Ignite Creation Date:
2024-05-06 @ 3:56 PM
Last Modification Date:
2024-10-26 @ 1:59 PM
Study NCT ID:
NCT04803019
Status:
UNKNOWN
Last Update Posted:
2021-03-19
First Post:
2021-03-15
Brief Title:
Transarterial Embolization Alone Versus Drug-Eluting Beads Chemoembolization for Hepatocellular Carcinoma
Sponsor:
IRCCS Azienda Ospedaliero-Universitaria di Bologna
Organization:
IRCCS Azienda Ospedaliero-Universitaria di Bologna
Study Overview
Official Title:
Transarterial Embolization Alone Versus Drug-Eluting Beads Chemoembolization for Hepatocellular Carcinoma A Randomized Controlled Trial
Status:
UNKNOWN
Status Verified Date:
2021-03
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
RAD-18-TAcE
Brief Summary:
Developed in Japan in the 1980s TACE became the most frequent treatment for unresectable hepatocellular carcinoma HCC in patients with preserved hepatic function after 2002 when two radiochemotherapies RCTs showed survival benefits for HCC patients who underwent conventional Lipiodol-based TACE cTACE Nowadays nearly half of HCC patients undergo this procedure during their clinical history In the last ten years cTACE has been challenged by an alternative procedure drug-eluting beads-TACE DEB-TACE after the introduction of calibrated embolizing microspheres loaded with a chemotherapeutic agent DEB-TACE is considered to be less toxic and better standardized than cTACE with reported no differences in patient survival Since 2006 DEB-TACE has become the standard in many centers worldwide Though the need of adding doxorubicin to small beads embolization alone TAE remains unsettled Though cTACEDEB-TACE and TAE have been compared in several RCTs no study demonstrated a clear survival benefit associated with the former
Our study aims to compare first-line DEB-TACE and TAE on a random sample of HCC with the hypothesis that the addition of drug to embolization with small size beads is not associated with a survival benefit when compared to embolization alone performed with tiny calibrated microspheres HCC is considered a chemo-resistant tumor and to date there is no clear evidence of benefits in associating anticancer agents to TAE On the other hand the optimal size of embolic agents has still to be defined A comparative evaluation of TACE and TAE is essential for two additional reasons a it is still unclear whether side effects following embolization procedures are related to the embolization itself to drug addition or both b DEB-TACE procedure is more expensive than TAE and given the current attention on cancer-related health care cost control identification of opportunities for cost savings in HCC treatments of an increasingly common cancer would be valuable
Our study aims to compare first-line DEB-TACE and TAE on a random sample of HCC with the hypothesis that the addition of drug to embolization with small size beads is not associated with a survival benefit when compared to embolization alone performed with tiny calibrated microspheres HCC is considered a chemo-resistant tumor and to date there is no clear evidence of benefits in associating anticancer agents to TAE On the other hand the optimal size of embolic agents has still to be defined A comparative evaluation of TACE and TAE is essential for two additional reasons a it is still unclear whether side effects following embolization procedures are related to the embolization itself to drug addition or both b DEB-TACE procedure is more expensive than TAE and given the current attention on cancer-related health care cost control identification of opportunities for cost savings in HCC treatments of an increasingly common cancer would be valuable
Detailed Description:
Specific Aims
Specific aim 1 Compare time to progression TTP treated with TAE and DEB-TACE in a homogeneous hepatocellular carcinoma HCC patient population
Specific aim 2 Compare
safety - severe adverse events SAE
radiologic tumor response mRECIST
overall survival OS
cost-effectiveness after the entire follow-up
Study plan
Experimental design This is an interventional with drug multicenter prospective randomized open label study
Experimental design Aim 1 The study was designed in relation to the primary endpoint as an equivalence trial between two intra-arterial HCC treatments ie DEB-TACE and TAE The TTP considered as the reference value for the DEB-TACE arm is 9 months on the basis of the results of our previous multicentric experience The study is designed as an equivalence trial on the primary endpoint The standard deviation of TTP is expected not to exceed 6 months through accurate selection criteria of included patients The equivalence limit is set to no more than 5 months between the two arms Thus using appropriate formulae each arm will be formed by 69 patients alpha005 beta080 Taking into account a 10 of drop-out the final sample size per each arm will be of 77 patients 154 total
Experimental design Aim 2
Safety Adverse events AEs and severe adverse events SAEs will be monitored and recorded AE will be assessed during and after each treatment and at all follow-up visits and graded according to the NCI Common Terminology Criteria for AE CTCAE version 30 The AEs occurring within 4 weeks after TACE will be considered as treatment related SAE incidence in both arms will be ascertained assuming a reduction of SAE from 25 after TACE to 19 after TAE 25 of reduction Such an assumption would require 607 patients per arm for being confirmed To accomplish this task the OBrien-Fleming stopping boundaries will be applied considering an analysis when 69 patients for each arm will be obtained and follow-up ended Applying stopping boundaries to this sample size a nominal p-value 0001 z-score 315 is needed to confirm the assumption If the p-value will be above this threshold even if 005 the null hypothesis will be not refused
