<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/NCT03236636</url>
  </required_header>
  <id_info>
    <org_study_id>SNG1705ICR-1</org_study_id>
    <nct_id>NCT03236636</nct_id>
  </id_info>
  <brief_title>The Phase III Study of Icaritin Versus HUACHANSU PIAN in Hepatocellular Carcinoma Subjects</brief_title>
  <official_title>Comparison of Efficacy and Safety of Icaritin Versus Cinobufotalin in First-line Treatment of Advanced Hepatocellular Carcinoma Subjects: a Multicenter, Randomized, Double-blind, Double-dummy Phase III Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Beijing Shenogen Biomedical Co., Ltd</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Cancer Institute and Hospital, Chinese Academy of Medical Sciences</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>NanJing PLA 81 Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Peking University Cancer Hospital &amp; Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Beijing Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Guang'anmen Hospital of China Academy of Chinese Medical Sciences</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Jinan Central Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Linyi Tumour Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The First Affiliated Hospital of Anhui Medical University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Anhui Provincial Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The First Affiliated Hospital with Nanjing Medical University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu Province, China</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Nanfang Hospital, Southern Medical University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>First People's Hospital of Foshan</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Affiliated Cancer Hospital &amp; Institute of Guangzhou Medical University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hebei Medical University Fourth Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The First Hospital of Jilin University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Haikou People's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Fudan University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>West China Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Chongqing Traditional Chinese Medicine Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Chifeng Municipal Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Affiliated Hospital of Hangzhou Normal University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The First Affiliated Hospital of Zhengzhou University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Guilin Medical University, China</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Third Xiangya Hospital of Central South University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Yunnan Provincial Hospital of Traditional Chinese Medicine</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Sixth People's Hospital of Shenyang</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Beijing Shenogen Biomedical Co., Ltd</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The enriched HBV-related advanced HCC patient population (composite biomarker score ≥ 2) and&#xD;
      overall survival (OS) were compared between the two groups.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The basis of enrichment design adjustment ： The latest published literature shows that the&#xD;
      heterogeneity and immune tolerance of patients with hepatitis B virus (HBV) - related HCC are&#xD;
      significantly correlated with a number of cytokines, including helper T cell subgroup 1 / 2&#xD;
      (Th1 / Th2) related factors. Moreover, the accumulated data show that the immunomodulatory&#xD;
      effect of flavonoids including Icaritin is related to Th1 / Th2 factors. At the same time,&#xD;
      the recent REACH2 study published in Lancet Oncology has successfully used serum alpha&#xD;
      fetoprotein (AFP≥400) to enrich patients with advanced HCC. Based on the updated published&#xD;
      data and our phase II clinical trial data, considering that the ongoing clinical trials are&#xD;
      still in a blind state and no statistical analysis has been conducted, with consulting of&#xD;
      clinical experts, regulatory agency advice, the protocol was amended and approved into&#xD;
      adaptive enrichment design. Before unblended and SAP, the amendment protocol was&#xD;
      prospectively pre-defined including sample size, patient population (CBS score positive), and&#xD;
      event number for interim and final analysis. combined with the latest FDA clinical trial&#xD;
      enrichment design guidelines (2019), several experts recommended to use the composite&#xD;
