.6% AND ALPHA TYPE ONE ERROR IS 13.3 % .... 20 
DECISION RULES FOR PHASE III TRIAL CONTINUATION: ................................ 20 
DESPITE RANDOMIZATION AND INCLUSION OF 35 PATIENT IN THE TACE 
ALONE ARM WE WILL NOT USE FLEMING DECISION RULES FOR TACE 
ALONE ARM TO PURSUE RANDOMIZATION SINCE THIS IS THE STANDARD 
ARM IN THE PHASE III TRIAL. ............................................................................... 20 
1. 
WE OBSERVED 7 OR LESS THAN 7 PATIENTS (20%) WITH SEVERE 
BLEEDING OR LIVER FAILURE 1 WEEK AFTER LAST ADMINISTRATION OF 
THE TACE-SUNITINIB ............................................................................................. 20 
WE WILL PURSUE RANDOMIZATION WHATEVER OCCURRENCE OF THESE 
TOXICITIES IN THE TACE ALONE ARM SINCE THIS IS THE STANDARD ARM IN 
THE PHASE III TRIAL.............................................................................................. 20 
2. 
WE OBSERVE 8 OR MORE THAN 8 PATIENTS (22.9 %) WITH SEVERE 
BLEEDING OR LIVER FAILURE 1 WEEK AFTER LAST ADMINISTRATION OF 
THE TACE-SUNITINIB. ............................................................................................ 20 
WE WILL CHECK AMONGST THE 35 PATIENTS RECEIVING TACE ALONE: ... 20 
- IF WE OBSERVED ALSO 8 OR MORE THAN 8 PATIENTS (22.9 %) WITH 
SEVERE BLEEDING OR LIVER FAILURE 1 WEEK AFTER LAST 
ADMINISTRATION OF THE TACE ALONE. THEN WE WILL ASK AN 
INDEPENDENT DATA MONITORING COMMITTEE (IDMC) ABOUT THE 
OPPORTUNITY TO PURSUE RANDOMIZATION FOR PHASE III TRIALS SINCE 
THESE RESULTS COULD REFLECT THE “NOISE” OF TACE TOXICITIES 
ALONE. .................................................................................................................... 20 
- IF WE OBSERVED ALSO 7 OR LESS THAN 7 PATIENTS (20%) WITH SEVERE 
BLEEDING OR LIVER FAILURE 1 WEEK AFTER LAST ADMINISTRATION OF 
THE TACE ALONE. THEN WE WILL ASK AN INDEPENDENT DATA 
MONITORING COMMITTEE (IDMC) ABOUT THE OPPORTUNITY TO STOP 
RANDOMIZATION FOR PHASE III TRIALS. .......................................................... 21 
THESE 70 PATIENTS WILL BE THEORETICALLY RECRUITED IN 9 MONTHS 
(7.5 PTS/ MONTH) AND AT LEAST 1 WEEK FOLLOW-UP AFTER LAST 


 
 
 
 
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ADMINISTRATION OF THE TACE-SUNITINIB COMBINATION IS REQUIRED 
THEN PHASE II STEP WILL BE ANALYSES ABOUT 9 MONTHS AND 1 WEEK 
AFTER THE INCLUSION OF THE FIRST PATIENT. .............................................. 21 
PHASE III STEP ....................................................................................................... 21 
XVII. 
POPULATIONS FOR ANALYSIS ............................................................... 23 
XVIII. 
ADVERSE EVENT REPORTING ................................................................ 24 
XIX. 
QUALITY OF LIFE ...................................................................................... 28 
XX. 
REFERENCES ............................................................................................ 29 
XXI. 
APPENDICES .............................................................................................. 34 


 
 
 
 
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STUDY 
SUMMARY 
Rational 
1. Transcatheter arterial chemoembolization (TACE) is widely used for selected patients 
with isolated hepatocellular carcinoma (HCC) 
2. Most of the patients undergoing TACE will relapse within two years 
3. HCC is one of the most vascularized tumors, with a crucial role for Vascular Endothelial 
Growth factor (VEGF) 
4. Angiogenesis inhibition is theoretically a logical approach to limit the risk of tumor 
relapse after TACE. 
5. Sunitinib malate is a novel angiogenesis inhibitor directed against VEGF receptors, with 
additional direct anti-tumor effect (by inhibiting PDGFR) 
6. Addition of sunitinib malate to TACE could reduce the risk of relapse  
Objectives (Pilot 
phase ) 
Inacceptable bleeding or hepatic failure 10 weeks after last administration of the TACE-sunitinib 
combination   
 
Objectives (phase II) 
Phase II :  
Primary endpoint :  
Inacceptable bleeding or hepatic failure 10 weeks after last administration of the TACE-sunitinib 
combination   
Secondary end-points 
Tumor stabilisation rate 
Relapse-free survival  
Overall survival  
Safety 
Quality of life 
Objectives (phase III) Primary end-point 
Overall survival  
Secondary end-points 
Overall survival rate at 2 years         Relapse-free survival 
Disease-free survival                        Tumor stabilisation rate 
Safety                                                Quality of life 
Design 
Multicentre, prospective randomized, double-blind, placebo-controlled, phase II- III study 
Treatments 
Arm A 
Sunitinib 37.5 mg/day (3 tablets of 12.5 mg) orally on the 4/2 schedule (4 weeks on 
treatment followed by 2 weeks off treatment) during one year 
Arm B  
Placebo 3 tablets/day for 4 weeks over 6 weeks during one year 
 
Treatment started 7 to 10 day before each TACE course for a total of 28 days per cycle, with 
a 3 days interruption (day preceding to day following TACE) 
Patients’ nb 
Non-randomized pilot phase: 10 chemoembolization sessions, regardless of the number of patients 
Phase II step: 70 patients (35 in each arm),  
Phase III step: 190 (95 in each arm), including the patients of the phase II step 
Inclusion criteria 
• 
Histologically proven HCC or liver tumor responding to the Barcelona criteria (18) 
• 
Child-Pugh score 5-6 (class A) 
• 
No portal vein thrombosis 
• 
Tumor suitable for TACE (one or more than one planned TACE courses allowed) 
• 
A prior radiofrequency ablation is allowed if the interval between radiofrequency and 
planned TACE is > 3 months 
• 
Tumor not suitable for surgical resection  
• 
ECOG performance status < 2  
• 
Age > 18  years 
• 
Adequate hematologic, renal and hepatic functions (neutrophil count > 1.5 109/L, 
platelet count > 70 x 109/L, haemoglobin level > 10 g/dL, prothrombin activity > 50 
%, creatinine < 120 mol/L, normal bilirubin level (< 15 mg/L), alanine and aspartate 
transaminases (ALT and AST) < 4 times the upper limit of normal (ULN), alkaline 
phosphatases < 5 times the ULN, fibrinogen level > 1.5 g/L)  
• 
Ability for patient to comply with scheduled follow-up and management of toxicity 
• 
Written informed consent 


 
 
 
 
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Non inclusion criteria 
• 
History of chemoembolization 
• 
Portal thrombosis 
• 
Extrahepatic metastases including brain metastases 
• 
Concomitant participation of the patient in another clinical trial 
• 
Uncontrolled hypertension or requiring at least 2 classes of antihypertensive agents 
• 
Concomitant illness or uncontrolled severe clinical situation 
• 
Patient treated with a CYP3A4 inhibitor within 7 days prior to treatment 
• 
Patient treated with a CYP3A4 potentiator within 12 days 
• 
Patient requiring long-term anticoagulant therapy 
• 
Patient with a contraindication to vascular exclusion procedures 
• 
Pregnancy or breastfeeding 
• 
Lack of effective contraception (for men or women of childbearing age) 
• 
Pretreatment with sunitinib, sorafenib or any other angiogenesis inhibitor 
• 
History of other cancers excluding cancers known to have been cured for more than 5 
years (in this case, histological evidence for HCC is required), or basocellular skin 
tumors or cervical cancer in situ treated adequately and with curative intent 
• 
Patient who for psychological, social, family or geographic reasons could not be 
followed regularly 
• 
Patient with a contraindication to vascular occlusion procedures 
Stratifications 
• 
Main tumour diameter < vs. > 5 cm 
• 
Uninodular vs. multinodular 
• 
Centre 
Duration  
Accrual duration : 24 months ; overall study duration : 60 months 


 
 
 
 
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I. 
RATIONALE 
 
 
Transcatheter arterial chemoembolization (TACE) is widely used for selected patients 
with isolated or limited hepatocellular carcinoma (HCC) not suitable for surgical resection. 
Recent randomized trials have demonstrated a survival benefit for patients treated with 
TACE, by comparison to symptomatic treatment (1-4). TACE is justified by the fact that 
HCC is one of the most vascularized tumors. Advances in the understanding of the 
mechanisms underlying HCC development confirm that angiogenesis plays a key role. After 
TACE, most of the patients will relapse within two years, and this relapse is associated with a 
tumor re-vascularisation. Especially, Vascular Endothelial Growth Factor (VEGF) has 
emerged as a prominent factor (5). In patients undergoing TACE, high pre-treatment serum 
VEGF concentrations are associated with a shorter survival (6, 7). Moreover, VEGF 
concentrations rise after TACE, probably as a consequence of tumor ischemia, and reach a 
peak after 1 day (8). In a murine model, VEGF has been demonstrated to play a crucial role in 
establishment of collateral circulation and reconstruction of blood supply of residual cancer 
tissue after TACE (9). In human, increase of VEGF levels during the month following TACE 
was associated with a higher risk of metastatic relapse (10). Altogether, these data suggest 
that neoadjuvant plus adjuvant therapy by angiogenesis inhibitors could represent a logical 
way to reduce the risk of relapse after TACE. 
 
Sunitinib malate (SUTENT) is a novel oral multitargeted receptor tyrosine kinase 
inhibitor that has shown antiangiogenic and antitumor activities. Antiangiogenic properties of 
sunitinib are based on its action on VEGFR-1, VEGFR-2 and VEGFR-3 (11). Additionally, 
sunitinib inhibits PDGFR, which is also involved in HCC growth (11-12). 
 
Based on these properties, we postulate that sunitinib might yield clinical benefit when 
administered before and after TACE in patients with HCC. Sunitinib might interfere with 
tumor re-vascularisation as well as tumor growth, and reduce the risk of relapse. Additionally, 
a recent experimental study performed on a glioma model, showed that sunitinib, by 
improving tumoral hemodynamics and blood flow, increases the delivery of doxorubicin to 
tumors (13). 
 
Some angiogenesis inhibitors are associated with a significant risk of bleeding, and 
this may raise concern regarding their use in patients with HCC developed on cirrhosis, since 
cirrhosis is frequently complicated by portal hypertension (14). In a retrospective study was 
assessed the risk of complications in 66 patients receiving sunitinib (n=21) or imatinib (n=45) 


 
 
 
 
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9
 
for 
Gastrointestinal Stromal Tumors, and who underwent a surgical debulking (15). Sunitinib was 
stopped a median of 5 days prior to surgery (range 0-26). Only 2 patients experienced 
postoperative bleeding requiring reoperation, but it was not mentioned if these patients were 
receiving sunitinib or imatinib. In patients with advanced HCC and cirrhosis, phase II studies 
have demonstrated a good tolerability of bevacizumab, an anti-VEGF monoclonal antibody 
(16, 17). This was confirmed by another phase II study assessing the combination 
gemcitabine-oxaliplatin-bevacizumab (18). In a pilot study performed in patients undergoing 
TACE, adjuvant treatment with bevacizumab was well tolerated and seemed to increase the 
disease control duration (19). More recently, were reported the results of two phase II studies 
assessing safety and efficacy of sunitinib in patients with advanced HCC. In the study by 
Faivre et al, sunitinib was administered at a dose of 50 mg/day for 4 weeks every 6 weeks in 
37 patients with advanced HCC with Child-Pugh A or B cirrhosis (20). Patients received a 
median of two cycles. According to the RECIST criteria, only one objective response was 
observed, but interestingly, a decrease of tumor density was observed in 68% of the patients. 
Moreover, tumor activity, as assessed by volumetric measurement of decrease in tumor 
enhancement percent, showed minor (< 50%) and major (> 50%) post-treatment tumor 
necrosis in 25 % and 46 % of the patients, respectively. Grade 3–4 toxicities included 
thrombocytopenia (43 %), neutropenia (24 %), central nervous system symptoms (24 %), 
asthenia (22 %) and haemorrhage (14 %). A dose reduction was required in 27 % of the 
patients. This safety profile suggested that patients should be better selected and sunitinib 
dose revised. In the study by Zhu et al, 26 patients with advanced HCC and < 3 Carcinoma of 
the Liver Italian Program (CLIP) score received sunitinib at a lower dose (37.5 mg/day for 4 
weeks every 6 weeks) (21). Only one objective response has been observed but the median 
progression-free and overall survivals were 4.1 and 11.6 months, respectively. Moreover, the 
mean tumor permeability, assessed by dynamic contrast-enhanced magnetic resonance 
imaging, decreased from a mean average of 38 %. The treatment was generally well tolerated. 
Grade 3/4 toxicities included neutropenia (12 %), lymphopenia (15 %), SGOT/SGPT (23/12 
%), fatigue (8 %), rash (8 %), and thrombocytopenia (12 %). 
 
Since TACE is restricted to patients without portal vein thrombosis, and without 
severe cirrhosis, sunitinib therapy should be even safer. Peri-TACE setting could so represent 
one of the most appropriate situations to assess efficacy and safety of sunitinib in patients 
with HCC. We have chosen to use sunitinib at a dose of 37.5 mg/day for 4 weeks every 6 


 
 
 
 
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10
 
weeks. Treatment 
will be started 
7 to 10 days before the first TACE course, for a total duration of one year. 
II. 
STUDY DESIGN 
 
• Prospective, multicentre, randomized, double-blind, placebo-controlled, parallel-
group, phase II-phase III clinical trial 
• Accrual period : 24 months 
• Study duration : 48 months 
 
III. 
PROMOTION 
 
The study will be run in the PRODIGE-AFEF cooperative group and sponsored by the 
‘‘Fédération Francophone de Cancérologie Digestive’’ (FFCD).  
 
