Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05391867 |
| Other study ID # |
Sirsalimullah |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2022 |
| Est. completion date |
June 30, 2023 |
Study information
| Verified date |
May 2022 |
| Source |
Sir Salimullah Medical College Mitford Hospital |
| Contact |
Mohammad S Hossain, MBBS, MD |
| Phone |
+8801727626789 |
| Email |
romelssmcmh[@]gmail.com |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Hepatocellular carcinoma is the most common type of liver cancer, which is the 3rd leading
cause of cancer deaths worldwide. The incidence is expected to increase as a consequence of
chronic liver disease with its multiple risk factors, including chronic hepatitis B virus
(HBV) and hepatitis C virus (HCV) infections, excessive alcohol consumption, nonalcoholic
fatty liver disease, hemochromatosis, and aflatoxin B1.It is estimated that 70%-90% of
patients with HCC have chronic liver disease and cirrhosis, which limits the feasibility of
surgical procedures in advanced cases. There are limited treatment options for HCC patients
who are ineligible for surgical resection. Locoregional therapies, such as radiofrequency
ablation, transarterial chemoembolization (TACE), transarterial embolization (TAE), or
hepatic arterial infusion chemotherapy (HAIC), are primarily recommended, and if one of those
fail, then systemic therapy is considered. The 2013 Japan Society of Hepatology HCC
Guidelines outlined that the factors influencing treatment decisions should be based on the
degree of liver damage (Child-Pugh), presence or absence of extrahepatic spread and
macrovascular invasion, the number of tumors, and tumor diameter. Sorafenib has been the
standard of care since 2007, when the SHARP trial demonstrated that sorafenib improved median
overall survival (OS) compared to placebo in patients who had not received prior systemic
therapy (10.7 vs 7.9 months, HR =0.69, P<0.001). In patients from the Asia-Pacific region
taking sorafenib, the median improvement in overall survival compared with placebo was 2.3
months (6.5 months vs 4.2 months; HR 0.68; p=0.014). Drug development for hepatocellular
carcinoma in the past 10 years has been marked by four failed global phase 3 trials (of
sunitinib, brivanib, linifanib, and erlotinib plus sorafenib) that did not show
non-inferiority. Sorafenib, an oral multikinase inhibitor, has been the only systemic therapy
demonstrated to extend overall survibility as a firstline treatment, showing a median
improvement of 2.8 months compared with placebo (10.7 months vs. 7.9 months; hazard ratio
[HR] 0.69; p\0.001).6 Inpatients from the Asia-Pacific region taking sorafenib, the median OS
(mOS) improvement compared with placebo was 2.3 months (HR 0.68; p = 0.014). The use of other
molecularly targeted agents has not demonstrated efficacy via non-inferiority or superiority
to sorafenib; thus, until the appearance of lenvatinib, sorafenib has also been widely used
as the first-line treatment for uHCC patients in Japan. Recently, regorafenib and Nivolumab
were approved as a second-line systemic treatment for patients who do not respond to the
first-line treatments. Otherwise, best supportive care or participation in clinical trials is
recommended in the second-line setting by treatment guidelines. Chemotherapy in combination
with sorafenib (doxorubicin) and radioembolization with SIR Spheres Y-90 resin microspheres
failed to demonstrate a survival benefit or showed a worse safety profile compared to
sorafenib in the first-line setting. Eventually, the PhaseIII non-inferiority REFLECT trial
showed that lenvatinib was non-inferior compared to sorafenib.
Description:
1. Introduction:
Hepatocellular carcinoma is one of the most common type of liver cancer, which is the
3rd leading cause of cancer deaths worldwide. The incidence is expected to increase as a
consequence of chronic liver disease with its multiple risk factors, including chronic
hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, excessive alcohol
consumption, nonalcoholic fatty liver disease, hemochromatosis, drugs and aflatoxin B1.