      biomarkers, including IFN-γ , TNF - α and AFP, which may demonstrate the clinical advantages&#xD;
      of the immunomodulation therapy with Icaritin for HBV-related advanced HCC patients in China&#xD;
      with poor prognosis, but currently lack of treatment options.&#xD;
&#xD;
      Definition of enriched HBV-related advanced HCC patient:&#xD;
&#xD;
      Patient with serum composite biomarker score (CBS)≥2&#xD;
&#xD;
      Enrichment design amendment:&#xD;
&#xD;
      Based on our previous phase II data of Icaritin collected from HBV-related advanced HCC&#xD;
      patients and the related literature, we assume that the mOS of the enriched population&#xD;
      (CBS≥2) is 420 days (14 months) in the experimental group and 240 days (8 months) in the&#xD;
      HUACHASHU control group; the HR of the experimental group relative to the control group is&#xD;
      0.57. A total of 106 target death events and 130 evaluable subjects were required for the&#xD;
      enrichment. Once the amendment protocol be effective, the enriched and non-enriched patients&#xD;
      will be continuously randomized into the experimental and the control arms accordingly (1:1).&#xD;
      When the number of enrolled cases reaches 280, or 60% of events (64) of 106 deaths has been&#xD;
      observed in the enriched population, interim analysis will be performed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">September 8, 2017</start_date>
  <completion_date type="Anticipated">December 30, 2022</completion_date>
  <primary_completion_date type="Anticipated">December 30, 2022</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>
    <intervention_model_description>multicenter, randomized, double-blind, double-dummy, adaptive enrichment design</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>2-4 years</time_frame>
    <description>OS is defined as the time from randomization to died from any cause. For the subjects who failed to visit, deletion is performed on the final date of knowing the survival of the subjects, for subjects who still survive, deletion is performed on the data expiration date.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>2-3 years</time_frame>
    <description>PFS is defined as the date from randomization to the first radiographic record of disease progression or death (whichever occurs first). See the Statistical Analysis Plan (SAP) for the definition of PFS deletion rule.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to progress（TTP）</measure>
    <time_frame>2-3 years</time_frame>
    <description>TTP is defined as the date from randomization to the first radiographic record of disease progression, see the Statistical Analysis Plan(SAP) for the definition of TTP deletion rule.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall response rate (ORR)</measure>
    <time_frame>2-3 years</time_frame>
    <description>ORR is defined as the proportion of subjects achieving optimal overall efficacy such as CR or partial remission (PR).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall disease control rate (DCR)</measure>
    <time_frame>2-3 years</time_frame>
    <description>DCR is defined as the proportion of subjects achieving optimal overall efficacy such as CR, PR or stable disease (SD).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment on Quality of life 1</measure>
    <time_frame>2-4 years</time_frame>
    <description>Quality of life (QOL) changes: Quality of life scores are assessed with EORTC QLQ-C30 and compared with baseline values.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment on Quality of life 2</measure>
    <time_frame>2-4 years</time_frame>
    <description>Quality of life (QOL) changes: Quality of life scores are assessed with EORTCQLQ-HCC-18 and compared with baseline values.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Biomarker analysis of proteome level (Immunohistochemical method)</measure>
    <time_frame>2-4 years</time_frame>
    <description>Baseline expression or expression changes of programmed cell death ligand 1 (PD-L1), heterogeneous ribonucleoprotein A2/B1 (hnRNPAB1) and interleukin -6 (IL-6) and so on.</description>
  </other_outcome>
  <other_outcome>
    <measure>Genome level (DNA, mRNA, miRNA) biomarker analysis</measure>
    <time_frame>2-4 years</time_frame>
    <description>Genetic variation(Liver cancer driver genes and hotspot gene mutations, such as IDH1/2, JAK2/3, PD-L1/2), expression levels of oncogenes and immune related genes(Gene copy number and RNA expression level) and epigenetics cohort analysis</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">312</enrollment>
  <condition>Advanced HBV-Related Hepatocellular Carcinoma (HCC)</condition>
  <arm_group>