 
IV. 
END-POINTS  
 
PILOT PHASE STUDY 
• End-point : Inacceptable bleeding or hepatic failure 10 weeks after last administration 
of the TACE-sunitinib combination   
 
 
 
INITIAL PHASE II STUDY 
• Primary end-point:  
 
 
Inacceptable bleeding or liver failure 10 weeks after last administration of the 
 
 
TACE-sunitinib combination   
• Secondary end-points:  
 
 
Tumor stabilisation rate 
Relapse-free survival  
Overall survival  
Safety 
Quality of life 
 
 
PHASE III STUDY 
• Primary end-point:  
Overall survival  
• Secondary end-points:  
 
 
Overall survival rate at 2 years 


 
 
 
 
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11
 
 
 
Relapse-free survival 
 
 
Disease-free survival 
 
 
Tumor stabilisation rate (stable size of the lipiodol deposition zones by two 
 
 
consecutive CT scans or prolonged normalisation of serum Alpha-Foetoprotein 
 
 
(AFP) 
 
 
Safety 
 
 
Quality of life 
 
V. 
INCLUSION CRITERIA 
 
• 
Age 18 to 75 years  
• 
ECOG performance status < 2  
• 
Histologically proven HCC or liver tumor responding to the Barcelona criteria (22) 
• 
Child-Pugh score 5-6 (class A) 
• 
No portal vein thrombosis 
• 
Tumor not suitable for surgical resection  
• 
Tumor suitable for TACE (one to three courses allowed)  
• 
A prior radiofrequency ablation is allowed if the interval between radiofrequency 
and planned TACE is > 3 months 
• 
Adequate haematological, renal and hepatic functions (neutrophil count > 1.5 
109/L, platelet count > 100 x 109/L, haemoglobin level > 10 g/dL, prothrombin 
activity > 50 %, creatinine < 120 mol/L, normal bilirubin level (< 12 mg/L), 
alanine and aspartate transaminases (ALT and AST) < 3.5 times the upper limit of 
normal (ULN), alkaline phosphatases < 4 times the ULN, fibrinogen level > 1.5 
g/L)  
• 
Ability for patient to comply with scheduled follow-up and management of 
toxicity 
• 
Written informed consent 
 
VI. 
NON-INCLUSION CRITERIA 
• History of chemoembolization 
• Portal thrombosis 


 
 
 
 
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12
 
• Extrahepatic metastases including brain metastases 
• Concomitant participation of the patient in another clinical trial 
• Uncontrolled hypertension or requiring at least 2 classes of antihypertensive agents 
• Concomitant illness or uncontrolled severe clinical situation 
• Patient treated with a CYP3A4 inhibitor within 7 days prior to treatment 
• Patient treated with a CYP3A4 potentiator within 12 days 
• Patient requiring long-term anticoagulant therapy 
• Patient with a contraindication to vascular exclusion procedures 
• Pregnancy or breastfeeding 
• Lack of effective contraception (for men or women of childbearing age) 
• Pretreatment with sunitinib, sorafenib or any other angiogenesis inhibitor 
• History of other cancers excluding cancers known to have been cured for more 
than 5 years (in this case, histological evidence for HCC is required), or 
basocellular skin tumors or cervical cancer in situ treated adequately and with 
curative intent 
• Patient who for psychological, social, family or geographic reasons could not be 
followed regularly 
• Patient with a contraindication to vascular occlusion procedures 
 
VII. 
RANDOMIZATION 
 
 
After checking the eligibility criteria, randomisation will be performed at the 
Fédération Francophone de Cancérologie Digestive (FFCD) data centre in Dijon. A 
minimization technique will be used. 
 
VIII. STRATIFICATIONS 
 
• Main tumour diameter < vs. > 5 cm 
• Uninodular vs. multinodular 
• Centre 
 
IX. 
STUDY TREATMENTS 


 
 
 
 
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• Treatment arm : Chemoembolization (1 to 3 sessions) + sunitinib (SUTENT®) 
37.5 mg / day (3 cps 12.5 mg) orally 4 weeks out of 6 (4 weeks of treatment then 
2 weeks of rest) during 1 year 
 
• Control arm : Chemoembolization (1 to 3 sessions) + placebo 3cps / d4 weeks 
out of 6 for 1 year 
 
Treatment will be started 7 to 10 days before each TACE course for a total of 28 days per 
cycle with a three days interruption: from the day preceding to the day following each TACE. 
Total treatment duration will be one year (8 cycles). Treatment will be discontinuated in case 
of documented tumor relapse or progression. 
Study drugs will be given in the morning with water and without regard to meals beginning. 
 
 
TACE modalities 
The use of Doxorubicin Coated Beads (DC Beads) has been retained on the basis of the 
PRECISION V study. This randomised study compared conventional TACE with doxorubicin 
to TACE with DC Beads (23). Although the overall tumor response rate achieved by DC 
Beads was not significant superior (p = 0.11), it was significantly higher in some subgroups of 
patients (especially ECOG 1 patients and patients with bilobar disease). Additionally, the use 
of DC Beads appeared safer, especially with significantly reduced liver toxicity (3 vs. 9 %). 
Finally, a theoretical advantage for using DC Beads is that this method is standardized and 
more reproducible than conventional TACE. 
The investigators must perform pre-treatment angiography to confirm the vascular anatomy 
and exclude significant arteriovenous shunting and are encouraged to identify and protect the 
cystic artery and gastric arteries. 
TACE in HCC using DC beads should respect the following guidelines: 1 vial 300-500 
micron followed by 1 vial 500-700 micron with a target dose of 150mg doxorubicin. 
 
Beads are mixed with non-ionic contrast media or saline at a ratio of one to 5 to ensure 
smooth delivery through the catheter. The beads should be delivered slowly, approximately 
1mL per minute, to minimise reflux and clogging within the catheter. A microcatheter is 


 
 
 
 
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recommended to 
obtain 
as 
superselective position as possible, namely in case of patients with finite number of tumors. 
 
Patients with finite number of tumors should be treated in order to deliver the full dose of 
doxorubicin to the target lesion if single, or to divide the dose between them, if several. 
Treatment must be repeated with the same schedule at least twice. The use of a microcatheter 
to obtain selective catheterization of the feeding artery(ies) is recommended. No additional 
embolization is recommended after the use of DC beads in order to leave the artery patent for 
a second course. 
 
Patients with diffuse bilobar disease must be treated for each lobe in separate treatments. In 
such setting, a catheter is placed in one lobar hepatic artery and the full dose of treatment is 
injected. Second course will target the other lobe. Embolization to nearly complete stasis in 
the 2nd to 3rd order branches must be obtained with additional embolic material if needed. 
 
The embolization technique should always include adequate pain management as well as 
prophylactic antibiotics and steroids at the physician’s discretion. 
 
Repetition of TACE courses Three courses are scheduled 6 to 8 weeks apart when patient is 
enrolled in the study. 
The choice of performing imaging between the two initial treatments is left on investigator 
preference  
Additional treatment after the two initial ones will be done according to tumor response and 
treatment schedule provide in the study. No further treatment is recommended if complete 
response according to EASL criteria is obtained or if a tumor progression exists on tumors 
already targeted with TACE.  
 
 


 
 
 
 
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X. 
DOSES ADJUSTMENTS 
 
The main expected toxicities are: 
- 
Fatigue 
- 
Diarrhoea 
- 
Anorexia 
- 
Vomiting 
- 
Hand-foot syndrome 
- 
Skin rash 
- 
Mucosal inflammation 
- 
Hypertension 
- 
Neutropenia 
- 
Thrombopenia 
- 
Anaemia 
- 
Hypothyroidism 
- 
 
In case of any toxicity, the following guidelines will be used 
 
Toxicity grade 
(NCI-CTC) 
Week 
CT-scan or MRI 
Sunitinib or placebo 
TACE 
1 
0 
4 
6 
10 
12 
16 
18 
22 
26 
7-10 days 
18-21 days 
28 days 


 
 
 
 
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1 
no dose modification 
2 
discontinuation of treatment for 1 week 
 
 
- recovery : no dose modification 
 
 
- non-recovery, 1 additional week rest 
 
 
 
- recovery : 2 tablets per day (25 mg) 
 
 
 
- non-recovery : withdraw of study 
3 
discontinuation of treatment for 1 week 
 
- recovery : 2 tablets per day (25 mg) 
 
 
 
- non-recovery : withdraw of study 
4 
withdraw of study 
 
In case of lymphopenia (of any grade), treatment can be continuated without dose 
modification. 
Particular case of sunitinib-induced hypothyroidism: results from the largest clinical series 
indicate that 53% to 85% of patients treated with sunitinib develop thyroid test abnormalities, 
and that 30% will develop clinical manifestations of thyroid dysfunction (24). In other hand, 
this hypothyroidism seems to be associated with a higher efficacy of sunitinib, relationship 
observed in patients treated for a renal cancer. In this trial, it is recommended to test TSH at 
baseline, at day 1 (+/- 7) of cycles 2, 3, 4, 6, 8, and 3 months after sunitinib or placebo 
retrieval: 
- 
if TSH > ULN but  < 10 mIU/L: replacement hormone therapy only in case 
of symptoms of hypothyroidism 
- 
TSH > 10 mIU/L: hormone replacement therapy aiming at normalization of 
THS 
In case of biological or clinical hypothyroidism, the patient must be addressed to an 
endocrinologist. 
 
XI. 
FOLLOW-UP 
 
• AFP concentration measurement before entry, every month until one month after the 
last TACE course, every 3 months for 2 years and every 6 months thereafter. TSH 
measurement at baseline, and every 3 months subsequently. Plasma samples will be 
simultaneously collected and stored for measurement of circulating soluble angiogenic 
factors. 


 
 
 
 
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• Liver CT-
scan 
and/or MRI before entry, one month after each TACE course, every 3 months for 2 
years and every 6 months thereafter, until tumor progression. All CT-scan and MRI 
will be reviewed by an external independent radiologist panel. 
• Additionally, a clinical examination, measurement of haematological, renal and 
hepatic parameters will be performed before initiation of each sunitinib or placebo 
course (every 6 weeks for one year), then every 3 month the second year and every 6 
months thereafter. 
• Haematological, renal and hepatic parameters will be also measured at each 
TACE course: d-1 or d0, d1, d2, d3. 
 
XII. 
RANDOMIZED PILOT AND PHASE II STEP 
 
 
The aim of this initial study is specially to assess safety of the combination TACE-
sunitinib. Independently of the respective common side effects of TACE and sunitinib, the 
phase II study will focus on the acute (1 week after last TACE and sunitinib combination 
administration) potent complications related to the combination of both treatments. Patients 
will be specially monitored for the detection of severe bleeding or liver failure. 
A severe bleeding is defined by  
 
Any bleeding (inguinal, tumoral, gastro-intestinal…) following TACE and requiring a 
 
 
local treatment (other than inguinal compression) 
 
Any bleeding requiring a systemic treatment (e.g. blood transfusion)  
 
An inguinal bleeding during more than 24 hours. 
A severe liver failure is defined by the occurrence of any of the following complications: 
 
Encephalopathy 
 
Ascitis 
 
Increase of bilirubin level > 10mg/L 
 
Decrease of Prothrombin Time > 50 % 
 
Increase of ALT and/or ALT > 6 x baseline value 
During this phase II step, patients will be hospitalized up to 5 days after each TACE course 
for clinical and biological monitoring. The biological monitoring will consist in the daily 
measurement of haematological, liver and kidney functions. 
 
 


 
 
 
 
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XIV. TRANSLATIONAL STUDY 
• Plasma samples will be collected and stored for measurement of circulating soluble 
angiogenic factors during the first TACE course: d-1 or d0, d1, d2, d3. 
• After specific written informed consent, a blood sample will be collected on EDTA for 
DNA extraction and assessment of polymorphisms within genes implicated in the 
angiogenesis pathway (e.g. VEGF receptors). It is recommended to collect this blood 
sample at entry in the study, but this can be performed thereafter. 
 
XV. 
DISCONTINUATION CRITERIA 
 
 
Patients will be informed that they have the right to withdraw from the trial at any 
time, without prejudice to their medical care, and are not obliged to state their reasons. Any 
discontinuations must be fully documented in the CRF and should be followed up by the 
Investigator. 
Additionally, the Investigator may withdraw a patient at any time if he/she considers this to be 
in the patient’s best interest. 
The treatment must be stopped for the following reasons: 
- 
Documented tumor progression 
- 
Initiation of other anti-tumor treatment, 
- 
Unacceptable toxicity (in the Investigator’s opinion) 
- 
Non-compliance with the treatment schedule, defined as the patient missing: 
two successive cycles or three cycles during the entire treatment phase. Yet, 
the patient should be followed and will be included in the intent-to-treat 
analysis. 
- 
Changes in medical status of the patient such that the investigator believes that 
patient safety will be compromised (e.g. worsening of cirrhosis). 
 
Additionally, patients may be discontinuated for any of the following reasons: 
- 
Protocol violations, including non-compliance with trial procedures, patient 
lost to follow-up and patient refusal 
- 
Serious intercurrent illness or significant worsening of intercurrent illness 
- 
Adverse events. 
 


 
 
 
 
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If a patient fails 
to return for a 
scheduled visit/follow up, attempts should be made to contact the patient to ensure that the 
reason for not returning is not an adverse event. Likewise if a patient declares his/her wish to 
discontinue from the trial e.g. for personal reasons, an attempt should be made to establish 
that the true reason is not an adverse event (bearing in mind the patient is not obliged to state 
his/her reason). 
 
 
XVI. STATISTICAL METHOD 
 
PILOT step 
During this stage, patients will not be randomized and will all receive sunitinib. After a 
total of 10 chemoembolization sessions, inclusions will be discontinued and tolerance 
results will be reviewed by a committee of independent experts. 
Patients included in this pilot phase will be particularly monitored for the purpose of 
detecting two potential complications associated with the combination of sunitinib-
chemoembolization: severe bleeding and liver failure. The observed rate of bleeding or 
liver failure after chemoembolization is in the order of 10 to 15% in recent studies . One 
or two toxicities are expected among the 10 chemoembolization sessions. If 4 or more 
toxicities occur, then the toxicity of the sunitinib-chemoembolization combination is 
considered unacceptable and the trial is discontinued. If 3 or fewer toxicities occur, the 
toxicity is considered acceptable and the trial is continued in phase II with randomization. 
Patients included in the pilot phase will not be included in the final analysis of the 
SATURN trial. 
The results of the pilot phase will be sent to AFFSAPS for information. 
 