Efficacy The response will be evaluated by CT or MRI as local per-lesion response and overall per-patient response according to mRECIST at 1 month after each TACE and thereafter every 3 months for at least 2 years
Survival Through the selection previously described we expected a standard deviation of the mean survival of no more than 10 months To design the present equivalence trial we also expected a difference in the mean survival not greater than 5 months equivalence limit between the two groups Using formulas proposed by Julious et al each arm will be formed by 69 patients alpha 005 beta 080 To obtain more robust estimate and accounting for possible dropout from the study a 10 of patients will be added to the initial sample size resulting in 77 patients for each arm
Cost-effectiveness will be assessed from a third payer perspective thus including only direct costs of the procedures and related costs hospitalization imaging etc The effectiveness will be assessed by measuring the life-expectancy Incremental cost-effectiveness ratio ICER will be used to evaluate the cost-effectiveness of one treatment over the counterpart
Study population The study involves the enrollment of a total of 154 patients 77 per randomization arm with a HCC diagnosis according to the guidelines of the American Association for the Study of the Liver Disease AASLD as in clinical practice The enrolled patients will have to meet the inclusion criteria and sign the informed consent for the participation in this study At the time of enrollment demographic clinical and radiological data will be collected as in standard clinical practice
Treatment
Treatment study In the present study only patients in the DEB-TACE arm Arm A will receive intra-arterial hepatic chemotherapy Doxorubicin Both treatment arms on the other hand will receive arterial embolization of the branches that vascularize the tumor lesions
Arm A DEB-TACE or chemoembolization with microspheres The chemotherapy used in this arm is the Doxorubicin that will be carried into the tumor by Embozene TANDEM Boston Scientific microspheres TANDEM embozene microspheres are made of non-resorbable biocompatible hydrogel microspheres subjected to precision calibration and coated with an inorganic perfluorate polymer Polyzene-F Thanks to their design the microspheres can be loaded with drugs such as doxorubicin in order to administer a local controlled and constant dose of the drug to the tumor sites affected after embolization
TANDEM embozene microspheres are available in three different sizes in 2 ml and 3 ml volumes of product and are supplied in preloaded vials and syringesThe maximum loadable amount on the hydrospheres 50 mg of Doxorubicina for ml The maximum injectable dose of Doxorubicin for each treatment is 150 mg and therefore the maximum amount of microspheres that can be used for each treatment is 3 ml The size of microspheres that will be used in this study is up to 100 25 μm
Arm B TAE or embolization with microspheres The TAE will be performed with Embozene microspheres Boston Scientific Embozene microspheres are spherical particles of hydrogel precisely calibrated biocompatible non-absorbable and coated with a perfluorinated inorganic polymer Polyzene-F This medical device is available in various sizes in this study to avoid that the particle size exceeds the one used for the treatment of arm A it will be possible to use microspheres with dimensions up to 100 μm range 75 125 μm
Embozene microspheres are offered in vials containing 1 ml of suspended product in physiological saline solution for apyrogenic sterile transport The total volume of the Embozene microspheres including the transport solution is about 7 ml To this product it is necessary to add an appropriate amount of non-ionic contrast medium in order to obtain a homogeneous suspension and with good visibility during the injection under fluoroscopy
In enrolled patients regardless of the treatment arm the possible presence of extra-hepatic shunts such as gastric and pulmonary arteries arising from the hepatic branches should be appropriately assessed As in standard radiological practice in case of intra-arterial hepatic treatments if these shunts are macroscopically evident the preventive closure of the same vessels will be evaluated using the devices that will be more suitable on a case-by-case basis If these shunts are not treatable by occlusive devices the enrolled patient will not be treated in the clinical study and the patient will be considered as drop-out Both treatments will be repeated on demand after demonstration to the imaging of the presence of vital tumor ie absence of complete response complete response CR or in case of intrahepatic distal recurrence at follow-up
Safety assessment The evaluation of the safety of the experimental treatment will consist in the monitoring and recording of AEs and SAEs
Specific aim 1 Compare time to progression TTP treated with TAE and DEB-TACE in a homogeneous hepatocellular carcinoma HCC patient population
Specific aim 2 Compare
safety - severe adverse events SAE
radiologic tumor response mRECIST
overall survival OS
cost-effectiveness after the entire follow-up
Study plan
Experimental design This is an interventional with drug multicenter prospective randomized open label study
Experimental design Aim 1 The study was designed in relation to the primary endpoint as an equivalence trial between two intra-arterial HCC treatments ie DEB-TACE and TAE The TTP considered as the reference value for the DEB-TACE arm is 9 months on the basis of the results of our previous multicentric experience The study is designed as an equivalence trial on the primary endpoint The standard deviation of TTP is expected not to exceed 6 months through accurate selection criteria of included patients The equivalence limit is set to no more than 5 months between the two arms Thus using appropriate formulae each arm will be formed by 69 patients alpha005 beta080 Taking into account a 10 of drop-out the final sample size per each arm will be of 77 patients 154 total