    <arm_group_label>Icaritin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Icaritin:600mg/time, 6 capsules/time(6×100mg/capsule), 2 times/day(30 minutes after breakfast, lunch and dinner), take orally, continuous administration until reach the standard of termination.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HUACHANSU PIAN</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>HUANCHANSU PIAN:Take orally 4 tablets/time(0.3g/tablet), 3 times/day(30 minutes after breakfast, lunch and dinner), continuous administration until reach the standard of termination.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Icaritin</intervention_name>
    <description>Icaritin：600mg/time, 6 capsules/time(6×100mg/capsule), 2 times/day(30 minutes after breakfast, lunch and dinner), take orally, continuous administration until reach the standard of termination.</description>
    <arm_group_label>Icaritin</arm_group_label>
    <other_name>SNG-162</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>HUACHANSU PIAN</intervention_name>
    <description>HUACHANSU PIAN:Take orally 4 tablets/time(0.3g/tablet), 3 times/day(30 minutes after breakfast, lunch and dinner), continuous administration until reach the standard of termination.</description>
    <arm_group_label>HUACHANSU PIAN</arm_group_label>
    <other_name>HUACHANSU PIAN（999）</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Only patients who meet all the following criteria are included in the study:&#xD;
&#xD;
             1) Age≥18years, no gender restriction; 2) Advanced or metastatic HCC patients in&#xD;
             strict compliance with the &quot;Primary Liver Cancer Diagnosis and Treatment Standard&quot;&#xD;
             (2017 Edition) issued by the National Health and Family Planning Commission, clinical&#xD;
             diagnostic criteria and/or diagnosed by pathology /cytology, patients who fail to&#xD;
             undergo liver surgery and/or other local treatment (ablation or hepatic artery&#xD;
             intervention), or patients who have recurrence and progression after surgery and/or&#xD;
             other local treatment; 3) Not previously accepted first-line system therapy (systemic&#xD;
             chemotherapy, molecular targeting, immunotherapy and research medication, etc.) for&#xD;
             advanced or metastatic HCC, including but not limited to systematic chemotherapy with&#xD;
             oxaliplatin, sorafenib, PD-1/PD-L1 antibody, Icaritin and cinobufotalin, etc.; 4)&#xD;
             Liver surgery was performed more than 3 months ago, ablation or interventional&#xD;
             treatment of hepatic artery was performed more than 4 weeks ago, and the adverse&#xD;
             reactions returned to normal; After surgery or other local treatment, if patients have&#xD;
             gone beyond the norm for systemic adjuvant chemotherapy, it will need more than 6&#xD;
             months after the chemotherapy, and disease progression and / or metastasis have&#xD;
             occurred; 5) For patients who are not suitable for first-line treatment of advanced&#xD;
             HCC which is recommended in &quot;Primary Liver Cancer Diagnosis and Treatment Standard.&quot;&#xD;
             issued by the National Health and Family Planning Commission, it's mainly due to&#xD;
             partial blood test indicators (See the relaxed scope in 11th inclusion criteria ) or&#xD;
             other indicators (Including mild ascites and so on) which are not suitable for the&#xD;
             existing first-line standard treatment; Or in particular cases, the patients insist on&#xD;
             refusing to accept the existing first-line standard treatment(For example, patients&#xD;
             feel that their physical condition is weak and / or economic constraints, which must&#xD;
             be strictly mastered and controlled); 6) 2 weeks before the first medication of the&#xD;
             trial, there is no use of modern Chinese medicine preparation with liver cancer&#xD;
             indication, including Delisheng injection, Kanglaite injection or soft capsule, Aidi&#xD;
             injection or Considi injection, elemene injection/oral liquid, 1) 7) no use of blood&#xD;
             transfusion or blood products, no use of hematopoietic stimulating factor, no&#xD;
             transfusion of albumin or blood products 14 days before screening; 8) According to the&#xD;
             evaluation criteria of solid tumor reaction (RECIST 1.1), it has at least one&#xD;
             measurable target lesion, which defined as non-lymph node lesions with the longest&#xD;
             diameter larger than 10mm, lymph node lesions with the short diameter larger than&#xD;
             15mm; the lesions previously received local treatment such as ablation or hepatic&#xD;
             artery interventional therapy should be detected by computed tomography (CT) /&#xD;
             magnetic resonance imaging (MRI) and according to RECIST1.1, It's sure that disease&#xD;