It is estimated that 70%-90% of patients with HCC have chronic liver disease and
cirrhosis, which limits the feasibility of surgical procedures in advanced cases. There
are limited treatment options for HCC patients who are ineligible for surgical
resection. Locoregional therapies, such as radiofrequency ablation (RFA), transarterial
chemoembolization (TACE), transarterial embolization (TAE), or hepatic arterial infusion
chemotherapy (HAIC), are primarily recommended, and if one of those fail, then systemic
therapy is considered. The 2013 Japan Society of Hepatology HCC Guidelines outlined that
the factors influencing treatment decisions should be based on the degree of liver
damage (Child-Pugh), presence or absence of extrahepatic spread and macrovascular
invasion, the number of tumors, and tumor diameter. Sorafenib has been the standard of
care since 2007, when the SHARP trial demonstrated that sorafenib improved median
overall survival (OS) compared to placebo in patients who had not received prior
systemic therapy (10.7 vs 7.9 months, HR =0.69, P<0.001). In patients from the
Asia-Pacific region taking sorafenib, the median improvement in overall survival
compared with placebo was 2.3 months (6.5 months vs 4.2 months; HR 0.68; p=0.014). Drug
development for hepatocellular carcinoma in the past 10 years has been marked by four
failed global phase 3 trials (of sunitinib, brivanib, linifanib, and erlotinib plus
sorafenib) that did not show non inferiority. Sorafenib, an oral multikinase inhibitor,
has been the only systemic therapy demonstrated to extend overall survibility as a
firstline treatment, showing a median improvement of 2.8 months compared with placebo
(10.7 months vs. 7.9 months; hazard ratio [HR] 0.69; p\0.001). Inpatients from the
Asia-Pacific region taking sorafenib, the median OS (mOS) improvement compared with
placebo was 2.3 months (HR 0.68; p = 0.014). The use of other molecularly targeted
agents has not demonstrated efficacy via non-inferiority or superiority to sorafenib;
thus, until the appearance of lenvatinib, sorafenib has also been widely used as the
first-line treatment for HCC patients in Japan. Recently, regorafenib and Nivolumab were
approved as a second-line systemic treatment for patients who do not respond to the
first-line treatments. Otherwise, best supportive care or participation in clinical
trials is recommended in the second-line setting by treatment guidelines. Chemotherapy
in combination with sorafenib (doxorubicin), and radioembolization with SIR Spheres Y-90
resin microspheres failed to demonstrate a survival benefit or showed a worse safety
profile compared to sorafenib in the first-line setting. Eventually, the PhaseIII
non-inferiority REFLECT trial showed that lenvatinib was non-inferior compared to
sorafenib.
2. Objectives
2.1 General objectives:
To assess and compare the efficacy of Lenvatinib versus Sorafenib in the management of
Hepatitis B virus related Hepatocellular Carcinoma.
2.2 Specific objectives:
a. To assess and compare the overall survibility of hepatocellular carcinoma patients
between the groups of Lenvatinib and Sorafenib. b. To assess and compare the progression
free survival outcome between the groups of Lenvatinib and Sorafenib. c. To assess and
compare the improvement of liver function tests between the groups of Lenvatinib and
Sorafenib. d. To assess and compare the improvement of AFP levels between the groups of
Lenvatinib and Sorafenib. e. To assess and compare the improvement of ECOG performance
status of the HCC patients between the groups of Lenvatinib and Sorafenib. f. To assess
and compare the improvement of Chil-Pugh scores among the HCC patients between the
groups of Lenvatinib and Sorafenib. g. To assess and compare the size and number of
target lesions by mRECIST criteria among the HCC patients between the groups of
Lenvatinib and Sorafenib.
3. Methodology:
The study will be conducted considering the following methodological aspects.
3.1 Study design: An open label randomized clinical control trial study.
3.2 Study duration: From the date of randomization to next 3 months or till death whichever
one will be earlier
3.3 Study place: Department of Hepatology, Sir Salimullah Medical College Mitford Hospital
3.4 Study population: Patients diagnosed as advanced Hepatocellular Carcinoma by imaging,
cytology or histology with no option of resectibility will be selected for the study.