Phase II step 
 
Patients included during this first step will be specially monitored for the detection of 
two complications: severe bleeding and liver failure (as defined above) in the sunitinib arm. 
The expected rate of severe haemorrhage and/or liver failure in patients undergoing TACE is 
approximately 10 % to 15%, as observed in recent studies with a TACE alone arm (25). We 
defined the unacceptable toxicity rate as 30 % in patients undergoing TACE plus sunitinib 
treatment. 
Using Fleming one step design with the following hypotheses:  


 
 
 
 
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H0: 
An 
occurrence 
rate of bleeding or liver failure 1 week after last administration of the TACE-
sunitinib combination of 30 % is unacceptable 
H1: An occurrence rate of bleeding or liver failure 1 week after last administration of the 
TACE-sunitinib combination of 15% is expected 
 
It would be required to include 35 patients in each arm.  
Among the 35 patients in the Sunitinib arm:  
 
If we observed 8 or more than 8 patients (22.9 %) with severe bleeding or liver 
failure 1 week after last administration of the TACE-sunitinib, the toxicity rate is 
not statistically different from 30%. This treatment would be declared 
unacceptable and inclusions will not be pursued for phase III trial. 
If we observed 7 or less than 7 patients (20 %) with severe bleeding or liver failure 1 week 
after last administration of the TACE-sunitinib, the toxicity rate is statistically 
different from 30 %. This treatment would be declared promising and inclusion 
will be pursued for phase III,  
Calculated power is 85.6% and alpha type one error is 13.3 % 
 
Decision rules for phase III trial continuation:  
Despite randomization and inclusion of 35 patient in the TACE alone arm we will not use 
Fleming decision rules for TACE alone arm to pursue randomization since this is the 
standard arm in the phase III trial.  
 
1. We observed 7 or less than 7 patients (20%) with severe bleeding or liver failure 1 
week after last administration of the TACE-sunitinib  
We will pursue randomization whatever occurrence of these toxicities in the TACE alone 
arm since this is the standard arm in the phase III trial.   
2. We observe 8 or more than 8 patients (22.9 %) with severe bleeding or liver failure 1 
week after last administration of the TACE-sunitinib.  
We will check amongst the 35 patients receiving TACE alone: 
- If we observed also 8 or more than 8 patients (22.9 %) with severe bleeding or liver failure 
1 week after last administration of the TACE alone. Then we will ask an independent data 
monitoring committee (IDMC) about the opportunity to pursue randomization for phase III 
trials since these results could reflect the “noise” of TACE toxicities alone.  


 
 
 
 
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- If we observed 
also 7 or less 
than 7 patients (20%) with severe bleeding or liver failure 1 week after last administration of 
the TACE alone. Then we will ask an independent data monitoring committee (IDMC) 
about the opportunity to stop randomization for phase III trials.  
 
 
These 70 patients will be theoretically recruited in 9 months (7.5 pts/ month) and at least 1 
week follow-up after last administration of the TACE-sunitinib combination is 
required then Phase II step will be analyses about 9 months and 1 week after the 
inclusion of the first patient. 
 
Phase III step 
 
As primary end-point of the phase III study, we have chosen the overall survival for 
the following reasons: 
- 
The overall survival is generally the primary end-point of trials assessing 
TACE.  
- 
The relapse-free survival has been recently recommended for trials performed 
in an adjuvant setting in patients treated for HCC (26). Yet, TACE is not a 
curative approach in most cases. Moreover, after TACE, it is frequently 
difficult to accurately define when an HCC is relapsing, and commonly used 
criteria (e.g. RECIST criteria) are probably not appropriate enough. 
- 
Management of patients with HCC requires a global approach in order to 
control the tumour progression, but also the underlying cirrhosis. After TACE, 
a significant part of the patients will not die from the cancer, but from a 
complication of the cirrhosis. Only the overall survival takes into account both 
parameters. If an investigational anticancer drug administered after TACE has 
an objective effect regarding the tumour growth, but is accompanied by a 
worsening in the cirrhosis outcome, its global contribution will be relative. 
 
 
 
In recent studies assessing TACE, the median overall survival was approximately 
60%, but these studies mainly included selected patients, especially with post-viral cirrhosis 
(1, 2, 25, 27). In France, the main cause of cirrhosis is alcohol. In a recent phase III trial 
conducted by the FFCD group, tamoxifen alone was compared to tamoxifen plus TACE (28). 
The cause of cirrhosis was alcohol in 73 % of the patients allocated to the combined therapy 


 
 
 
 
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arm. In this arm, 
the 
2-year 
survival rate was 32 %, but 26 % of included patients had a Child-B cirrhosis. In another 
French randomised study comparing TACE and conservative treatment in patients with Child-
A cirrhosis, the survival rate at 2 years was 38 % in the TACE arm (29). Since the present 
study is also restricted to patients with Child-A cirrhosis, we estimated that the survival rate at 
2 years will be 40 % in the TACE plus placebo arm.  
Hypothesis : to improve OS rate at 2 years from 40 % vs. 60% for Sunitinib arm, with a 90% 
power and an alpha type I error (bilateral) of 0.05 it is required to observe 130 events and to 
include 180 pts during 2 years (+5 % lost of follow-up = 10 pts + 180 = 190 pts).  
Based on the inclusion of 70 patients in the phase II study, then it will be required to include 
190 – 70 = 120 extra patients for the phase III trial. 
 
The minimum follow-up to observe the required number of deaths for final analysis of phase 
III trial will be about 36 months after the inclusion of the last included patients for total study 
duration of 5 years. 
 
Two interim analyses are planed to reject H0 or H1. The p value will be done according to 
East software (Version 5).Using the alpha-spending function (Lan and DeMets, 1983) and 
O’Brien-Fleming method (O’Brien and Fleming, 1979). 
The first interim analysis is planned at the final analysis (9 to 10 months after the inclusion of 
the first patient) of the phase II study with an expected number of events equal to 10 deaths 
representing 8 % of the total number of deaths required for the final analysis.  
 
The second interim analysis is planned 34 months after the inclusion of the first patient with 
an expected number of events equal to 80 deaths representing 2/3 of the total number of 
deaths required for the final analysis 
 
Overall survival: Time interval between randomization and death (all causes). Alive patients 
will be censored at the last follow-up 
Relapse-free survival: Time interval between randomization and local or distant relapse or 
death (all causes). Alive patients without relapse will be censored at the last follow-up. Alive 
patients with secondary cancer will be censored at the last follow-up 
Disease-free survival: Time interval between randomization and local or distant relapse or 
second cancer or death (all causes). Alive patients will be censored at the last follow-up.  


 
 
 
 
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An analysis plan will produced before the database is frozen. All of the analyses will be 
conducted with a 5% (bilateral) type one error. Analyses of the principal and secondary 
objectives will be conducted on an intent-to-treat basis and will bear on all of the patients 
enrolled:  
 
The data for each arm will be presented as means (standard deviation), median and range or 
percentages and will be compared using the Student t test, Anova or Kruskal Wallis and 
Wilcoxon for quantitative variables or the Chi 2 and Fisher exact test for qualitative variables. 
 
 
Median follow up will be calculated according to the so-called « reverse Kaplan Meier » 
method for each of the Arms, with its 95% confidence interval. 
 
Survival curves will be estimated using the Kaplan-Meier analyses from time to 
randomization, and compared by the log-rank test and stratified log rank test. Cox 
proportional hazard models will be used to estimate univariate and multivariate hazard ratios 
(HR) with 95 % confidence intervals (CI).  
 
The incidence rate of the side effects and of the unexpected serious side effects will be 
reported using frequencies and percentages for: 
- Number and percentage of patients with at least one side effect 
- Number and percentage of patients with at least one grade 3-4 side effect 
- Number and percentage of patients with at least one SAE 
- Number and percentage of patients with at least one side effect and grade 3-4 side effect due 
to the treatment. 
- Number and percentage of patients with at least one side effect that lead to cessation of the 
treatment 
Time to the first occurrence of grade 3-4 toxicity will be estimated by the Kaplan-Meier 
method. 
  
XVII. POPULATIONS FOR ANALYSIS 
The populations for the analysis are defined as follows: 


 
 
 
 
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Intention to treat: The intention to treat population will be composed by all included patients 
who were randomised to one of the two treatment groups, and patients will be analysed 
according to the treatment to which they were randomised. This will be the primary 
population for all analyses of efficacy data and baseline characteristics. 
 
Per protocol: The per protocol population excludes patients randomised who did not receive 
any trial medication or who had a major violation of the protocol inclusion or exclusion 
criteria. Patients will be analysed according to the treatment to which they were randomised. 
 
Safety: The safety population will include all patients who received at least one dose of trial 
medication. Only patients with clear documentation that no trial medication was received may 
be excluded. Patients will be analysed according to the treatment, which they actually 
received. This will be the population for the analysis of all safety data. 
 
XVIII. ADVERSE EVENT REPORTING 
 
1. Definition 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product, which does not necessarily have 
a causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product. 
AE include the following: 
- All suspected adverse medication reactions, 
- All reactions from medication overdose, abuse, discontinuation, sensitivity, or toxicity. 
- Apparently unrelated illnesses, including the worsening of a pre-existing illness. 
- Injury or accidents. Note that if a medical condition is known to have caused the injury or 
accident, the medical condition and the accident should be reported as two separate AE. 
- Abnormalities in physiological testing or physical examination findings that require clinical 
intervention or further investigation (beyond ordering a repeat [confirmatory] test). 
- Laboratory abnormalities that require clinical intervention or further investigation (beyond 
ordering a repeat [confirmatory] test) unless they are associated with an already reported 


 
 
 
 
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clinical 
event. 
Laboratory 
abnormalities associated with a clinical event (e.g. elevated liver enzymes in a patient with 
jaundice) should be described in the comments of the report of the clinical event rather than 
listed as a separate AE. 
 
2. Reporting 
All AE, as defined above, encountered during the clinical trial as well as any Serious 
Adverse Events (SAE) will be reported in the appropriate section of the CRF. It is important 
that this includes the duration of the AE (onset/resolution dates), the severity, the relationship 
to the drug and any concomitant treatment dispensed (or other action taken). Adverse event 
data should be obtained through observation of the patient, from any information volunteered 
by the patient, or through patient questioning. The general type of question asked could be 
similar to: “Do you have any health problems?” or “Have you had any health problems since 
your last clinic visit?” 
 
 
2.1. Definition of Relationship of AE to the Investigational Medicinal Product 
The Investigator will also be asked to assess the possible relationship between the AE and the 
investigational medication. The relationship should be assessed according to the following 
criteria: 
 
Relationship of the Adverse Event to the Investigational Medicinal Product 
None (Intercurrent Event) 
An event that is not and cannot be related to the Investigational Medicinal Product, e.g. 
patient is a passenger in a road traffic accident. 
 
Unlikely (remote) 
Relationship is not likely e.g. a clinical event including laboratory test abnormality with 
temporal relationship to drug administration which makes a causal relationship improbable 
and in which other drugs, chemicals or underlying disease provide plausible explanations. 
 
Possible Relationship may exist, but could have been produced by the patient’s condition or 
treatment or other cause. 
 


 
 
 
 
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Probable 
Relationship is likely; the adverse event abates upon discontinuation of Investigational 
Medicinal Product and cannot be due to the patient’s condition. 
 
Highly Probable 
Strong relationship, the event abates upon discontinuation of Investigational Medicinal 
Product and, if applicable, re-appears upon repeat exposure. 
 
2.2. Definition of Severity of Adverse Events 
Severity of any AE will be graded according to National Cancer Institute (NCI) Common 
Toxicity Criteria (CTC) version 3.0, where applicable. For each episode, the highest severity 
grade attained should be reported. If an AE occurs that is not listed in the CTC, the 
Investigator will evaluate its severity using the following criteria: 
 
Definition of Severity of Adverse Events 
 
Mild Grade 1 - Does not interfere with subject's usual function (awareness of symptoms or 
signs, but easily tolerated [acceptable]). 
 
Moderate Grade 2 - Interferes to some extent with subject's usual function (enough 
discomfort to interfere with usual activity [disturbing]). 
 
Severe Grade 3 - Interferes significantly with subject's usual function (incapacity to work or 
to do usual activities [unacceptable]) 
 
Life Threatening Grade 4 - Results in risk of death, organ damage, or permanent disability 
(unacceptable) 
Note the distinction between the seriousness and the intensity of an AE. Severe is a measure 
of intensity; thus, a severe reaction is not necessarily a serious reaction. For example, a 
headache may be severe in intensity, but would not be classified as serious unless it met one 
of the criteria for serious events listed in section 3. 
 


 
 
 
 
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2.3. Frequency of Adverse Events 
 
Once The AE occurred only once and cleared in < 24 hours. 
 
Occasionally The AE occurred sporadically or episodically between the onset and clearance 
dates. 
 
Continuously The AE was present for the entire time between onset and clearance dates and 
was > 24 hours duration. 
 
3. Serious Adverse Events 
3.1. Definition of a Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that at any dose: 
- Results in death. 
- 
Is life-threatening (i.e. the patient was at risk of death at the time of the event. It does not 
refer to an event which hypothetically might have caused death if it were more severe). 
- Requires inpatient hospitalisation or prolongation of existing hospitalisation. 
- Results in persistent or significant disability/incapacity. 
- Is a congenital anomaly/birth defect. 
Medical and scientific judgement should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately lifethreatening or result in death or hospitalisation but may jeopardise the patient 
or may require intervention to prevent one of the other outcomes listed above. These should 
also usually be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalisation; or development of drug dependency or drug abuse. 
 
3.2. SAE Reporting Procedure for Investigators to Sponsor 
The Investigator must report all SAE, regardless of presumed causal relationship, to the 
Promotor by fax on a Serious Adverse Event form within 24 hours of learning of the event. 
Details of the relevant fax number for SAE will be provided as a separate document. 


 
 
 
 
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Information 
on 
Serious 
Adverse Events (SAE) will be recorded on a specific Non Carbon Repeat (NCR) SAE form. 
Blank copies are included in the trial Investigator’s File. The Investigator should follow up 
the event until resolution or stabilisation of the condition. Follow-up reports (as many as 
required) should be completed and faxed following the same procedure above. 
A final report is required in any case once the condition is resolved or stabilised and no more 
information about the event is expected. The final report should be completed and faxed 
following the same procedure above. 
 