             progression has occurred and the longest diameter is more than 1.0cm,it can be used as&#xD;
             a measurable target lesions; 9) The Child-Pugh score of liver function is grade A or&#xD;
             better grade B (score≤7); 10) The ECOG score of physical condition is 0-1; 11)&#xD;
             Expected survival time≥12 weeks; 12) The function of the main organs is basically&#xD;
             normal and meets the following requirements:&#xD;
&#xD;
             ①Marrow: There is no blood transfusion and use of hematopoietic cell stimulating&#xD;
             agent, including granulocyte colony stimulating factor (G-CSF)within 14 days before&#xD;
             screening, platelet≥60×10E9/L, hemoglobin≥ 85g/L, white blood cell≥3.0×10E9/L; After a&#xD;
             thorough measurement of the patient's condition, the above three items can be&#xD;
             appropriately relaxed by the principal researchers at the research centre as: platelet&#xD;
             50 ~60×10E9/L, hemoglobin 80~85g/L, white blood cell 2.5 ~3.0×10E9/L (contains&#xD;
             critical values);&#xD;
&#xD;
             ②Liver: Total bilirubin≤1.5 times of the upper limit of normal(ULN), Aspartate&#xD;
             aminotransferase (AST) and alanine aminotransferase (ALT)≤5 × ULN; albumin≥ 28g/L;&#xD;
&#xD;
             ④ Kidney: Serum creatinine≤ 1.5 x ULN, or creatinine clearance rate≥ 50ml/min; 13) If&#xD;
             HBV-DNA≥104 copies/ml(2000IU/ml), antiviral therapy must be done first, the patient&#xD;
             can be included in the group until HBV-DNA&lt;104 copies /ml(2000IU/ml); and continue to&#xD;
             take antiviral drugs, monitor liver function and hepatitis B virus load; 14) Women of&#xD;
             childbearing age must receive pregnancy tests 14 days before treatment and the results&#xD;
             are negative; Men of childbearing age need effective contraception during treatment&#xD;
             and within 3 months after treatment; 15) Patients are volunteered to join the study,&#xD;
             sign the informed consent, have good compliance and cooperate with follow-up; 16) The&#xD;
             subjects do not participate in other clinical trials within 4 weeks before screening;&#xD;
             If the subject fails in other test screening, but meets the requirements of this test,&#xD;
             then can be enrolled.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who meet any of the following criteria are not allowed to enter the test:&#xD;
&#xD;
               1. Imaging examination shows that HCC liver tumors are huge (≥60% of the liver&#xD;
                  volume), or cancer embolus of portal trunk (occupying ≥50% of the vascular&#xD;
                  diameter), or cancer embolus invading mesenteric vein or inferior vena cava;&#xD;
&#xD;
               2. Middle or higher ascites which is clinically significant, it requires therapeutic&#xD;
                  abdominal paracentesis /drainage, or the Child-Pugh score &gt; 2;&#xD;
&#xD;
               3. Local anticancer therapy (including surgery, ablation, hepatic arterial&#xD;
                  chemotherapy, embolization or radiotherapy) or major surgery was performed 28&#xD;
                  days prior to randomization;&#xD;
&#xD;
               4. Hepatocholangiocarcinoma and fibrolamellar cell carcinoma; In the past 5 years or&#xD;
                  at the same time, there were other malignancies, except cervical carcinoma in&#xD;
                  situ, previously treated basal cell carcinoma and superficial bladder tumor (Ta,&#xD;
                  Tis, T1);&#xD;
&#xD;
               5. Pregnant or lactating women;&#xD;
&#xD;
               6. The patient suffers from CTCAE classification type II or above myocardial&#xD;
                  ischemia or myocardial infarction, poorly controlled arrhythmia; and/or NYHA&#xD;
                  standard III to IV cardiac dysfunction.&#xD;
&#xD;
               7. Allograft transplants including liver transplantation were performed previously,&#xD;
                  or a liver transplant was planned during the trial;&#xD;
&#xD;
               8. Hepatic encephalopathy and / or hepatic nephropathy occurred within 6 months;&#xD;
&#xD;
               9. Patient with active hepatitis C, that is, anti -HCV positive or HCV-RNA positive&#xD;
                  and abnormal liver function;&#xD;
&#xD;
              10. Human immunodeficiency virus (HIV) tests are positive or severe infection&#xD;
                  requiring systemic treatment with antibiotics;&#xD;
&#xD;
              11. Inability to swallow, chronic diarrhea or intestinal obstruction that&#xD;
                  significantly affecting medication intake and absorption;&#xD;
&#xD;