3.5 Sample size calculation:
"n=" "P1" ("1-P1" )"+P2" ("1-P2" )/("P1" -"P2" )^2 ×〖(Zα+Zβ)〗^2
P1= Proportion of patients developed objective response in one arm (Lenvatinib group) P2=
Proportion of patients developed objective response in another arm (Sorafenib group) Zα=
Z-value (two tail) at a definite level of significance e.g. 1.96 at 5% level of significance
Zβ= Z-value (one tail) at a definite power e.g. 0.84
Here, P1= 40.6% objective response with Lenvatinib (0.406), P2= 12.4% objective response with
Sorafenib (0.124), Zα=1.96 and Zβ= 0.8419
n=(0.406(1-0.406)+ 0.124(1-0.124))/〖(0.406-0.124)〗^2 ×〖(1.96+0.84)〗^2 = 34.3 in each group =
35 in each group Total sample number 70 (35 in Lenvatinib group and 35 in Sorafenib group)
3.6 Sampling technique and recruitment of study subjects:
Participants of the study will be recruited via 1:1 randomization from patients admitted in
the department of Hepatology, Sir Salimullah Medical College Mitford Hospital and diagnosed
as a case of advanced Hepatocellular Carcinoma with no option of resectibility.
3.7 Eligibility criteria:
3.7.1 Inclusion criteria:
1. Patients with Hepatocellular Carcinoma (Diagnosed histologically or cytologically or by
imaging criteria with CT or MRI) with no option of resectibility (BCLC stage B or C)
2. Age ≥ 18 years
3.7.2 Exclusion criteria:
1. Patients with very early stage Hepatocellular Carcinoma (BCLC stage 0)
2. Patients with early stage Hepatocellular Carcinoma (BCLC stage A)
3. Patients with terminal stage Hepatocellular Carcinoma (BCLC stage D)
4. Patients with Hepatocellular Carcinoma with obvious invasion to bile duct.
5. Patients who received previous systemic therapy for Hepatocellular Carcinoma.
7. Patients with jaundice (serum bilirubin ≥ 3 mg/dl) 8. Patients with aminotransferases ≥
5ULN 8. Patients with other co-morbid conditions (COPD, CKD, Heart failure, IHD, pregnancy)
3.7.3 Primary outcome measure:
1. To measure overall survival of the patients from the date of randomization up to 6
months or till death whichever one will be earlier.
3.7.4 Secondary outcome measure:
1. Progression free survival
2. Time to progress
3. Objective response rate
4. Quality of life
5. Assessment of safety
3.8 Outcome measure:
1. Primary endpoint
a. Overall survibility (From the date of Randomization to next 3 months or till death)
2. Secondary endpoint
1. Progression free survival
2. Time to progress
3. Quality of life measurement (By ECOG performance status)
4. Liver function tests (By S.Bilirubin, ALT, AST, ALP, Prothrombin time, INR, Serum
albumin)
5. AFP level
6. Child-turcotte-Pugh score
7. Tumor assessment by mRECIST criteria.
3.9 Research instrument
For collection of primary data about patient a semi-structured questionnaire will
be developed based on research objective. Pre-testing of the questionnaire will be
done on other patients admitted at the same facility. After the pretesting,
amendment of the items and question will be done based on study finding. In the
final questionnaire both structured and open questions will be kept.
A check list will be prepared to compile the data from hospital records, treatment
records, outcome of treatment and laboratory investigation reports.
3.10 Data collection procedure:
All data will be collected by face-to-face interview of the patients attendant by
the researcher at health facility upon their consent and convenience. Socio
demographic and personal information will be recorded from patient through
interview, with a semi structured pre-tested questionnaire. Information regarding
risk factors and risk behavior will be inquired taking effort to minimize the
recall bias.
3.11 Data processing
Data processing will include data cleaning and quality control check, editing of
data, coding of data and data entry into computer. The edited data will be entered
on to the template of SPSS® 23.