Experimental design Aim 2
Safety Adverse events AEs and severe adverse events SAEs will be monitored and recorded AE will be assessed during and after each treatment and at all follow-up visits and graded according to the NCI Common Terminology Criteria for AE CTCAE version 30 The AEs occurring within 4 weeks after TACE will be considered as treatment related SAE incidence in both arms will be ascertained assuming a reduction of SAE from 25 after TACE to 19 after TAE 25 of reduction Such an assumption would require 607 patients per arm for being confirmed To accomplish this task the OBrien-Fleming stopping boundaries will be applied considering an analysis when 69 patients for each arm will be obtained and follow-up ended Applying stopping boundaries to this sample size a nominal p-value 0001 z-score 315 is needed to confirm the assumption If the p-value will be above this threshold even if 005 the null hypothesis will be not refused
Efficacy The response will be evaluated by CT or MRI as local per-lesion response and overall per-patient response according to mRECIST at 1 month after each TACE and thereafter every 3 months for at least 2 years
Survival Through the selection previously described we expected a standard deviation of the mean survival of no more than 10 months To design the present equivalence trial we also expected a difference in the mean survival not greater than 5 months equivalence limit between the two groups Using formulas proposed by Julious et al each arm will be formed by 69 patients alpha 005 beta 080 To obtain more robust estimate and accounting for possible dropout from the study a 10 of patients will be added to the initial sample size resulting in 77 patients for each arm
Cost-effectiveness will be assessed from a third payer perspective thus including only direct costs of the procedures and related costs hospitalization imaging etc The effectiveness will be assessed by measuring the life-expectancy Incremental cost-effectiveness ratio ICER will be used to evaluate the cost-effectiveness of one treatment over the counterpart
Study population The study involves the enrollment of a total of 154 patients 77 per randomization arm with a HCC diagnosis according to the guidelines of the American Association for the Study of the Liver Disease AASLD as in clinical practice The enrolled patients will have to meet the inclusion criteria and sign the informed consent for the participation in this study At the time of enrollment demographic clinical and radiological data will be collected as in standard clinical practice
Treatment
Treatment study In the present study only patients in the DEB-TACE arm Arm A will receive intra-arterial hepatic chemotherapy Doxorubicin Both treatment arms on the other hand will receive arterial embolization of the branches that vascularize the tumor lesions
Arm A DEB-TACE or chemoembolization with microspheres The chemotherapy used in this arm is the Doxorubicin that will be carried into the tumor by Embozene TANDEM Boston Scientific microspheres TANDEM embozene microspheres are made of non-resorbable biocompatible hydrogel microspheres subjected to precision calibration and coated with an inorganic perfluorate polymer Polyzene-F Thanks to their design the microspheres can be loaded with drugs such as doxorubicin in order to administer a local controlled and constant dose of the drug to the tumor sites affected after embolization
TANDEM embozene microspheres are available in three different sizes in 2 ml and 3 ml volumes of product and are supplied in preloaded vials and syringesThe maximum loadable amount on the hydrospheres 50 mg of Doxorubicina for ml The maximum injectable dose of Doxorubicin for each treatment is 150 mg and therefore the maximum amount of microspheres that can be used for each treatment is 3 ml The size of microspheres that will be used in this study is up to 100 25 μm
Arm B TAE or embolization with microspheres The TAE will be performed with Embozene microspheres Boston Scientific Embozene microspheres are spherical particles of hydrogel precisely calibrated biocompatible non-absorbable and coated with a perfluorinated inorganic polymer Polyzene-F This medical device is available in various sizes in this study to avoid that the particle size exceeds the one used for the treatment of arm A it will be possible to use microspheres with dimensions up to 100 μm range 75 125 μm
Embozene microspheres are offered in vials containing 1 ml of suspended product in physiological saline solution for apyrogenic sterile transport The total volume of the Embozene microspheres including the transport solution is about 7 ml To this product it is necessary to add an appropriate amount of non-ionic contrast medium in order to obtain a homogeneous suspension and with good visibility during the injection under fluoroscopy
In enrolled patients regardless of the treatment arm the possible presence of extra-hepatic shunts such as gastric and pulmonary arteries arising from the hepatic branches should be appropriately assessed As in standard radiological practice in case of intra-arterial hepatic treatments if these shunts are macroscopically evident the preventive closure of the same vessels will be evaluated using the devices that will be more suitable on a case-by-case basis If these shunts are not treatable by occlusive devices the enrolled patient will not be treated in the clinical study and the patient will be considered as drop-out Both treatments will be repeated on demand after demonstration to the imaging of the presence of vital tumor ie absence of complete response complete response CR or in case of intrahepatic distal recurrence at follow-up
Safety assessment The evaluation of the safety of the experimental treatment will consist in the monitoring and recording of AEs and SAEs
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None