              12. Having a history of digestive tract bleeding within 6 months, or with a clear&#xD;
                  gastrointestinal bleeding tendency, including local active ulcerative lesions,&#xD;
                  positive fecal occult blood;&#xD;
&#xD;
              13. The patient has or is suspected to have known active autoimmune disease;&#xD;
&#xD;
              14. If a central nervous system metastasis is known and a metastasis of the central&#xD;
                  nervous system is suspected, the cranial MRI examination should be performed to&#xD;
                  exclude it;&#xD;
&#xD;
              15. Abnormal coagulation function: international normalized ratio (INR) &gt;1.5 or&#xD;
                  prothrombin time (PT) &gt;16S;&#xD;
&#xD;
              16. There is a history of schizophrenia or psychotropic substance abuse;&#xD;
&#xD;
              17. Known to be allergic or intolerant to Icaritin or cinobufotalin and excipients;&#xD;
&#xD;
              18. Other conditions that researchers believe discourage patients from participating&#xD;
                  in trials.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Yan Sun, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cancer Institute and Hospital, Chinese Academy of Medical Sciences</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Shukui Qin</last_name>
    <role>Principal Investigator</role>
    <affiliation>NanJing PLA 81 Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Yan Sun, MD</last_name>
    <phone>+86 10 67781331</phone>
    <email>suny@csco.org.cn</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Shukui Qin</last_name>
    <phone>+86 25 80864806</phone>
    <email>qinsk@csco.org.cn</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Anhui Provincial Hospital</name>
      <address>
        <city>Hefei</city>
        <state>Anhui</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yueyin Pan</last_name>
    </contact>
    <investigator>
      <last_name>Yueyin Pan</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The First Affiliated Hospital of Anhui Medical University</name>
      <address>
        <city>Hefei</city>
        <state>Anhui</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kangsheng Gu</last_name>
    </contact>
    <investigator>
      <last_name>Kangsheng Gu</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Cancer Hospital Chinese Academy of Medical Sciences</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <zip>100021</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Chengxu Cui, MD</last_name>
      <phone>+86 010-87788120</phone>
      <email>13701212251@139.com</email>
    </contact>
    <investigator>
      <last_name>Chengxu Cui, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Beijing Hospital</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yunbo Zhao</last_name>
    </contact>
    <investigator>
      <last_name>Yunbo Zhao</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>General Hospital of Chinese Armed Police Forces</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <country>China</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location>
    <facility>
      <name>Guang'anmen Hospital of China Academy of Chinese Medical Sciences</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Wei Hou</last_name>
    </contact>
    <investigator>
      <last_name>Wei Hou</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Peking University Cancer Hospital</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Chunyi Hao</last_name>
    </contact>
    <investigator>
      <last_name>Chunyi Hao</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Chongqing Traditional Chinese Medicine Hospital</name>
      <address>
        <city>Chongqing</city>
        <state>Chongqing</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lingzhan Meng</last_name>
    </contact>
    <investigator>
      <last_name>Lingzhan Meng</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The First People's Hospital of Foshan</name>
      <address>
        <city>Foshan</city>
        <state>Guangdong</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Bin Hu</last_name>
    </contact>
    <investigator>
      <last_name>Bin Hu</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Affiliated Hospital of Guilin Medical University</name>
      <address>
        <city>Guilin</city>
        <state>Guangxi</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Qian Chen</last_name>
    </contact>
    <investigator>
      <last_name>Qian Chen</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Guangxi Medical University Affiliated Tumor Hospital</name>
      <address>
        <city>Nanning</city>
        <state>Guangxi</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Bangde Xiang</last_name>
    </contact>
    <investigator>