4. Adverse Event Reporting Period 
All AE that occur during the treatment period i.e. from the date of written informed consent to 
the final trial visit will be recorded in the CRF. In addition, any known untoward event that 
occurs subsequent to the AE reporting period that the Investigator assesses as possibly, 
probably or highly probably related to the Investigational. Medicinal Product should also be 
reported as an AE. 
 
XIX. QUALITY OF LIFE 
 
Quality of life (QOL) will be measured by the general thirty-question EORTC quality of life 
questionnaire QLQ-C30. QOL is measured at baseline and every 3 months the first year 
(treatment period) and every 6 months the second year. Patients who withdraw will have a 
QOL assessment at discontinuation. These discontinuation data will be listed, but will not be 
included in tables or analyses. Every effort must be made to complete the QOL questionnaire. 
Where a whole questionnaire has not been completed but the patient has survived to the 
appropriate time, one of the following options will be recorded on the CRF. 
1 = patient felt too ill 
2 = clinician or nurse felt the patient was too ill 
3 = patient felt it was inconvenient, takes too much time 
4 = patient felt it was a violation of privacy 
5 = patient didn’t understand the actual language/ illiterate 
6 = administrative failure to distribute the questionnaire to the patient 
7 = other, please specify 
 
For codes 1 or 2, data will be regarded as ‘missing too ill’ whereas for any of the other  


 
 
 
 
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Firstly mean differences of QoL scores between last available measurement and inclusion will 
be compared using Wilcoxon test. Secondly Time until definitive score deterioration will 
estimated using Kaplan Meier, and compared using log-rank tests. They will be defined as the 
time interval between randomization and the first occurrence of a decrease in QLQ-C30 score 
of ≥ 5 points without any further improvement in QoL score of ≥ 5 points or any further 
available QoL data..  
These analyses were repeated using a 10 points MCID, and by including deaths as event 
 
 
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combined with radiofrequency ablation for patients with hepatocellular carcinoma larger than 
3 cm: a randomized controlled trial. JAM 2008, 299: 1669-77. 
 
26. Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni R, Zhu AX, Sherman M, 
Schwartz M, Lotze M, Talwalkar J, Gores GJ; Panel of Experts in HCC-Design Clinical 
Trials. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst 
2008, 100: 698-711. 
 
27. Yamagiwa K, Shiraki K, Yamakado K, Mizuno S, Hori T, Yagi S, Hamada T, Iida T, 
Nakamura I, Fujii K, Usui M, Isaji S, Ito K, Tagawa S, Takeda K, Yokoi H, Noguchi T. 
Survival rates according to the Cancer of the Liver Italian Program scores of 345 
hepatocellular carcinoma patients after multimodality treatments during a 10-year period in a 
retrospective study. J Gastroenterol Hepatol 2008, 23: 482-90. 
 
28. Doffoël M, Bonnetain F, Bouché O, Vetter D, Abergel A, Fratté S, Grangé JD, 
Stremsdoerfer N, Blanchi A, Bronowicki JP, Caroli-Bosc FX, Causse X, Masskouri F, 
Rougier P, Bedenne L; Fédération Francophone de Cancérologie Digestive. Multicentre 


 
 
 
 
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randomised phase 
III 
trial 
comparing Tamoxifen alone or with Transarterial Lipiodol Chemoembolisation for 
unresectable hepatocellular carcinoma in cirrhotic patients (Fédération Francophone de 
Cancérologie Digestive 9402). Eur J Cancer 2008, 44: 528-38. 
 
29. Groupe d’Etude et de Traitement du Carcinome Hepatocellulaire. A comparison of 
lipiodol chemoembolization and conservative treatment for unresectable hepatocellular 
carcinoma. Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire. N Engl J Med 
1995, 332: 1256-61.  
 


 
 
 
 
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XXI. APPENDICES 
 
 
List of participating centres 
 
Declaration of Helsinki 
 
ICH-Good Clinical Practice-investigator’s responsabilities 
 
Example of Performance Status (ECOG/Karnofski scale) 
 
BCLC classification 
 
Child-Pugh score 
 
CLIP score 
 
Information notice to the patient 
 
Informed consent 
 
Specific informed consent for genetic study 
 
 
 
 


 
 
 
 
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35
 
The World 
Medical 
Association  
Declaration of Helsinki  
World Medical Association Declaration of Helsinki: Recommendations 
Guiding Medical Doctors in Biomedical Research Involving Human 
Subjects  
Adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964 and 
as revised by the World Medical Assembly in Tokyo, Japan in 1975, in 
Venice, Italy in 1983, and in Hong Kong in 1989.  
 
Introduction  
It is the mission of the physician to safeguard the health of the people. His or her knowledge 
and conscience are dedicated to the fulfilment of this mission.  
The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my patient will be my first consideration," and the International Code 
of Medical Ethics declares that, "A physician shall act only in the patient's interest when 
providing medical care which might have the effect of weakening the physical and mental 
condition of the patient."  
The Purpose of biomedical research involving human subjects must be to improve diagnostic, 
therapeutic and prophylactic procedures and the understanding of the aetiology and 
pathogenesis of disease.  
In current medical practice most diagnostic, therapeutic or prophylactic procedures involve 
hazards. This applies especially to biomedical research.  
Medical progress is based on research which ultimately must rest in part on experimentation 
involving human subjects.  
In the field of biomedical research a fundamental distinction must be recognized between 
medical research in which the aim is essentially diagnostic or therapeutic for a patient, and 
medical research, the essential object of which is purely scientific and without implying direct 
diagnostic or therapeutic value to the person subjected to the research.  
Special caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected.  
Because it is essential that the results of laboratory experiments be applied to human beings to 
further scientific knowledge and to help suffering humanity, the World Medical Association 
has prepared the following recommendations as a guide to every physician in biomedical 
research involving human subjects. They should be kept under review in the future. It must be 
stressed that the standards as drafted are only a guide to physicians all over the world. 
Physicians are not relieved from criminal, civil and ethical responsibilities under the laws of 
their own countries.  
 


 
 
 
 
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I. Basic 
Principles  
1. Biomedical research involving human subjects must conform to generally accepted scientific principles 
and should be based on adequately performed laboratory and animal experimentation and on a thorough 
knowledge of the scientific literature.  
2. The design and performance of each experimental procedure involving human subjects should be 
clearly formulated in an experimental protocol which should be transmitted for consideration, comment 
and guidance to a specially appointed committee independent of the investigator and the sponsor 
provided that this independent committee is in conformity with the laws and regulations of the country 
in which the research experiment is performed.  
3. Biomedical research involving human subjects should be conducted only by scientifically qualified 
persons and under the supervision of a clinically competent medical person. The responsibility for the 
human subject must always rest with a medically qualified person and never rest on the subject of the 
research, even though the subject has given his or her consent.  
4. Biomedical research involving human subjects cannot legitimately be carried out unless the importance 
of the objective is in proportion to the inherent risk to the subject.  
5. Every biomedical research project involving human subjects should be preceded by careful assessment 
of predictable risks in comparison with foreseeable benefits to the subject or to others. Concern for the 
interests of the subject must always prevail over the interests of science and society.  
6. The right of the research subject to safeguard his or her integrity must always be respected. Every 
precaution should be taken to respect the privacy of the subject and to minimize the impact of the study 
on the subject's physical and mental integrity and on the personality of the subject.  
7. Physicians should abstain from engaging in research projects involving human subjects unless they are 
satisfied that the hazards involved are believed to be predictable. Physicians should cease any 
investigation if the hazards are found to outweigh the potential benefits.  
8. In publication of the results of his or her research, the physician is obliged to preserve the accuracy of 
the results. Reports of experimentation not in accordance with the principles laid down in this 
Declaration should not be accepted for publication.  
9. In any research on human beings, each potential subject must be adequately informed of the aims, 
methods, anticipated benefits and potential hazards of the study and the discomfort it may entail. He or 
she should be informed that he or she is at liberty to abstain from participation in the study and that he 
or she is free to withdraw his or her consent to participation at any time. The physician should then 
obtain the subject's freely-given informed consent, preferably in writing.  
10. When obtaining informed consent for the research project the physician should be particularly cautious 
if the subject is in a dependent relationship to him or her or may consent under duress. In that case the 
informed consent should be obtained by a physician who is not engaged in the investigation and who is 
completely independent of this official relationship.  
11. In case of legal incompetence, informed consent should be obtained from the legal guardian in 
accordance with national legislation. Where physical or mental incapacity makes it impossible to obtain 
informed consent, or when the subject is a minor, permission from the responsible relative replaces that 
of the subject in accordance with national legislation. Whenever the minor child is in fact able to give a 
consent, the minor's consent must be obtained in addition to the consent of the minor's legal guardian.  
12. The research protocol should always contain a statement of the ethical considerations involved and 
should indicate that the principles enunciated in the present Declaration are complied with.  
II. Medical Research Combined with Professional Care (Clinical Research)  
1. In the treatment of the sick person, the physician must be free to use a new diagnostic and therapeutic 
measure, if in his or her judgment it offers hope of saving life, reestablishing health or alleviating 
suffering.  


 
 
 
 
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2. The 
potential benefits, hazards and discomfort of a new method should be weighed against the advantages 
of the best current diagnostic and therapeutic methods.  
3. In any medical study, every patient--including those of a control group, if any--should be assured of the 
best proven diagnostic and therapeutic method.  
4. The refusal of the patient to participate in a study must never interfere with the physician-patient 
relationship.  
5. If the physician considers it essential not to obtain informed consent, the specific reasons for this 
proposal should be stated in the experimental protocol for transmission to the independent committee 
(I,2).  
6. The physician can combine medical research with professional care, the objective being the acquisition 
of new medical knowledge, only to the extent that medical research is justified by its potential 
diagnostic or therapeutic value for the patient.  
III. Non-Therapeutic Biomedical Research Involving Human Subjects (Non-Clinical Biomedical 
Research)  
1. In the purely scientific application of medical research carried out on a human being, it is the duty of 
the physician to remain the protector of the life and health of that person on whom biomedical research 
is being carried out.  
2. The subjects should be volunteers--either healthy persons or patients for whom the experimental design 
is not related to the patient's illness.  
3. The investigator or the investigating team should discontinue the research if in his/her or their judgment 
it may, if continued, be harmful to the individual.  
4. In research on man, the interest of science and society should never take precedence over considerations 
related to the well-being of the subject.  
 


 
 
 
 
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ICH 
HARMONIZED TRIPARTITE GUIDELINE E6: 
GOOD CLINICAL PRACTICE: CONSOLIDATED GUIDELINE 
 
4. INVESTIGATOR 
 
4.1 Investigator's Qualifications and Agreements 
4.1.1 The investigator(s) should be qualified by education, training, and experience to assume 
responsibility for the proper conduct of the trial, should meet all the qualifications specified by the applicable 
regulatory requirement(s), and should provide evidence of such qualifications through up-to-date curriculum 
vitae and/or other relevant documentation requested by the sponsor, the IRB/IEC, and/or the regulatory authority 
(ies). 
4.1.2 The investigator should be thoroughly familiar with the appropriate use of the investigational product(s), as 
described in the protocol, in the current Investigator's Brochure, in the product information and in other 
information sources provided by the sponsor. 
4.1.3 The investigator should be aware of, and should comply with, GCP and the applicable regulatory 
requirements. 
4.1.4 The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by the 
appropriate regulatory authority (ies). 
4.1.5 The investigator should maintain a list of appropriately qualified persons to whom the 
investigator has delegated significant trial-related duties. 
 
4.2 Adequate Resources 
4.2.1 The investigator should be able to demonstrate (e.g., based on retrospective data) a potential for recruiting 
the required number of suitable subjects within the agreed recruitment period. 
4.2.2 The investigator should have sufficient time to properly conduct and complete the trial within the agreed 
trial period. 
4.2.3 The investigator should have available an adequate number of qualified staff and adequate facilities for the 
foreseen duration of the trial to conduct the trial properly and safely. 
4.2.4 The investigator should ensure that all persons assisting with the trial are adequately informed about the 
protocol, the investigational product(s), and their trial-related duties and functions. 
 
4.3 Medical Care of Trial Subjects 
4.3.1 A qualified physician (or dentist, when appropriate), who is an investigator or a sub-investigator for the 
trial, should be responsible for all trial-related medical (or dental) decisions. 
4.3.2 During and following a subject's participation in a trial, the investigator/institution should ensure that 
adequate medical care is provided to a subject for any adverse events, including clinically significant laboratory 
values, related to the trial. The investigator/institution should inform a subject when medical care is needed for 
intercurrent illness(es) of which the investigator becomes aware. 
4.3.3 It is recommended that the investigator inform the subject's primary physician about the subject's 
participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician 
being informed. 
4.3.4 Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the 
investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights. 
 
4.4 Communication with IRB/IEC 
4.4.1 Before initiating a trial, the investigator/institution should have written and dated approval/favourable 
opinion from the IRB/IEC for the trial protocol, written informed consent form, consent form updates, subject 
recruitment procedures (e.g., advertisements), and any other written information to be provided to subjects. 
4.4.2 As part of the investigator's/institution's written application to the IRB/IEC, the investigator/institution 
should provide the IRB/IEC with a current copy of the Investigator's Brochure. If the Investigator's Brochure is 
updated during the trial, the investigator/institution should supply a copy of the updated Investigator's Brochure 
to the IRB/IEC. 
4.4.3 During the trial the investigator/institution should provide to the IRB/IEC all documents subject to review. 
 
4.5 Compliance with Protocol 
4.5.1 The investigator/institution should conduct the trial in compliance with the protocol agreed to by the 
sponsor and, if required, by the regulatory authority(ies) and which was given approval/favourable opinion by 


 
 
 
 
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39
 
the 
IRB/IEC. 
The 
investigator/institution and the sponsor should sign the protocol, or an alternative contract, to confirm agreement. 
4.5.2 The investigator should not implement any deviation from, or changes of the protocol without agreement 
by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of an 
amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s) 
involves only logistical or administrative aspects of the trial [e.g., change in monitor(s), change of telephone 
number(s)]. 
4.5.3 The investigator, or person designated by the investigator, should document and explain any deviation from 
the approved protocol. 
4.5.4 The investigator may implement a deviation from, or a change of, the protocol to eliminate an immediate 
hazard(s) to trial subjects without prior IRB/IEC approval/favourable opinion. As soon as possible, the 
implemented deviation or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) 
should be submitted: 
(a) to the IRB/IEC for review and approval/favourable opinion, 
(b) to the sponsor for agreement and, if required, 
(c) to the regulatory authority(ies). 
 
