<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03278444</url>
  </required_header>
  <id_info>
    <org_study_id>HETCT-001</org_study_id>
    <nct_id>NCT03278444</nct_id>
  </id_info>
  <brief_title>Treatment of Advanced Hepatocellular Carcinoma</brief_title>
  <acronym>TAHCC</acronym>
  <official_title>The Efficacy and Safety of Arginine Hydrochloride Combined With Trimetazidine Hydrochloride Tablets in the Treatment of Patients With Hepatocellular Carcinoma. A Multicenter, Open, Randomized, Prospective Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The First Affiliated Hospital of Zhengzhou University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>First Affiliated Hospital of Xinjiang Medical University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Jiaozuo third people's hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Luoyang Central Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Nanyang Central Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Anyang Tumor Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Pingmei Shenma Medical Group General Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>First People's Hospital of Shangqiu</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>The First Affiliated Hospital of Zhengzhou University</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the efficacy and safety of arginine hydrochloride&#xD;
      combined with trimetazidine hydrochloride tablets in the treatment of patients with&#xD;
      hepatocellular carcinoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause&#xD;
      of cancer-related deaths in the world. Because HCC is insidious and early diagnosis is&#xD;
      difficult, most patients have locally advanced or distant metastasis at the time of&#xD;
      diagnosis. So they are not suitable candidates for curative treatments by resection or&#xD;
      transplantation. Currently, Sorafenib is the only choice approved by FDA for advanced HCC,&#xD;
      although it prolongs the survival for less than 3 months. Recently, metabolomics studies of&#xD;
      HCC have shown that typical Warburg effect was observed in hepatoma carcinoma cells. Arginine&#xD;
      hydrochloride is a new anticancer drug in the treatment of liver cancer, which is mainly&#xD;
      aimed at the pathway of energy metabolism. Trimetazidine hydrochloride may play an anti-tumor&#xD;
      role by inhibiting fatty acid oxidation. The investigators have been proceeding this trial to&#xD;
      evaluate the efficacy and safety of arginine hydrochloride combined with trimetazidine&#xD;
      hydrochloride tablets in the treatment of patients with hepatocellular carcinoma.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">July 18, 2017</start_date>
  <completion_date type="Anticipated">July 2021</completion_date>
  <primary_completion_date type="Anticipated">July 2021</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>36 months</time_frame>
    <description>from start of treatment to death from any cause, or last known date of survival</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival</measure>
    <time_frame>24 months</time_frame>
    <description>Time from start of treatment until the first documented event of symptomatic progression or death.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate (DCR)</measure>
    <time_frame>28 days</time_frame>
    <description>the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate(ORR)</measure>
    <time_frame>28 days</time_frame>
    <description>Proportion of patients with reduction in tumor burden of a predefined amount</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>biomarker</measure>
    <time_frame>approximately 24 months</time_frame>
    <description>decrease in tumor markers</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chinese Quality of Life Questionnaire - EORTC QLQ-C30 score</measure>
    <time_frame>approximately 36 months</time_frame>
    <description>The overall enjoyment of life.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">300</enrollment>
  <condition>HCC</condition>
  <arm_group>
    <arm_group_label>One-drug Regimes</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Basic drugs therapy of HCC</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Two-Drug Regimens</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Basic drugs therapy of HCC; Arginine hydrochloride</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Three-Drug Regimens</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Basic drugs therapy of HCC; Arginine hydrochloride;Trimetazidine hydrochloride</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Basic drugs therapy of HCC</intervention_name>