      <last_name>Bangde Xiang</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Haikou People's Hospital</name>
      <address>
        <city>Haikou</city>
        <state>Hainan</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Juan Meng</last_name>
    </contact>
    <investigator>
      <last_name>Juan Meng</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The Fourth Hospital of Hebei Medical University</name>
      <address>
        <city>Shijiazhuang</city>
        <state>Hebei</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ruixing Zhang</last_name>
    </contact>
    <investigator>
      <last_name>Ruixing Zhang</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The First Affiliated Hospital of Zhengzhou University</name>
      <address>
        <city>Zhengzhou</city>
        <state>Henan</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Wang Ma</last_name>
    </contact>
    <investigator>
      <last_name>Wang Ma</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The Third Xiangya Hospital of Central South University</name>
      <address>
        <city>Changsha</city>
        <state>Hunan</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Peiguo Cao</last_name>
    </contact>
    <investigator>
      <last_name>Peiguo Cao</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Eastern Theater General Hospital,QinHuai District Medical Area</name>
      <address>
        <city>Nanjing</city>
        <state>Jiangsu</state>
        <zip>210002</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Shukui Qin, MD</last_name>
      <phone>025-84453932</phone>
      <email>qinsk@csco.org.cn</email>
    </contact>
    <investigator>
      <last_name>Shukui Qin, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The First Affiliated Hospital with Nanjing Medical University</name>
      <address>
        <city>Nanjing</city>
        <state>Jiangsu</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yongqian Su</last_name>
    </contact>
    <investigator>
      <last_name>Yongqian Su</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The Affiliated Tumor Hospital of Nantong University</name>
      <address>
        <city>Nantong</city>
        <state>Jiangsu</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Aibing Xu</last_name>
    </contact>
    <investigator>
      <last_name>Aibing Xu</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>First Hospital of Jilin University</name>
      <address>
        <city>Changchun</city>
        <state>Jilin</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Wei Li</last_name>
    </contact>
    <investigator>
      <last_name>Wei Li</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The Sixth People's Hospital in Shenyang</name>
      <address>
        <city>Shenyang</city>
        <state>Liaoning</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Wei Wu</last_name>
    </contact>
    <investigator>
      <last_name>Wei Wu</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Chifeng Municipal Hospital</name>
      <address>
        <city>Chifeng</city>
        <state>Neimenggu</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hongbo Ji</last_name>
    </contact>
    <investigator>
      <last_name>Hongbo Ji</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Jinan Central Hospital</name>
      <address>
        <city>Jinan</city>
        <state>Shandong</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yuping Sun</last_name>
    </contact>
    <investigator>
      <last_name>Yuping Sun</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Linyi Cancer Hospital</name>
      <address>
        <city>Linyi</city>
        <state>Shandong</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jianhua Shi</last_name>
    </contact>
    <investigator>
      <last_name>Jianhua Shi</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Fudan University Shanghai Cancer Center</name>
      <address>
        <city>Shanghai</city>
        <state>Shanghai</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Zhiqiang Meng</last_name>
    </contact>
    <investigator>
      <last_name>Zhiqiang Meng</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>West China Hospital of Sichuan University</name>
      <address>
        <city>Chengdu</city>
        <state>Sichuan</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ying Zhang</last_name>
    </contact>
    <investigator>
      <last_name>Ying Zhang</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Yunnan Provincial Hospital of Traditional Chinese Medicine</name>
      <address>
        <city>Kunming</city>
        <state>Yunnan</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yi Li</last_name>
    </contact>
    <investigator>
      <last_name>Yi Li</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>The Affiliated Hospital of Hangzhou Normal University</name>