4.6 Investigational Product(s) 
4.6.1 Responsibility for investigational product(s) accountability at the trial site(s) rests with the 
investigator/institution. 
4.6.2 Where allowed/required, the investigator/institution may/should assign some or all of the 
investigator's/institution's duties for investigational product(s) accountability at the trial site(s) to an appropriate 
pharmacist or another appropriate individual who is under the supervision of the investigator/institution. 
4.6.3 The investigator/institution and/or a pharmacist or other appropriate individual, who is designated by the 
investigator/institution, should maintain records of the product's delivery to the trial site, the inventory at the site, 
the use by each subject, and the return to the sponsor or alternative disposition of unused product(s). These 
records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique 
code numbers assigned to the investigational product(s) and trial subjects. Investigators should maintain records 
that document adequately that the subjects were provided the doses specified by the protocol and reconcile all 
investigational product(s) received from the sponsor. 
4.6.4 The investigational product(s) should be stored as specified by the sponsor and in accordance with 
applicable regulatory requirement(s). 
4.6.5 The investigator should ensure that the investigational product(s) are used only in accordance with the 
approved protocol. 
4.6.6 The investigator, or a person designated by the investigator/institution, should explain the correct use of the 
investigational product(s) to each subject and should check, at intervals appropriate for the trial, that each subject 
is following the instructions properly. 
 
4.7 Randomization Procedures and Unblinding 
The investigator should follow the trial's randomization procedures, if any, and should ensure that the code is 
broken only in accordance with the protocol. If the trial is blinded, the investigator should promptly document 
and explain to the sponsor any premature unblinding (e.g., accidental unblinding, unblinding due to a serious 
adverse event) of the investigational product(s). 
 
4.8 Informed Consent of Trial Subjects 
4.8.1 In obtaining and documenting informed consent, the investigator should comply with the applicable 
regulatory requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the 
Declaration of Helsinki. Prior to the beginning of the trial, the investigator should have the IRB/IEC's written 
approval/favourable opinion of the written informed consent form and any other written information to be 
provided to subjects. 
4.8.2 The written informed consent form and any other written information to be provided to subjects should be 
revised whenever important new information becomes available that may be relevant to the subject's consent. 
Any revised written informed consent form, and written information should receive the IRB/IEC's 
approval/favourable opinion in advance of use. The subject or the subject's legally acceptable representative 
should be informed in a timely manner if new information becomes available that may be relevant to the 
subject's willingness to continue participation in the trial. The communication of this information should be 
documented. 
4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to 
continue to participate in a trial. 


 
 
 
 
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4.8.4 None of the 
oral and written 
information concerning the trial, including the written informed consent form, should contain any language that 
causes the subject or the subject's legally acceptable representative to waive or to appear to waive any legal 
rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from 
liability for negligence. 
4.8.5 The investigator, or a person designated by the investigator, should fully inform the subject or, if the 
subject is unable to provide informed consent, the subject's legally acceptable representative, of all pertinent 
aspects of the trial including the written information given approval/favourable opinion by the IRB/IEC. 
4.8.6 The language used in the oral and written information about the trial, including the written informed 
consent form, should be as non-technical as practical and should be understandable to the subject or the subject's 
legally acceptable representative and the impartial witness, where applicable. 
4.8.7 Before informed consent may be obtained, the investigator, or a person designated by the investigator, 
should provide the subject or the subject's legally acceptable representative ample time and opportunity to 
inquire about details of the trial and to decide whether or not to participate in the trial. All questions about the 
trial should be answered to the satisfaction of the subject or the subject's legally acceptable representative. 
4.8.8 Prior to a subject's participation in the trial, the written informed consent form should be signed and 
personally dated by the subject or by the subject's legally acceptable representative, and by the person who 
conducted the informed consent discussion. 
4.8.9 If a subject is unable to read or if a legally acceptable representative is unable to read, an impartial witness 
should be present during the entire informed consent discussion. After the written informed consent form and 
any other written information to be provided to subjects, is read and explained to the subject or the subject's 
legally acceptable representative, and after the subject or the subject's legally acceptable representative has orally 
consented to the subject's participation in the trial and, if capable of doing so, has signed and personally dated 
the informed consent form, the witness should sign and personally date the consent form. By signing the consent 
form, the witness attests that the information in the consent form and any other written information was 
accurately explained to, and apparently understood by, the subject or the subject's legally acceptable 
representative, and that informed consent was freely given by the subject or the subject's legally acceptable 
representative. 
4.8.10 Both the informed consent discussion and the written informed consent form and any other written 
information to be provided to subjects should include explanations of the following: 
(a) That the trial involves research. 
(b) The purpose of the trial. 
(c) The trial treatment(s) and the probability for random assignment to each treatment. 
(d) The trial procedures to be followed, including all invasive procedures. 
(e) The subject's responsibilities. 
(f) Those aspects of the trial that are experimental. 
(g) The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, 
or nursing infant. 
(h) The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should 
be made aware of this. 
(i) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their important 
potential benefits and risks. 
(j) The compensation and/or treatment available to the subject in the event of trial-related injury. 
(k) The anticipated prorated payment, if any, to the subject for participating in the trial. 
(l) The anticipated expenses, if any, to the subject for participating in the trial. 
(m) That the subject's participation in the trial is voluntary and that the subject may refuse to participate or 
withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled. 
(n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority (ies) will be granted direct 
access to the subject's original medical records for verification of clinical trial procedures and/or data, without 
violating the confidentiality of the subject, to the extent permitted by the applicable laws and regulations and 
that, by signing a written informed consent form, the subject or the subject's legally acceptable representative is 
authorizing such access. 
(o) That records identifying the subject will be kept confidential and, to the extent permitted by the applicable 
laws and/or regulations, will not be made publicly available. If the results of the trial are published, the subject's 
identity will remain confidential. 
(p) That the subject or the subject's legally acceptable representative will be informed in a timely manner if 
information becomes available that may be relevant to the subject's willingness to continue participation in the 
trial. 
(q) The person(s) to contact for further information regarding the trial and the rights of trial subjects, and whom 
to contact in the event of trial-related injury. 


 
 
 
 
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(r) The foreseeable 
circumstances 
and/or reasons under which the subject's participation in the trial may be terminated. 
(s) The expected duration of the subject's participation in the trial. 
(t) The approximate number of subjects involved in the trial. 
4.8.11 Prior to participation in the trial, the subject or the subject's legally acceptable representative should 
receive a copy of the signed and dated written informed consent form and any other written information provided 
to the subjects. During a subject's participation in the trial, the subject or the subject's legally acceptable 
representative should receive a copy of the signed and dated consent form updates and a copy of any 
amendments to the written information provided to subjects. 
4.8.12 When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the 
trial with the consent of the subject's legally acceptable representative (e.g., minors, or patients with severe 
dementia), the subject should be informed about the trial to the extent compatible with the subject's 
understanding and, if capable, the subject should sign and personally date the written informed consent. 
4.8.13 Except as described in 4.8.14, a non-therapeutic trial (i.e., a trial in which there is no anticipated direct 
clinical benefit to the subject), should be conducted in subjects who personally give consent and who sign and 
date the written informed consent form. 
4.8.14 Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative 
provided the following conditions are fulfilled: 
(a) The objectives of the trial can not be met by means of a trial in subjects who can give informed consent 
personally. 
(b) The foreseeable risks to the subjects are low. 
(c) The negative impact on the subject's well-being is minimized and low. 
(d) The trial is not prohibited by law. 
(e) The approval/favourable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and 
the written approval/favourable opinion covers this aspect. Such trials, unless an exception is justified, should be 
conducted in patients having a disease or condition for which the investigational product is intended. Subjects in 
these trials should be particularly closely monitored and should be withdrawn if they appear to be unduly 
distressed. 
4.8.15 In emergency situations, when prior consent of the subject is not possible, the consent of the subject's 
legally acceptable representative, if present, should be requested. When prior consent of the subject is not 
possible, and the subject's legally acceptable representative is not available, enrollment of the subject should 
require measures described in the protocol and/or elsewhere, with documented approval/favourable opinion by 
the IRB/IEC, to protect the rights, safety and well-being of the subject and to ensure compliance with applicable 
regulatory requirements. The subject or the subject's legally acceptable representative should be informed about 
the trial as soon as possible and consent to continue and other consent as appropriate should be requested. 
 
4.9 Records and Reports 
4.9.1 The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to 
the sponsor in the CRFs and in all required reports. 
4.9.2 Data reported on the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. 
4.9.3 Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and should not 
obscure the original entry (i.e., an audit trail should be maintained); this applies to both written and electronic 
changes or corrections. Sponsors should provide guidance to investigators and/or the investigators' designated 
representatives on making such corrections. Sponsors should have written procedures to assure that changes or 
corrections in CRFs made by sponsor's designated representatives are documented, are necessary, and are 
endorsed by the investigator. The investigator should retain records of the changes and corrections. 
4.9.4 The investigator/institution should maintain the trial documents as specified in Essential Documents for the 
Conduct of a Clinical Trial (see 8.) and as required by the applicable regulatory requirement(s). The 
investigator/institution should take measures to prevent accidental or premature destruction of these documents. 
4.9.5 Essential documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period however if required by the 
applicable regulatory requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to 
inform the investigator/institution as to when these documents no longer need to be retained. 
4.9.6 The financial aspects of the trial should be documented in an agreement between the sponsor and the 
investigator/institution. 
4.9.7 Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the investigator/institution should 
make available for direct access all requested trial-related records. 


 
 
 
 
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4.10 Progress Reports 
4.10.1 The investigator should submit written summaries of the trial status to the IRB/IEC annually, or more 
frequently, if requested by the IRB/IEC. 
4.10.2 The investigator should promptly provide written reports to the sponsor, the IRB/IEC and, where 
applicable, the institution on any changes significantly affecting the conduct of the trial, and/or increasing the 
risk to subjects. 
 
4.11 Safety Reporting 
4.11.1 All serious adverse events (SAE) should be reported immediately to the sponsor except for those SAEs 
that the protocol or other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting. 
The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up 
reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects' 
names, personal identification numbers, and/or addresses. The investigator should also comply with the 
applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the 
regulatory authority (ies) and the IRB/IEC. 
4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety evaluations 
should be reported to the sponsor according to the reporting requirements and within the time periods specified 
by the sponsor in the protocol. 
4.11.3 For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any additional 
requested information (e.g., autopsy reports and terminal medical reports). 
 
4.12 Premature Termination or Suspension of a Trial 
If the trial is prematurely terminated or suspended for any reason, the investigator/institution should promptly 
inform the trial subjects, should assure appropriate therapy and follow-up for the subjects, and, where required 
by the applicable regulatory requirement(s), should inform the regulatory authority (ies). In addition: 
4.12.1 If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator 
should inform the institution where applicable, and the investigator/institution should promptly inform the 
sponsor and the IRB/IEC, and should provide the sponsor and the IRB/IEC a detailed written explanation of the 
termination or suspension. 
4.12.2 If the sponsor terminates or suspends a trial, the investigator should promptly inform the institution where 
applicable and the investigator/institution should promptly inform the IRB/IEC and provide the IRB/IEC a 
detailed written explanation of the termination or suspension. 
4.12.3 If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial, the investigator should 
inform the institution where applicable and the investigator/institution should promptly notify the sponsor and 
provide the sponsor with a detailed written explanation of the termination or suspension. 
 
4.13 Final Report(s) by Investigator 
Upon completion of the trial, the investigator, where applicable, should inform the institution; the 
investigator/institution should provide the IRB/IEC with a summary of the trial's outcome, and the regulatory 
authority (ies) with any reports required. 
 


 
 
 
 
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43
 
 
PERFORMANCE STATUS (ECOG/KARNOFSKY SCALE) 
 
 
 
 


 
 
 
 
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44
 
 
 
CHILD-PUGH SCORE 
 
 
 
 
1 
2 
3 
Encephalopathy 
Absent 
Confusion 
Coma 
Ascitis 
Absent 
Mild 
Abundant 
Albumine (g/l) 
> 35 
28-35 
< 28 
Bilirubine (μmol/l) < 35 
35-50 
>50 
Prothrombin 
activity (%) 
>50 
40-50 
<40 
 
 
 
Child A: score 5 or 6 
Child B: score 7- 9 
Child C: score 10-15 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- Randomized, double-blind, phase II/III trial evaluating combination 
chemoembolization with Sunitinib 
or placebo in patients with hepatocellular carcinoma  
Randomized Phase II/III 
PRODIGE 16 (FFCD 0905) - SATURNE 
 
 
 
Statistical Analysis Plan 
Phase II  
 
 
 
 
 
Version: Final 
Date: February 2015 
 
Editor: Karine Le Malicot 
Review committee: Pr Mohammed Hebbar, Dr Thierry de Baere, Dr Jean-Didier Grangé, Carole Montérymard, 
Emilie Maillard. 
 