    <description>Basic drugs include: 1. Molecular targeted drugs for HCC：apatinib; 2. Antiviral drugs (ETV or TDF) should be given to patients who were infected with HBV or HCV; 3. Patients with liver dysfunction should be treated with conventional hepatoprotective agents drugs (including glycyrrhizin, reduced glutathione, vitamin C，etc); 4. Patients with ascites symptoms should be treated with furosemide and spironolactone according to the urine volume, and they also should be treated with proton pump inhibitors in the prevention of gastrointestinal bleeding; 5. Other basic diseases were treated routinely.</description>
    <arm_group_label>One-drug Regimes</arm_group_label>
    <arm_group_label>Three-Drug Regimens</arm_group_label>
    <arm_group_label>Two-Drug Regimens</arm_group_label>
    <other_name>BDT</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Arginine hydrochloride</intervention_name>
    <description>Arginine hydrochloride injection 5g/dose; 40g/d; ivgtt; sustained medication for 24 days; drug withdrawal for 4 days.</description>
    <arm_group_label>Three-Drug Regimens</arm_group_label>
    <arm_group_label>Two-Drug Regimens</arm_group_label>
    <other_name>AH</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trimetazidine hydrochloride</intervention_name>
    <description>Trimetazidine hydrochloride tablets 20mg/tablet, 40mg, twice a day.</description>
    <arm_group_label>Three-Drug Regimens</arm_group_label>
    <other_name>TH</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  1. Ages 18-65 years&#xD;
&#xD;
          -  2. The diagnosis of HCC: in accordance with &quot;diagnostic and treating standards on&#xD;
             primary liver cancer&quot; (2011 Edition) or histological/cytological diagnosis of&#xD;
             recurrent / metastatic primary liver cancer&#xD;
&#xD;
          -  3. Un-resectable HCC (single or multiple metastasis of HCC after surgery, TACE, or&#xD;
             radio frequency ablation; surgery cannot be tolerated because of some basic diseases);&#xD;
             Patients with treatment failure or non tolerance to sorafenib. ｛note: Definition of&#xD;
             treatment failure: progression of disease during treatment or recurrence of disease&#xD;
             after the end of treatment(accepting sorafenib and other molecular targeted therapies&#xD;
             must be at least 14 days); Definition of intolerance: ≥ grade Ⅳ hematological toxicity&#xD;
             or ≥ grade III non hematologic toxicity or ≥ grade Ⅱ heart, liver, kidney and other&#xD;
             organ damage｝;Refusing surgical treatment and volunteering join the group&#xD;
&#xD;
          -  4. first-line systematic treatment failure (or residual lesion) was over 2 weeks from&#xD;
             the study enrolled (time for signature of informed consent) and the adverse events&#xD;
             were almost normal (NCI-CTCAE≤ grade Ⅰ）&#xD;
&#xD;
          -  5. Child-Pugh liver function class A/B (score: ≤ 9)&#xD;
&#xD;
          -  6. Barcelona stage (BCLC) B-C&#xD;
&#xD;
          -  7. Performance status 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale in&#xD;
             one week before admission&#xD;
&#xD;
          -  8. Estimated survival time &gt; 3 months&#xD;
&#xD;
          -  9. HBV DNA&lt;2000 IU/ml（10^4 copies/ml); or HBV DNA≥2000 IU/ml and are accepting&#xD;
             effective antiviral therapy&#xD;
&#xD;
          -  10. The major organ function is normal. that is meeting the following standards:&#xD;
&#xD;
               1. Blood routine examination: (No blood transfusion, no G-CSF and no medication were&#xD;
                  corrected within 14 days before screening)&#xD;
&#xD;
                  a.HB≥80g/L； b.ANC≥1.5×109/L；c.PLT≥50×109/L；&#xD;
&#xD;
               2. Biochemical examination: (ALB was not transfused within 14 days before screening)&#xD;
                  a.ALB ≥29 g/L； b.ALT和AST&lt;5ULN；c.TBIL ≤3ULN；d.creatinine ≤1.5ULN( albumin and&#xD;
                  bilirubin, two indicators of Child-Pugh liver function class, can only have one&#xD;
                  for 2 points)&#xD;
&#xD;
          -  11. For women of childbearing age, the results of serum/urine pregnancy tests must be&#xD;
             negative within 7 days before initiation of treatment. All men and women who&#xD;
             participate in the study have to take reliable contraceptive measures within the trial&#xD;
             and eight weeks after the trial is completed&#xD;
&#xD;
          -  12. volunteers must signed informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  1. Patients with hepatobiliary cell carcinoma, mixed cell carcinoma or lamellar cell&#xD;
             carcinoma; in the past (within 5 years) or at the same time suffering from other&#xD;
             untreated malignant tumors; excluding cured basal cell carcinoma and carcinoma in&#xD;
             situs of cervix&#xD;
&#xD;
          -  2. Patients who are undergoing liver transplantation or have a history of organ&#xD;
             transplantation(excluding the patient who has undergone liver transplantation before)&#xD;