      <address>
        <city>Hangzhou</city>
        <state>Zhejiang</state>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Gongying Chen</last_name>
    </contact>
    <investigator>
      <last_name>Gongying Chen</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Nanfang Hospital of Southern Medical University</name>
      <address>
        <city>Guangzhou</city>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Yabing Guo</last_name>
    </contact>
    <investigator>
      <last_name>Yabing Guo</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>January 2021</verification_date>
  <study_first_submitted>July 26, 2017</study_first_submitted>
  <study_first_submitted_qc>July 28, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 2, 2017</study_first_posted>
  <last_update_submitted>January 25, 2021</last_update_submitted>
  <last_update_submitted_qc>January 25, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">January 27, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Hepatocellular</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03236636
org study id: SNG1705ICR-1
nct id: NCT03236636
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has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The enriched HBV-related advanced HCC patient population (composite biomarker score ≥ 2) and
      overall survival (OS) were compared between the two groups.
The basis of enrichment design adjustment ： The latest published literature shows that the
      heterogeneity and immune tolerance of patients with hepatitis B virus (HBV) - related HCC are
      significantly correlated with a number of cytokines, including helper T cell subgroup 1 / 2
      (Th1 / Th2) related factors. Moreover, the accumulated data show that the immunomodulatory
      effect of flavonoids including Icaritin is related to Th1 / Th2 factors. At the same time,
      the recent REACH2 study published in Lancet Oncology has successfully used serum alpha
      fetoprotein (AFP≥400) to enrich patients with advanced HCC. Based on the updated published
      data and our phase II clinical trial data, considering that the ongoing clinical trials are
      still in a blind state and no statistical analysis has been conducted, with consulting of
      clinical experts, regulatory agency advice, the protocol was amended and approved into
      adaptive enrichment design. Before unblended and SAP, the amendment protocol was
      prospectively pre-defined including sample size, patient population (CBS score positive), and
      event number for interim and final analysis. combined with the latest FDA clinical trial
      enrichment design guidelines (2019), several experts recommended to use the composite
      biomarkers, including IFN-γ , TNF - α and AFP, which may demonstrate the clinical advantages
      of the immunomodulation therapy with Icaritin for HBV-related advanced HCC patients in China
      with poor prognosis, but currently lack of treatment options.

      Definition of enriched HBV-related advanced HCC patient:

      Patient with serum composite biomarker score (CBS)≥2

      Enrichment design amendment:

      Based on our previous phase II data of Icaritin collected from HBV-related advanced HCC
      patients and the related literature, we assume that the mOS of the enriched population
      (CBS≥2) is 420 days (14 months) in the experimental group and 240 days (8 months) in the
      HUACHASHU control group; the HR of the experimental group relative to the control group is
      0.57. A total of 106 target death events and 130 evaluable subjects were required for the
      enrichment. Once the amendment protocol be effective, the enriched and non-enriched patients
      will be continuously randomized into the experimental and the control arms accordingly (1:1).
      When the number of enrolled cases reaches 280, or 60% of events (64) of 106 deaths has been
      observed in the enriched population, interim analysis will be performed.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: multicenter, randomized, double-blind, double-dummy, adaptive enrichment design
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Overall survival (OS)
time frame: 2-4 years
description: OS is defined as the time from randomization to died from any cause. For the subjects who failed to visit, deletion is performed on the final date of knowing the survival of the subjects, for subjects who still survive, deletion is performed on the data expiration date.
measure: Progression-free survival (PFS)
time frame: 2-3 years
description: PFS is defined as the date from randomization to the first radiographic record of disease progression or death (whichever occurs first). See the Statistical Analysis Plan (SAP) for the definition of PFS deletion rule.