 
 
 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 2of 26 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 3of 26 
Developer  
FFCD 
Faculty of Medicine, 7 boulevard Jeanne d'Arc, BP87900, 21079, Dijon Cedex 
Tel: 03 80 39 33 87- Fax: 03 80 38 18 41 
Email : cecile.girault@u-bourgogne.fr 
 
Coordinator 
  
Pr Mohammed Hebbar 
Medical Oncology Department, CHU Lille 
Tel: 03 20 44 54 61 
Email : m-hebbar@chru-lille.fr 
 
Scientific co-leaderDr  Thierry de Baere 
Interventional Radiology Department - Institut Gustave Roussy - Villejuif 
Phone: 01 42 11 54 28 
E-mail : debaere@igr.fr 
 
Scientific co-leaderDr  Jean-Didier Grangé 
Hepato-gastroenterology department - Hôpital Tenon - Paris 
Tel: 01 56 01 70 09 
E-mail : jean-didier.grange@tnn.ap-hop-paris.fr 
 
Project Manager  
  
Ms. Marie Moreau 
FFCD 
Faculty of Medicine, 7 boulevard Jeanne d'Arc, BP87900, 21079, Dijon Cedex 
Tel: 03 80 73 77 84 
Email : marie.moreau@u-bourgogne.fr 
 
Statistician :  
  
Ms. Karine Le Malicot 
FFCD 
Faculty of Medicine, 7 boulevard Jeanne d'Arc, BP87900, 21079, Dijon Cedex 
Tel: 03 80 39 34 71 
Email : karine.le-malicot@u-bourgogne.fr 
 
 
 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 4of 26 
1 Table of contents  
1 
Table of contents .........................................................................................................................................................................................................4 
2 
Abbreviations and definitions ...............................................................................................................................................................................6 
3 
Introduction ..................................................................................................................................................................................................................7 
3.1 
Rationale for the study .................................................................................................................................................................................7 
3.2 
Objectives ...........................................................................................................................................................................................................7 
3.2.1 
Pilot phase .....................................................................................................................................................................................................7 
3.2.2 
Phase II ...........................................................................................................................................................................................................7 
3.2.3 
Phase III .........................................................................................................................................................................................................7 
4 
Study population .........................................................................................................................................................................................................8 
4.1 
Inclusion criteria .............................................................................................................................................................................................8 
4.2 
Criteria for non-inclusion ............................................................................................................................................................................8 
5 
Experimental design ..................................................................................................................................................................................................9 
5.1 
Scheme of the study .......................................................................................................................................................................................9 
5.2 
Study arms .........................................................................................................................................................................................................9 
5.3 
Randomization and blinding ......................................................................................................................................................................9 
5.4 
Chronological sequence ...............................................................................................................................................................................9 
5.5 
Justification of the number of subjects needed ............................................................................................................................... 11 
5.5.1 
Pilot phase .................................................................................................................................................................................................. 11 
5.5.2 
Phase II ........................................................................................................................................................................................................ 11 
5.5.3 
Phase III ...................................................................................................................................................................................................... 11 
5.6 
Steps of the test ............................................................................................................................................................................................. 12 
5.6.1 
Pilot phase .................................................................................................................................................................................................. 12 
5.6.2 
Phase II ........................................................................................................................................................................................................ 12 
5.6.3 
Phase III ...................................................................................................................................................................................................... 12 
5.6.4 
Transition between steps .................................................................................................................................................................... 12 
5.7 
Judgement criteria for phase II .............................................................................................................................................................. 13 
5.7.1 
Main criterion ........................................................................................................................................................................................... 13 
5.7.2 
Secondary efficacy criteria ................................................................................................................................................................. 14 
5.7.3 
Secondary safety criteria ..................................................................................................................................................................... 15 
5.7.4 
Quality of life ............................................................................................................................................................................................. 16 
5.7.5 
Other criteria ............................................................................................................................................................................................ 16 
5.7.6 
Exploratory analyses ............................................................................................................................................................................. 16 
5.7.7 
Management of criteria between Phase II and Phase III ....................................................................................................... 16 
6 
Study populations .................................................................................................................................................................................................... 17 
6.1 
Definition of Analysis Populations ....................................................................................................................................................... 17 
6.1.1 
Intent-to-treat (ITT) population ...................................................................................................................................................... 17 
6.1.2 
Modified intention-to-treat population (mITT) ........................................................................................................................ 17 
6.1.3 
Population for Tolerance Analysis (SP) ........................................................................................................................................ 17 
6.2 
Definition of analysis subgroups ........................................................................................................................................................... 17 
7 
Recruitment and analysis planning ................................................................................................................................................................. 17 
7.1 
Recruitment .................................................................................................................................................................................................... 17 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 5of 26 
7.2 
Planning of analyses ................................................................................................................................................................................... 18 
7.2.1 
Pilot phase .................................................................................................................................................................................................. 18 
7.2.2 
Phase II ........................................................................................................................................................................................................ 18 
7.2.3 
Phase III ...................................................................................................................................................................................................... 18 
7.2.4 
Transition from Phase II to Phase III ............................................................................................................................................. 18 
7.3 
Adjustments .................................................................................................................................................................................................... 18 
8 
Statistical methods .................................................................................................................................................................................................. 18 
8.1 
General information on statistical analysis methods ................................................................................................................... 18 
8.1.1 
Software ...................................................................................................................................................................................................... 18 
8.1.2 
Agreements concerning dates and durations ............................................................................................................................ 18 
8.1.3 
Outlier Conventions ............................................................................................................................................................................... 19 
8.1.4 
Missing Data Conventions ................................................................................................................................................................... 19 
8.1.5 
Definition of the baseline .................................................................................................................................................................... 19 
8.1.6 
Statistics ...................................................................................................................................................................................................... 19 
8.2 
Patient characteristics at inclusion ...................................................................................................................................................... 20 
8.2.1 
Patient eligibility ..................................................................................................................................................................................... 20 
8.2.2 
Demographic characteristics ............................................................................................................................................................. 20 
8.2.3 
Clinical characteristics ......................................................................................................................................................................... 20 
8.2.4 
Biological characteristics .................................................................................................................................................................... 20 
8.2.5 
Disease-related characteristics ........................................................................................................................................................ 21 
8.3 
Follow-up characteristics (if Phase III not done) .......................................................................................................................... 21 
8.4 
Phase II primary endpoint assessment .............................................................................................................................................. 22 
8.5 
Evaluation of effectiveness ...................................................................................................................................................................... 22 
8.5.1 
Description of chemo-embolization ............................................................................................................................................... 22 
8.6 
Evaluation of tolerance .............................................................................................................................................................................. 23 
8.6.2 
Quality of life ............................................................................................................................................................................................. 23 
8.6.3 
Other criteria ............................................................................................................................................................................................ 23 
8.7 
Common criteria for Phase II and Phase III ...................................................................................................................................... 23 
8.7.1 
Progression-free survival .................................................................................................................................................................... 23 
8.7.2 
Overall survival ........................................................................................................................................................................................ 24 
8.7.3 
Tumor control rate at 3, 6, 9, 12 months ...................................................................................................................................... 24 
8.7.4 
Remedial treatments ............................................................................................................................................................................. 24 
8.8 
Exploratory analyses .................................................................................................................................................................................. 24 
9 
Quality Assurance .................................................................................................................................................................................................... 24 
9.1 
Input ................................................................................................................................................................................................................... 24 
9.2 
Monitoring of the base ............................................................................................................................................................................... 24 
9.2.1 
Test analyses ............................................................................................................................................................................................. 24 
9.2.2 
Forecast on the analyses ..................................................................................................................................................................... 25 
9.2.3 
Dual programming ................................................................................................................................................................................. 25 
10 
Bibliographic references ................................................................................................................................................................................ 26 
 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 6of 26 
2 Abbreviations and definitions  
 
ALAT : 
 Alanine transaminases 
ASAT :  
 Aspartate transaminases 
HCC : 
 
HepatoCellular Carninoma 
VEF : 
 
Ventricular Ejection Fraction 
LSN :  
 
Upper Normal Limit 
WHO :   
World Health Organization 
RECISTm : 
RECIST Modified 
TACE: Transarterial  
chemoembolization 
TSH 
 
Thyroid Stimulin 
AFP 
 
Alpha Foeto Protein 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 7of 26 
3 Introduction  
3.1 Rationale for the study  
Transarterial chemoembolization (TACE) is a commonly used technique in the treatment of patients with isolated or 
small hepatocellular carcinoma not amenable to surgical resection (intermediate stage), with an advantage in terms of 
survival time over symptomatic treatments. This approach is justified by the fact that HCC is a highly vascularized 
tumor, with a major role of angiogenesis. 
Sunitinib is a novel multi-targeted tyrosine kinase inhibitor with both angiogenesis inhibition and direct anti-tumor 
properties. The addition of sunitinib may therefore reduce the risk of tumor recurrence in HCC patients treated with 
TACE. Nevertheless, some angiogenesis inhibitors are associated with an increased risk of bleeding complications, 
which may raise concerns about their use in patients with HCC. Thus, it is important to evaluate the safety of the 
sunitinib-chimioembolization combination, and compare it to chemoembolization alone (chemoembolization plus 
placebo). 
 
3.2 Objectives  
 
3.2.1 Pilot phase  
To assess the rate of bleeding and/or severe liver failure within one week of chemoembolization sessions in patients 
receiving sunitinib. 
 
3.2.2 Phase II  
 
3.2.2.1 
Main objective 
Assess the rate of bleeding and/or severe liver failure within one week of chemoembolization sessions. 
 
3.2.2.2 
Secondary objectives 
The secondary objectives of the phase II study are to evaluate: 
 tumor control rate* at 3, 6, 9 months after the last TACE ; 
 Progression-free survival  
 Overall survival*; 
 Tolerance*; 
 Quality of life*. 
*These objectives are common objectives with la phase III 
 
3.2.3 Phase III  
 
3.2.3.1 
Main objective 
Compare overall survival in the sunitinib and placebo groups. 
 
3.2.3.2 
Secondary objectives 
 The common criteria between la Phase IIand la Phase IIIare described in Section 3.2.2.2 (marked with an *). 
 Disease-free survival 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 8of 26 
 
4 Study population  
4.1 Inclusion criteria  
 
  Histologically proven hepatocellular carcinoma (HCC) or liver tumor meeting the Barcelona criteria. 
 Child-Pugh A score. 
 Tumor not accessible to surgical resection or radiofrequency. 
 Tumor undergoing transarterial chemoembolization (TACE). 
 Age ≥ 18 years. 
 Performance Index (WHO) ≤ 2. 
 A previous radiofrequency treatment is allowed if it took place more than 3 months before. 
 Satisfactory hematologic, renal, and hepatic function (neutrophils ≥ 1.5 x109/L, platelets ≥ 70 x 109/L, hemoglobin ≥ 
10 g/dL, prothrombin time ≥ 50%, creatinine level ≤ 120 μmol/L, bilirubin level (≤ 15 mg/L), alanine and aspartate 
transaminases (ALAT and ASAT) ≤4 times the upper limit of normal (ULN), alkaline phosphatases ≤ 5 times ULN, 
and fibrinogen level ≥1.5 g/L. 
 Signed written consent. 
 
4.2 Non-inclusion criteria  
 History of chemoembolization. 
 Portal thrombosis. 
 Extra-hepatic metastases including brain metastases. 
 Uncontrolled hypertension or requiring at least 2 classes of antihypertensive agents (uncontrolled hypertension 
(systolic pressure > 160 160 mmdiastolic pressure > 100 mm100 mmwell-conducted antihypertensive treatment) 
 Uncontrolled heart failure (left LVEF < 50%) or coronary artery disease, recent myocardial infarction (less than one 
year), QT interval prolongation > 450 ms in men and > 470 ms in women. 
 Concomitant disease or severe uncontrolled clinical situation. 
 Uncontrolled severe infection. 
 Patient treated with a CYP3A4 inhibitor within 7 days prior to treatment. 
 Patient treated with a CYP3A4 potentiator within 12 days. 
 Patients requiring long-term anticoagulant treatment. 
 Pregnancy or breastfeeding. 
 Lack of effective contraception (for men or women of childbearing age). 
 Prior treatment with sunitinib, sorafenib or other angiogenesis inhibitors. 
 History of other cancers excluding cancers known to be cured for more than 5 years (in this case histological 
evidence of HCC is required), or basal cell skin tumors or cervical cancer in situ adequately treated with curative 
intent. 
 Patient who for psychological, social, family or geographical reasons could not be followed regularly. 
 Concurrent participation of the patient in another experiment. 
 Patient with a contraindication to vascular occlusion procedures. 
o 
Vascular anatomy that precludes catheterization or injection of emboli.  
o 
Presence or likely onset of vasospasm. 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 9of 26 
o 
Presence or probable occurrence of a hemorrhage. 
o 
Presence of severe atheromatous damage. 
o 
Presence of feeder arteries smaller than the distal branches from which they emerge. 
o 
Presence of extra to intracranial anastomoses or patent shunts. 
o 
Presence of collateral vascular pathways potentially endangering normal territories during embolization. 
o 
Presence of terminal arteries leading directly to the cranial nerves. 
o 
Presence of arteries irrigating the lesion not wide enough to receive the microbeads. 
o 
Peripheral vascular resistance of the feeding arteries excluding the passage of microbeads into the lesion. 
o 
Do not use microbeads in the following applications:  
 
embolization of non-malignant tumors; 
 
embolization of large-diameter arteriovenous shunts (i.e., where the blood does not pass through the 
arterial/capillary/venous transition but goes directly from the artery to the vein); 
 
any vascular system where the microbead embolic agent is CN00103.2 likely to pass directly into the 
internal carotid artery or other non-target territory. 
 
5 Experimental design  
5.1 Scheme of the study  
The study is a phase II-III, parallel-group, multicenter study.  
 
5.2 Study arms  
 
Arm A: chemoembolization plus sunitinib. 
 
Arm B: chemoembolization plus placebo. 
 
5.3 Randomization and blinding  
 
The study is double-blind for sunitinib or placebo (neither the doctor nor the patient knows which treatment is being 
given). 
Stratification by minimization is performed, starting in la phase II, on: 
 diameter of the primary tumor (< 5 versus ≥ 5 5 cm 
 the presence of one nodule versus the presence of more than one nodule; 
 the investigating center. 
 
When a stratified analysis will be performed, it will be performed only according to the diameter of the main tumor and 
the number of nodules, according to 4 groups:  
 
diameter < 5 cm and a nodule,  
 
diameter ≥ 5 cmand a nodule,  
 
diameter < 5 cm and more than one nodule, 
 
  diameter ≥ 5 cmand more than one nodule. 
 
5.4 Chronological sequence  
The chronological sequence for a patient is described in the following graph: 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 10of 26 
 
The study design is as follows: 
 
Pre-inclusion assessment 1 
within 21 days of starting treatment 
 imaging, electrocardiogram 
Pre-inclusion assessment 2 
within 14 days prior to inclusion 
clinical, biological and quality of life examination 
Randomization 
Start of treatment 
sunitinib or placebo for 1 year, 4 of 6 weeks 
1 to 3 chemoembolizations 
Follow-up 
clinical and biological examination before each cycle of 
sunitinib/placebo, and then every 3 to 6 months for up to 1 to 
2 years 
TACE imaging: 1 month after each TACE 
post-TACE imaging: 3 months after imaging of la dernière  
TACE, then every 3 months for 2 years, then every 6 months 
until progression 
l
3
h f
1
Week 
MRI 
Sunitinib or placebo 
Chemoembolization 
1 
0 
4 
6 
10 
12 
16 
18 
22 
24 
28 
7-14 
15-18 
28 days 
30 
36 
40 
42 
34 
46 
52 
48 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 11of 26 
5.5 Justification of the number of subjects needed  
5.5.1 Pilot phase  
A non-randomized pilot phase was performed on 10 chemoembolizations performed with sunitinib (regardless of the 
number of patients included). An independent committee ruled on the safety data for continuation or not in phase II 
and a specific report was sent to the ANSM for information. 
 