&#xD;
          -  3. Patients with an allergic history of arginine hydrochloride and trimetazidine&#xD;
             hydrochloride&#xD;
&#xD;
          -  4. Patients with renal insufficiency&#xD;
&#xD;
          -  5. The blood pressure can not be reduced to the normal range by the antihypertensive&#xD;
             drug treatment in patients with hypertension(systolic pressure&gt;140 mmHg, diastolic&#xD;
             pressure&gt;90 mmHg)&#xD;
&#xD;
          -  6. Patients with myocardial ischemia or myocardial infarction over grade II or a&#xD;
             poorly controlled arrhythmia (including QTc interval: men ≥ 450 ms; women ≥ 470 ms)&#xD;
&#xD;
          -  7. Cardiac functional insufficiency of grade III to IV according to NYHA standard;&#xD;
             echocardiography: LVEF&lt;50%&#xD;
&#xD;
          -  8. Many factors that influence oral medication, such as unable to swallow; chronic&#xD;
             diarrhea; intestinal obstruction; the situations which significantly affect the use&#xD;
             and absorption of drugs&#xD;
&#xD;
          -  9. With a history of alimentary tract hemorrhage or a definite tendency of&#xD;
             gastrointestinal bleeding, such as varices of fundus of stomach and esophagus with&#xD;
             bleeding risk; local active ulcer lesions; fecal occult blood ≥（++）&#xD;
&#xD;
          -  10. Abdominal fistula, gastrointestinal perforation, or abdominal abscess occurred&#xD;
             within 28 days before participating the study&#xD;
&#xD;
          -  11. Dysfunction of blood coagulation(INR&gt;2.0 or PT&gt; 16s，APTT &gt; 43s、TT &gt; 21s，Fbg &lt;&#xD;
             2g/L), having a tendency to bleed or undergoing thrombolysis or anticoagulant therapy;&#xD;
             ascites with clinical symptoms, that is requiring therapeutic abdominal paracentesis&#xD;
             or drainage or Child-Pugh score ≥2&#xD;
&#xD;
          -  12. Patients of central nervous system metastasis or brain metastasis&#xD;
&#xD;
          -  13. Objective evidence of pulmonary fibrosis history, interstitial pneumonia,&#xD;
             pneumoconiosis, radiation pneumonitis, drug associated pneumonia, and severe lung&#xD;
             function impairment in the past and at present&#xD;
&#xD;
          -  14. Urine routine showed that urine protein ≥++ or the urine protein in 24 hours&gt;1.0 g&#xD;
&#xD;
          -  15. Patients who have been treated with potent CYP3A4 inhibitors (ketoconazole,&#xD;
             itraconazole, voriconazole, ritonavir, clarithromycin, telithromycin, troleandomycin,&#xD;
             erythromycin, cimetidine and so on) within 28 days before participating the study, or&#xD;
             potent CYP3A4 inducers (dexamethasone, phenytoin, rifampin, rifabutin, carbamazepine,&#xD;
             phenobarbitone and so on) within 12 days before participating the study&#xD;
&#xD;
          -  16. Pregnant or lactating women; fertile patients who are unwilling or unable to adopt&#xD;
             effective contraceptives&#xD;
&#xD;
          -  17. Patients with mental sickness or the history of psychotropic drug abuse&#xD;
&#xD;
          -  18. Patients who had bone metastases received palliative radiotherapy within 4 weeks&#xD;
             before participating the study (radiotherapy area &gt; 5% bone marrow region)&#xD;
&#xD;
          -  19. Patients with severe infection (unable to control the infection effectively)&#xD;
&#xD;
          -  20. The treatment history affecting this program or its efficacy, such as stem cell&#xD;
             transplantation, immune regulation (including PD-1 and other test regimens) recently&#xD;
             (within half a year)&#xD;
&#xD;
          -  21. The researchers believe that any other factors unsuitable for entering into the&#xD;
             study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Zujiang Yu, Pro,Dr</last_name>
    <role>Principal Investigator</role>
    <affiliation>The First Affiliated Hospital of Zhengzhou University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Zujiang Yu, Pro,Dr</last_name>
    <phone>0086-0371-67966942</phone>
    <email>johnyuem@zzu.edu.cn</email>
  </overall_contact>
  <location>
    <facility>
      <name>The First Affiliated Hospital of Zhengzhou University</name>
      <address>
        <city>Zhengzhou</city>
        <state>Henan</state>
        <zip>450000</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>August 27, 2017</study_first_submitted>
  <study_first_submitted_qc>September 7, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 11, 2017</study_first_posted>
  <last_update_submitted>September 9, 2017</last_update_submitted>
  <last_update_submitted_qc>September 9, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 12, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The First Affiliated Hospital of Zhengzhou University</investigator_affiliation>