3.12 Data analysis
The edited data will then be entered on to the template of SPSS® 23. For Back
ground variables and socio-demographic data descriptive statistics and relative
frequency (percentage) will be generated. All data will be presented as mean ± SD.
Qualitative data will be analyzed by Chi-square test and quantitative data will be
analyzed by student's t-test. Through univariate analysis the base line
characteristics and treatment outcome will be compared. The effect of treatment
will be identified through Multivariate analysis after adjusting for possible
confounders. Relative risk with 95% CI will be generated through binary logistic
regression adjusting for all possible confounders. A statistically significant
result will be considered when p value < 0.05.
3.13 Data Presentation
Data will be presented in the form of table and graphs. Descriptive statistics will
be presented with frequency table. Association will be illustrated with cross
tables and test statistics will be added in the foot note of the table. Bar and pie
charts will be generated to illustrate descriptive statistics.
4) Ethical considerations
Approval from the ethical review committee of Sir Salimullah Medical College and
Mitford Hospital will be taken prior to commencement of the study. Informed written
consent will be taken from the participants after explaining about the details of
the study. The participants will be assured that the information acquired will be
used for academic purpose. They will be assured of confidentiality, and for the
purpose of data analysis no individual data were reported rather de identified data
will be preceded for analysis.
5) Facilities (Resources, Equipments, Chemicals, Subjects etc. required for the
study)
- Principal investigator has full-fledged Department of Hepatology at "Sir
Salimullah Medical College Mitford Hospital, Dhaka."
- "Sir Salimullah Medical College Mitford Hospital, Dhaka" has adequate
facilities to carry out all the investigations required for this study.
"Sir Salimullah Medical College Mitford Hospital, Dhaka" has adequate facility to
deal with the adverse effect of the drug under trial as well as management of the
subjects of the current study.
6) Material & methods:
The study will be conducted in the department of Hepatology, Sir Salimullah Medical
College Mitford Hospital. It will be an open label randomized clinical control
trial study. Patients admitted in the department of Hepatology, diagnosed as a case
of Hepatocellular Carcinoma by imaging or cytopathology or histopathology will be
primarily targeted for the study. Initial assessment of each patient will be done
by Chil-pugh score, ECOG performance status, Tumor assessment by mRECIST criteria
and BCLC staging. According to initial assessment the patients who will fulfill the
inclusion criteria (BCLC stage C) will be informed about the study procedure.
Patients who will give informed written consent will be randomly assigned 1:1 ratio
to receive either Lenvatinib or Sorafenib. Macroscopic portal vein invasion,
extrahepatic spread, or both (yes or no), Eastern Cooperative Oncology Group
performance status (0 or 1) will be considered as stratification factors. As the
study will be open labeled, the treatment will not be masked to the patients or
investigators. After randomization there will be two groups; Lenvatinib group
(Group A) and Sorafenib group (Group B). Group A patients will receive Cap.
Lenvatinib 8 mg/day in two divided doses and group B patients will receive tab.
Sorafenib 400 mg/day in two divided doses. Tumor evaluation will be done in each
treatment arm in accordance with mRECIST criteria. Liver will be examined with CT
or MRI by using a triphasic scanning technique. Patient follow-up and tumor
assessment will be done in every 6 weeks interval by liver function tests (S.
Bilirubin, ALT, AST, ALP, Prothrombin time, S. Albumin), AFP and imaging (triphasic
CT or MRI). Quality of life will be assessed by ECOG performance status on
follow-up. Patients will followed up for next 3 months or till death whichever one
will be earlier. After 3 months of treatment the two groups (Group A and Group B)
will be compared of overall survibility, improvement of patient's clinical and
biochemical status, reduction of tumor size as well as the tumor marker.
7) Statistical Analysis:
The result of the study will be collected in a separate questionnaire sheet. After
collection of data it will be compiled and analyzed using SPSS software version 23.
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