5.5.2 Phase II  
The assumptions for calculating the number of subjects needed are: 
 H0: A rate of bleeding and/or severe liver failure occurring within one week of the chemoembolization session of 
30% is considered unacceptable; 
 
H1: A rate of bleeding and/or severe liver failure occurring in the week following the chemoembolization session of 
less than 30% is necessary to consider the treatment non-toxic; a rate of 15% is expected. 
 
To achieve 85% power (assuming a 15% rate of severe bleeding and/or liver failure), with a two-sided first-step risk of 
13.3%, 35 patients per arm are required (in a one-step Fleming design).  
 
5.5.3 Phase III  
The assumptions for calculating the number of subjects needed are: 
 H0: Overall survival in the sunitinib arm is not different from that in the placebo arm; expected 2-year overall 
survival in the placebo arm is 40%; 
 
H1: Overall survival in the sunitinib arm is different from that in the placebo arm; a 20% difference at 2 years in favor 
of sunitinib is expected between the two arms (corresponding to a hazard ratio of 0.56). 
 
With a two-sided 5% risk of first-species error, 130 events will be required to achieve 90% power under the previously 
stated assumption H1. Assuming uniform patient inclusion over 2 years, and allowing for a 3-year follow-up after the last 
inclusion, the number of patients will be 180. To account for a 5% rate of patient attrition, a total of 190 patients will 
need to be included. 
 
The 70 patients already included in la phase IIwill be retained for la Phase III, leaving 120 patients to be included. 
 
An interim analysis of the primary endpoint is planned at death 65. This may provide early evidence of superiority of 
the sunitinib arm. A method of expenditure of the first kind risk (DeMets, 1994), will be used to calculate the nominal 
values of "p"; this method will make it possible to adjust these threshold values if the intermediate and final analyses 
are not carried out exactly at the right numbers of events. The expenditure function chosen is an O'Brien function. 
 
Calculations were performed using the R software and the gsDesign library. 
 
Analysis 
Number of events 
Nominal value of p 
Power to the analysis under hypothesis 
H1 
Inter 1 analysis 
65 
0.0054 
0.3156 
Final analysis 
130 
0.0439 
0.5811 
These values will be adjusted according to the number of actual events at the time of the analyses. 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 12of 26 
 
5.6 Stages of the test  
  
5.6.1 Pilot phase  
 
During the pilot phase, 10 chemoembolizations (8 patients included) were performed with sunitinib. Of these 10 
chemoembolizations, less than 4 toxicities were retained for the primary endpoint (see protocol, Amendment 3), the 
trial continued in randomized phase II. Patients included in the pilot phase are not included in la phase II. 
The pilot phase was the subject of a specific report which was sent to the ANSM for information 
 
5.6.2 Phase II  
 
At the end of the 35 patients/arm inclusions of the phase II: 
 if the number of patients with severe toxicity (liver failure, bleeding) in the sunitinib arm is less than or equal to 7, 
the trial will be continued in phase III; 
 if the number of patients with severe toxicity (liver failure, bleeding) in the sunitinib arm is greater than or equal to 
8, the number of complications (liver failure, bleeding) in the placebo arm should also be considered: 
o 
if the complication rate (liver failure, bleeding) in the placebo arm is greater than or equal to 8, an independent 
committee of experts will have to judge the appropriateness of continuing the trial in phase III since the 
toxicity in the sunitinib arm may be related to the "background noise" of the toxicity of chemoembolization 
alone; 
o 
if the complication rate (liver failure, bleeding) in the placebo arm is less than or equal to 7, the independent 
expert committee will have to judge whether to stop the trial. 
The decision rules will apply only to the sunitinib/chimio/embolization arm; the placebo/chimio/embolization arm 
will be maintained in all cases for la phase III, if it occurs, with this arm serving as the control arm. 
 
5.6.3 Phase III  
This step will only be performed if the trial has not been stopped at the end of la Phase II. 
 
5.6.3.1 
Intermediate Analysis 
An interim analysis at 65 deaths is planned. This may provide early evidence of superiority of the sunitinib arm. 
 
5.6.3.2 
Final Analysis 
The final analysis will be done at approximately the 130th event (death), after inclusion of all 180 patients and a 
minimum follow-up for the last included patient of 3 years. 
 
5.6.4 Transition between steps  
A suspension of inclusions is planned between la phase IIand la phase IIIresults of la phase II.analyzed. 
Inclusions between the 2 stages of la phase IIIwill not be suspended for the time of the interim statistical analysis. 
 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 13of 26 
5.7 Judgement criteria for la phase II 
 
5.7.1 Main criterion  
 
The primary endpoint of la phase IIis the rate of bleeding and/or severe liver failure within one week of 
chemoembolization sessions (TACE), over all chemoembolization sessions for a patient. The precise definition of 
bleeding and liver failure to be retained is given in the protocol with amendment 3 : 
 Severe liver failure is defined by the occurrence of at least one of the following complications: 
o 
encephalopathy; 
o 
clinical ascites; in case of clinical ascites already present at inclusion and persistence of ascites at the time of 
evaluation for liver failure, an independent committee will have to judge from the case report whether ascites 
has evolved since inclusion and should be counted as an event in the definition of the primary endpoint or not; 
if clinical ascites is present at inclusion, it will be graded according to NCI-CTC v4 and reported through a CID; 
during follow-up, clinical encephalopathy and ascites will be graded according to NCI-CTC v4 and will appear 
on form 3.1 of the case report form in the other toxicities tab  
o 
bilirubin levels greater than or equal to 50 mg/L (85.5 µmol/L); 
o 
TP ≤ 40%; 
 bleeding : (definition p14 of the protocol) 
 
These events count as primary endpoints if they occur within 1 week of chemoembolization, i.e., between D0 and D7 
inclusive.  
In the case of an event counting for the primary endpoint after D7, it will be recorded in the case report form 3.1 in the 
column after D5 only if the investigator considers that this event is related to the TACE, and the day must then be filled 
in. For events recorded after D7 in the case report form, an independent committee will meet to decide whether or not 
this event counts in the definition of the primary endpoint. 
 
Patients who did not receive their oral treatment will still be counted in the primary endpoint; however, a very precise 
description of the reason for not taking the oral treatment will be made. 
 
Patients who did not have chemoembolization will be excluded from this analysis (modified ITT). 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 14of 26 
5.7.2 Secondary efficacy criteria  
 
5.7.2.1 
RECISTm definition of treatment response  
 
This definition will be used for progression-free survival, disease-free survival and tumor control rate. 
 
Progression of target and non-target lesions will always be measured relative to the inclusion MRI. 
 
 
For evaluations following TACE: treatment response will be assessed only for lesions (target and non-target) 
treated during TACE according to RECISTm criteria. Progression is defined as either a treated lesion that 
progresses or the appearance of a new hepatic or extrahepatic lesion. Progression related to untreated lesions 
will not be taken into account with the exception of one case: progression of an untreated lesion that prevents 
further treatment with TACE (this information will be reported manually by the CRAs).  
 
 
For follow-up evaluations (after TACE is completed), response to treatment will be assessed in relation to all 
lesions, whether treated during TACE or not. 
 
5.7.2.2 
Tumor control rates at 3, 6, 9, 12 months  
 
It is defined as the percentage of patients in Complete Response or Partial Response or in stability at the given time.  
Patients for whom tumor assessments would not allow classification will be reviewed by a clinician.  
Patients who died will be considered uncontrolled.  
 
 
5.7.2.3 
Progression-free survival (if Phase III not done) 
 
It is defined as the time interval between the date of randomization and the date of first progression or death 
(regardless of cause). Progression is defined as progression of lesions according to RECISTm criteria, the appearance of 
a new liver lesion or an extra-hepatic lesion.  
Since progress can be documented on the in-process assessments or the monitoring form, the definition in 5.7.2 
applies. The dates to be considered are the dates of the CTs. 
Live patients without progression will be censored at the date of the last informative examination or at the date of last 
news if a surveillance sheet is provided not documenting progression or at the point date. 
  
Clinical progressions will not be taken into account, based on the principle that for this type of pathology, a progression 
in imaging is necessarily associated with a clinical progression. 
 
5.7.2.4 
Disease-free survival (if Phase III not done) 
It is defined as the time interval between the date of randomization and the date of progression, or the date of a second 
cancer, or death (from any cause). 
Since progression or second cancer may be documented on in-process assessments or the surveillance form, the 
definition in Section 5.7.2 applies. The dates to be considered are the dates of the CT scans. 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 15of 26 
 
Living patients without progression or second cancers will be censored at the date of the last informative review or at 
the date of last news if a surveillance form is provided that does not document progression or second cancers at the 
point date. 
 
5.7.2.5 
Overall survival (if Phase III not done) 
 
Overall survival is defined as the time from the date of randomization to the date of death (from any cause).  
Patients lost to follow-up or alive at the time of analysis will be censored at the last news date or the point date. 
This time will also be used to calculate the median follow-up time. 
 
 
5.7.3 Secondary tolerability criteria  
 
Tolerance to treatment will be assessed by: 
 
chemo-embolization  
 
duration of sunitinib/placebo treatment, number of tablets administered, dose reductions, treatment 
discontinuations and their causes ; 
The duration of the treatment (converted into months) will be calculated by adding the cycle durations: (cycle end 
date - cycle start date) + 1 
 
Toxicities, collected at the end of each treatment cycle, will be described according to the NCI-CTC version 4.0 
criteria and their grade;  
 
the time to onset of grade 3-4 toxicity will be assessed;  
It is defined as the time interval between the date of randomization and the date of first grade 3-4 toxicity 
estimated by the cycle start date + 2 weeks. Patients without Grade 3-4 toxicity at the earlier of the point or last 
date will be censored at the point or last date; 
 
 
The description of SAEs (analysis of pharmacovigilance) 
 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 16of 26 
5.7.4 Quality of life  
 
It will be assessed using the QLQ-C30 (version 3) questionnaire for cancer and the FACT-HEP questionnaire specific to 
HCC. 
Internal validation of the 30-item QLQ-C30 questionnaire identified 15 dimensions and calculated 15 scores: 5 
functional ability scores (physical ability, ability to work or perform any household task, cognitive ability, emotional 
state, social state), a global quality of life score, a financial problems score, and 8 symptom scores (fatigue, 
nausea/vomiting, pain, dyspnea, sleep disturbance, loss of appetite, constipation, diarrhea). 
The FACT-HEP (version 4) is composed of the 27 items of the FACT-G evaluating 4 dimensions (physical, social and 
family, emotional, functional) and 18 specific items (HepCS) allowing to evaluate the specific symptoms of HCC and the 
side effects of its management.  Three scores will be calculated: the FACT-Hep TOI, taking into account the physical, 
functional, and specific symptoms of HCC; the FACT-G Total score, taking into account the physical, functional, 
emotional, social, and family dimensions; and the FACT-Hep Total score, taking into account all dimensions.  
 
These different scores will be described at inclusion and during follow-up. 
 
For the QLQ-C30 Global Health, Physical Ability, Cognitive Ability, and Fatigue scores, and the FACT-Hep TOI, FACT-G 
Total score, and FACT-Hep Total score, longitudinal progression will be studied, with the percentage of symptomatic 
progression defined as the percentage of patients who had a score decrease of at least 5 points from inclusion without 
subsequent improvement (Osoba, 1998). Patients lost to follow-up without a decrease in score of at least 5 points from 
inclusion will be considered without symptomatic progression. For the overall health score, FACT-Hep TOI, FACT-G 
Total score, and FACT-Hep Total score, time to definite deterioration, defined as the time interval between the date of 
randomization and the date of a score decrease of more than 5 points (from the inclusion score) without subsequent 
improvement of more than 5 points, will also be studied. Patients alive or deceased without a score decrease of more 
than 5 points will be censored at the point date or the date of last news if earlier. For these last three criteria, patients 
who did not have a quality of life questionnaire at inclusion will be excluded (their number and percentage will be 
given). 
 
5.7.5 Other criteria  
 
 
The evolution of AFP rates over time. 
 
 
5.7.6 Exploratory analyses  
Not Applicable 
 
5.7.7 Management of criteria between la phase II and la phase III 
The common criteria for la phase IIand la phase III(Section 5.7.2 and 5.7.4.) will be reviewed at the end of la phase III, 
or at the end of la phase II if la phase IIIis not performed. If these criteria are only assessed in la phase II, there will be 
no comparison made between arms.  
In order not to introduce operational bias, all criteria can be described in la phase II(common or not to la  phase III), but 
the common criteria must remain confidential. 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 17of 26 
In all cases, a description of the TACE treatment and a description of the catch-up treatments will be made. 
 
6 Study populations  
The study focuses on patients with hepatocellular carcinoma. 
 
6.1 Definition of Analysis Populations  
  
6.1.1 Intent-to-treat (ITT) population  
The intention-to-treat population is defined as all patients included in the study, regardless of eligibility criteria and 
amount of treatment taken.  
The description of the population at inclusion will be based on this population.  
 
 
6.1.2 Modified intention-to-treat population (mITT)  
  The modified IIT population is defined as all patients included in the study, regardless of eligibility criteria and amount 
of treatment taken who had at least one chemoembolization. 
 
The primary endpoint will be assessed in this population. 
 
6.1.3 Population for Tolerance Analysis (SP)  
 
It is defined as la population ITTthat received at least one day of treatment with sunitinib/placebo (no constraints on 
chemoembolization). 
The analysis of secondary efficacy endpoints will be done in this population (depending on the randomization arm) 
Patients who did not take treatment will be described by individual data.  
 