    <investigator_full_name>Zujiang YU</investigator_full_name>
    <investigator_title>The director of infectious diseases department</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma, Hepatocellular</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Trimetazidine</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03278444
org study id: HETCT-001
nct id: NCT03278444
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to evaluate the efficacy and safety of arginine hydrochloride
      combined with trimetazidine hydrochloride tablets in the treatment of patients with
      hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause
      of cancer-related deaths in the world. Because HCC is insidious and early diagnosis is
      difficult, most patients have locally advanced or distant metastasis at the time of
      diagnosis. So they are not suitable candidates for curative treatments by resection or
      transplantation. Currently, Sorafenib is the only choice approved by FDA for advanced HCC,
      although it prolongs the survival for less than 3 months. Recently, metabolomics studies of
      HCC have shown that typical Warburg effect was observed in hepatoma carcinoma cells. Arginine
      hydrochloride is a new anticancer drug in the treatment of liver cancer, which is mainly
      aimed at the pathway of energy metabolism. Trimetazidine hydrochloride may play an anti-tumor
      role by inhibiting fatty acid oxidation. The investigators have been proceeding this trial to
      evaluate the efficacy and safety of arginine hydrochloride combined with trimetazidine
      hydrochloride tablets in the treatment of patients with hepatocellular carcinoma.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Survival
time frame: 36 months
description: from start of treatment to death from any cause, or last known date of survival
measure: Progression-free Survival
time frame: 24 months
description: Time from start of treatment until the first documented event of symptomatic progression or death.
measure: Disease Control Rate (DCR)
time frame: 28 days
description: the percentage of patients with advanced or metastatic cancer who have achieved complete response, partial response and stable disease
measure: Objective Response Rate(ORR)
time frame: 28 days
description: Proportion of patients with reduction in tumor burden of a predefined amount
measure: biomarker
time frame: approximately 24 months
description: decrease in tumor markers
measure: Chinese Quality of Life Questionnaire - EORTC QLQ-C30 score
time frame: approximately 36 months
description: The overall enjoyment of life.
arm group label: One-drug Regimes
arm group type: Experimental
description: Basic drugs therapy of HCC
arm group label: Two-Drug Regimens
arm group type: Experimental
description: Basic drugs therapy of HCC; Arginine hydrochloride
arm group label: Three-Drug Regimens
arm group type: Experimental
description: Basic drugs therapy of HCC; Arginine hydrochloride;Trimetazidine hydrochloride
intervention type: Other
intervention name: Basic drugs therapy of HCC
description: Basic drugs include: 1. Molecular targeted drugs for HCC：apatinib; 2. Antiviral drugs (ETV or TDF) should be given to patients who were infected with HBV or HCV; 3. Patients with liver dysfunction should be treated with conventional hepatoprotective agents drugs (including glycyrrhizin, reduced glutathione, vitamin C，etc); 4. Patients with ascites symptoms should be treated with furosemide and spironolactone according to the urine volume, and they also should be treated with proton pump inhibitors in the prevention of gastrointestinal bleeding; 5. Other basic diseases were treated routinely.
arm group label: One-drug Regimes
arm group label: Three-Drug Regimens
arm group label: Two-Drug Regimens
other name: BDT
intervention type: Drug
intervention name: Arginine hydrochloride
description: Arginine hydrochloride injection 5g/dose; 40g/d; ivgtt; sustained medication for 24 days; drug withdrawal for 4 days.
arm group label: Three-Drug Regimens
arm group label: Two-Drug Regimens
other name: AH
intervention type: Drug
intervention name: Trimetazidine hydrochloride
description: Trimetazidine hydrochloride tablets 20mg/tablet, 40mg, twice a day.
arm group label: Three-Drug Regimens
other name: TH
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Zujiang Yu, Pro,Dr
role: Principal Investigator
affiliation: The First Affiliated Hospital of Zhengzhou University
last name: Zujiang Yu, Pro,Dr
phone: 0086-0371-67966942
email: johnyuem@zzu.edu.cn
facility: 
status: Recruiting
country: China
responsible party type: Principal Investigator
investigator affiliation: The First Affiliated Hospital of Zhengzhou University
investigator full name: Zujiang YU
investigator title: The director of infectious diseases department
mesh term: Carcinoma, Hepatocellular
mesh term: Trimetazidine