measure: Time to progress（TTP）
time frame: 2-3 years
description: TTP is defined as the date from randomization to the first radiographic record of disease progression, see the Statistical Analysis Plan(SAP) for the definition of TTP deletion rule.
measure: Overall response rate (ORR)
time frame: 2-3 years
description: ORR is defined as the proportion of subjects achieving optimal overall efficacy such as CR or partial remission (PR).
measure: Overall disease control rate (DCR)
time frame: 2-3 years
description: DCR is defined as the proportion of subjects achieving optimal overall efficacy such as CR, PR or stable disease (SD).
measure: Assessment on Quality of life 1
time frame: 2-4 years
description: Quality of life (QOL) changes: Quality of life scores are assessed with EORTC QLQ-C30 and compared with baseline values.
measure: Assessment on Quality of life 2
time frame: 2-4 years
description: Quality of life (QOL) changes: Quality of life scores are assessed with EORTCQLQ-HCC-18 and compared with baseline values.
measure: Biomarker analysis of proteome level (Immunohistochemical method)
time frame: 2-4 years
description: Baseline expression or expression changes of programmed cell death ligand 1 (PD-L1), heterogeneous ribonucleoprotein A2/B1 (hnRNPAB1) and interleukin -6 (IL-6) and so on.
measure: Genome level (DNA, mRNA, miRNA) biomarker analysis
time frame: 2-4 years
description: Genetic variation(Liver cancer driver genes and hotspot gene mutations, such as IDH1/2, JAK2/3, PD-L1/2), expression levels of oncogenes and immune related genes(Gene copy number and RNA expression level) and epigenetics cohort analysis
arm group label: Icaritin
arm group type: Experimental
description: Icaritin:600mg/time, 6 capsules/time(6×100mg/capsule), 2 times/day(30 minutes after breakfast, lunch and dinner), take orally, continuous administration until reach the standard of termination.
arm group label: HUACHANSU PIAN
arm group type: Active Comparator
description: HUANCHANSU PIAN:Take orally 4 tablets/time(0.3g/tablet), 3 times/day(30 minutes after breakfast, lunch and dinner), continuous administration until reach the standard of termination.
intervention type: Drug
intervention name: Icaritin
description: Icaritin：600mg/time, 6 capsules/time(6×100mg/capsule), 2 times/day(30 minutes after breakfast, lunch and dinner), take orally, continuous administration until reach the standard of termination.
arm group label: Icaritin
other name: SNG-162
intervention type: Drug
intervention name: HUACHANSU PIAN
description: HUACHANSU PIAN:Take orally 4 tablets/time(0.3g/tablet), 3 times/day(30 minutes after breakfast, lunch and dinner), continuous administration until reach the standard of termination.
arm group label: HUACHANSU PIAN
other name: HUACHANSU PIAN（999）
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Yan Sun, MD
role: Principal Investigator
affiliation: Cancer Institute and Hospital, Chinese Academy of Medical Sciences
last name: Shukui Qin
role: Principal Investigator
affiliation: NanJing PLA 81 Hospital
last name: Yan Sun, MD
phone: +86 10 67781331
email: suny@csco.org.cn
last name: Shukui Qin
phone: +86 25 80864806
email: qinsk@csco.org.cn
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
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facility: 
status: Recruiting
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status: Recruiting
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status: Terminated
facility: 
status: Recruiting
contact: 
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facility: 
status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
contact: 
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status: Recruiting
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facility: 
status: Recruiting
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status: Recruiting
contact: 
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status: Recruiting
contact: 
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status: Recruiting
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status: Recruiting
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status: Recruiting
contact: 
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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facility: 
status: Recruiting
contact: 
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facility: 
status: Recruiting
contact: 
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country: China
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Carcinoma, Hepatocellular
sharing ipd: No