The analyses for tolerability will be performed according to the actual treatment received. Thus, if despite 
randomization, a patient received placebo instead of sunitinib from baseline to the end of treatment, this patient will be 
analyzed for safety in the placebo arm (and vice versa).  
However, if a change of treatment (sunitinib/placebo) occurs during treatment, the patient will be analyzed in the 
group corresponding to the first treatment he/she received.  
 
6.2 Definition of analysis subgroups  
 Not applicable 
 
7 Recruitment and analysis planning  
7.1 Recruiting  
The expected rate of inclusion is 7 to 8 patients per month. 
 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 18of 26 
7.2 Analysis planning  
7.2.1 Pilot phase  
The analysis of the pilot phase was conducted in April 2011. 
 
7.2.2 Phase II  
The cut-off date for the la phase IIanalysis will be one week after the completion of the last chemoembolization of the 
last included la phase II.patient. 
 
7.2.3 Phase III  
7.2.3.1 
Intermediate Analysis 
An interim analysis is planned during la phase III. Cetteanalysis is planned at the midpoint of the number of events, i.e. 
at 65 deaths. Based on the assumptions made, this analysis could take place 28 months after the inclusion of the first 
patient. 
 
7.2.3.2 
Final Analysis 
The point date for the final analysis is the 130th event. 
 
7.2.3.3 
Late analysis after Phase III 
A final analysis will be performed to account for overall survival at 4 years. The time point is 4 years after inclusion of 
the last patient. 
 
7.2.4 Transition from Phase II to Phase III  
In case of transition to phase III, only results concerning the primary endpoint, safety data, and control rates during 
each TACE will be reported for la phase II 
 
7.3 Adjustments  
Adjustments may be made to this analysis plan in case of amendments to the protocol, or if phenomena not initially 
foreseen require statistical adaptations. In all cases, these modifications must be made before the database is frozen. 
 
8 Statistical methods  
Statistical analyses will be performed by the CRGA. 
 
8.1 General information on statistical analysis methods  
8.1.1 Software  
Statistical analyses will be performed with SAS version 9 or later and STATA version 10 or later. Some graphs can be 
made with R software version 2.11or later. 
 
8.1.2 Agreements concerning dates and durations  
Time since randomization will be defined as the time since the day of randomization, with the day of randomization 
considered day 1. 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 19of 26 
Time since initiation of treatment will be defined as the time since the first day of sunitinib/placebo, which is 
considered Day 1. 
Therefore, the durations will be calculated using the following rule, for example, for the time between death and 
randomization: day of death - day of randomization + 1. 
The day before the randomization day (resp. the day before the treatment day) will be considered as day -1 (day 0 does 
not exist). 
 
The date of last news will be the date mentioned on the monitoring form, and in case of missing information, the date of 
the last examination performed or the last treatment. 
 
The following conversion rules will be used to convert the number of days into months or years: 1 month = 30.4375 
days; 1 year = 365.25 days. 
 
8.1.3 Outlier Conventions  
Outliers will be subject to a confirmation request to the investigating center. In case of confirmation, their value will not 
be modified and will be taken into account as it is during the analysis. 
 
8.1.4 Missing Data Conventions  
Except in the cases specified, missing data will not be replaced. 
In case of partially missing data concerning dates, the following rule will be applied: when the day is missing, the day 
will be considered as the 15th of the month. 
 
8.1.5 Definition of the baseline  
Baseline measurements will be the last measurements taken before la randomisation. Encase of missing data, the last 
measurement taken before the first treatment will be used. 
 
8.1.6 Statistics  
The confidence intervals provided will be two-sided 95% confidence intervals. 
 
Quantitative data will be described by treatment group and for the entire population, using the following descriptive 
statistics: number of patients, number of missing values, mean, standard deviation, median, first and third quartile, and 
minimum and maximum. These statistics will be considered as the usual statistics for the analysis of quantitative 
variables. Quantitative variables may be categorized using their median or a cut-off known from the medical literature. 
 
Categorical variables will be summarized by treatment group and for the entire population, using the following 
descriptive statistics: frequencies and percentages for each level of the variable and missing values (missing values will 
be included in the denominator of the frequency calculation). These statistics will be considered the usual statistics for 
the analysis of categorical variables. 
When necessary, confidence intervals for the proportions will be calculated from the exact binomial distribution. 
 
The estimation of survival for the censored variables will be done by the Kaplan Meier method (Kaplan and Meier, 
1958). This will be described by the median and rates calculated at different times. The 95% confidence intervals will 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 20of 26 
be provided. Confidence intervals for the rates will be constructed from the Greenwood variance calculated using the 
log-log transformation. For the median confidence interval, the upper bound will be defined as the smallest time for 
which the upper bound of the associated survival rate confidence interval, calculated from the Greenwood method, is 
less than or equal to 50%. Similarly, the lower bound will be the smallest time whose lower bound of the confidence 
interval of the associated survival rate is less than or equal to 50%.  
 
The estimation of the treatment-related hazard ratios will be carried out using a stratified Cox model (Cox, 1984); the 
proportionality hypothesis of the rates will be tested using the graphical representation and the test based on 
Schöenfeld residuals (Grambsch, 1994); the linearity of the effect of the continuous variables on the risk will be 
assessed from the graphical representation of the martingale residuals.  
Confidence intervals for the coefficient estimates of the Cox models will be calculated using the Wald method.  
 
The median follow-up time will be calculated using the reverse Kaplan-Meier method (Shemper, 1996). 
 
Unless otherwise stated, results will be described separately for each treatment arm; therefore, when "total 
number of patients" is specified, the total number of patients in the arm should be considered. 
 
8.2 Patient characteristics at inclusion  
Patient characteristics at inclusion will be described by treatment group and on the total population. 
8.2.1 Patient Eligibility  
A description of the stratification factors will be performed to ensure proper distribution of prognostic factors, but no 
statistical testing will be performed : 
 diameter of the main tumor (< 5cm vs. ≥ 5cm) 
 number of nodules (1 vs > 1) 
 inclusion center (Number of patients included per center) 
 
Similarly, a description of the inclusion and non-inclusion criteria will be provided 
8.2.2 Demographic characteristics  
The following characteristics at inclusion will be described using descriptive statistics (no statistical tests): 
 
Age (years); 
 
Gender  
 
 
8.2.3 Clinical characteristics  
The following characteristics at inclusion will be described using descriptive statistics (no statistical tests): 
 
 
weight (kg) ; 
 
blood pressure (mmHg); if more than one SBP or DBP is indicated then the values will be averaged  
 
General condition WHO (0, 1, or 2)  
 
8.2.4 Biological characteristics  
The following characteristics at inclusion will be described using descriptive statistics (no statistical tests): 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 21of 26 
 
TSH (mU/l); 
 
AFP (µg/l). 
 
8.2.5  Characteristics related to the disease  
The following characteristics at inclusion will be described using descriptive statistics (no statistical tests): 
 
CHILD-PUGH score (5 or 6); 
 
HCC involvement: unilobar or bilobar; 
 
number of hepatic nodules; 
 
diagnostic method: histological or according to the Barcelona criteria; 
 
Associated cirrhosis: yes or no; if yes, etiology: alcohol, hemochromatosis, HBV, HCV or other (A listing of other 
etiologies will be edited). 
 
8.3 Follow-up characteristics (if Phase III not done)  
The median follow-up time and its 95% confidence interval will be calculated in months for each treatment arm using 
the Inverse Kaplan-Meier method. 
 


 
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8.4 Evaluation of the primary endpoint of la phase II 
For the primary endpoint analysis, the number of patients with at least one bleed and/or liver failure, the percentage of 
patients, and the 95% confidence interval will be calculated by treatment group: 
 
Similarly, a more precise analysis will be performed describing, across all TACEs and by treatment group: 
 
the number of TACEs during which severe bleeding was observed; 
 
the number of TACEs during which at least one liver failure was noted; 
 
the number of TACEs during which at least one clinical ascites was noted ; 
 
the number of TACEs during which at least one encephalopathy was reported; 
 
The number of TACEs during which at least one bilirubin assay ≥ 50 mg/L was reported; 
 
the number of TACEs during which at least one decrease in prothrombin time of more than 40% from baseline 
was reported. 
 
8.5 Evaluation of effectiveness  
(See Section 8.7) 
 
8.5.1 Description of chemo-embolization  
The description of chemoembolization will be done by treatment group. 
 
8.5.1.1 
Description of the treatment 
For each TACE (1, 2, 3 or more) will be described: 
 
the number of patients who received this TACE; 
 
the percentage of patients (from TACE) with all target lesions treated; ; 
 
the percentage of non-target lesions treated ; 
 
the treated area: total liver, lobar, sectorial, segmental, sub-segmental. 
 
A listing of reasons why CEAT was not done will be provided per patient 
 
 
8.5.1.2 
Response to treatment during treatment 
For each of the TACE numbers (1, 2, 3 or more) will be described: 
 
The overall response to TACE for treated target lesions and/or for treated non-target lesions; 
 
the number of TACE followed by at least one new liver injury 
 
The number of TACE followed by at least one new extrahepatic lesion; 
 
The number of TACEs with the development of a second cancer, and the number of TACEs requiring additional 
TACE), 
 
8.5.1.3 
Toxicities during the days following HEC 
 
A description of the toxicities reported on the HEC charts will be made according to grade and treatment arm. 
 
 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 23of 26 
8.6 Assessment of tolerance  
The assessment of tolerability will be described by treatment group. 
 
8.6.1.1 
Treatment administration 
 
The duration of treatment with sunitinib/placebo described using standard statistics 
 
The percentage of patients with at least one dose reduction will be calculated.  
 
For all treatments administered (at least one treatment), the complete or incomplete administration will be 
described as well as the causes if applicable (no reduction, toxicity, therapeutic pause, personal convenience of 
the patient, other; a listing of other causes will be provided)   
 
In case of premature discontinuation of treatment (sunitinib or placebo), the causes of discontinuation will be 
described; a listing of other causes will be provided.  
 
8.6.1.2 
Serious adverse events 
 
A document will be produced by Pharmacovigilance. 
 
8.6.1.3 
Toxicity analysis 
 
Toxicities will be described by treatment arm according to NCI-CTC version 4.0 criteria: 
 
by grade and type at the end of cycles during TACE treatment, over all cycles and during follow-up; 
 
Patients with at least one grade 3-4 toxicity of any type (during cycles including TACE and over all cycles), with 
95% confidence interval; 
 
Time to Grade 3-4 toxicity will be (Toxicities collected during HEC and cycles) plotted with 95% confidence 
intervals and rates at different times (time to be adapted according to data) and their 95% confidence 
intervals. 
8.6.2 Quality of life  
 
Each of the dimensions will be described at inclusion and at the end of follow-up; in addition, for each dimension, 
the difference between the score at inclusion and the score at the last visit will be described.  
 
The time without definite deterioration for each of these scores will be described by a survival curve with 95% 
confidence intervals.  
 
 
8.6.3 Other criteria  
 
The evolution of AFP rates will be represented graphically. 
 
8.7 Criteria common to la Phase II and la Phase III 
These endpoints will only be studied in la Phase II if la Phase III not occur.  Comparisons between arms will only be 
made in Phase III.  
 
8.7.1 Progression-free survival  
Progression-free survival will be compared between the 2 treatment groups (Phase III) or described (Phase II) using 
the stratified logrank test and using the simple logrank test. 
The estimation of treatment-related hazard ratios will be performed using a stratified Cox model (Cox, 1984); 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 24of 26 
 
 
8.7.2 Overall survival  
Overall survival will be compared between the 2 treatment groups (Phase III) or described (Phase II) using the 
stratified logrank test and using the simple logrank test. 
The estimation of treatment-related hazard ratios will be performed using a stratified Cox model (Cox, 1984); 
 
8.7.3 Tumor control rates at 3, 6, 9, 12 months  
 
The percentages will be from the Kaplan-Meier analysis as well as the confidence intervals. 
 
8.7.4 Remedial treatments  
 
The number of patients who had at least one salvage treatment, and the type of salvage treatment: line 1 treatment, 
line 2 treatment, line 3 treatment, radiotherapy, radiofrequency, surgery, other. 
 
For each patient who had a 1st line, the average duration of the line will be calculated, and a listing of treatments will 
be provided. The description of the 2nd and 3rd line will be done in the same way. 
 
For each patient who had at least one radiation treatment, the number of radiation treatments will be described, 
and the average duration of radiation treatments will be calculated. 
 
For each of the patients who had radiofrequency treatment, the number of sessions will be described  
 
For patients who had surgery, the type of resection will be described. The number of patients who had a transplant 
will also be calculated. 
 
For each patient who has had other remedial treatment, a listing describing the treatments will be provided, and 
the average duration of treatment will be calculated. 
 
8.8 Exploratory analyses  
Not Applicable 
 
9 Quality Assurance  
9.1 Input  
The input and consistency check are described in the data management plan. 
 
9.2 Monitoring of the base  
 
9.2.1 Test analyses  
At several times during the study, test analyses will be performed. All statistical analyses will be performed on the 
database extracted during the test analysis. The purpose of these analyses is to: 
 anticipate the writing of statistical analysis programs; 
 highlight inconsistencies in patient records not identified by the data management rules; 
 Identify problems not considered when writing the protocol and statistical analysis plan. 
Problems encountered on the patient charts will be discussed with a clinician; if no answer is provided by the clinician, 
they will eventually be the subject of a request for additional information. 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 25of 26 
Identified problems requiring modification or clarification of the protocol or analysis plan will be discussed with the 
coordinator.  
 
 
9.2.2 Forecast on analysis  
 
 
Phase 
Period 
Action 
Objectives 
Phase II 
As soon as possible  Test analysis 
 main criterion 
 all study criteria (phase II and III, 
including quality of life) 
 
35 patients per 
arm + 1 week after 
the latest TACE of 
last patient on 
treatment 
Pre-gel base 
Test analysis for base gel 
 main criterion 
 all the criteria of the study (phase II and 
III, including quality of life),  
 basic freeze decision 
 
 
Base gel 
Phase II analysis 
 main criterion 
 tolerance criteria 
 
9.2.3 Double programming  
 
At least a double programming of the main criterion will be done by two different statisticians. Other criteria may be 
double-programmed (at the discretion of the statistician). The results will be compared, and errors discussed and 
corrected. 
 
 
 


 
Statistical Analysis Plan - Prodige 16 (Phase II)- Final -February 2015 Page 26of 26 
 
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