<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/NCT03026972</url>
  </required_header>
  <id_info>
    <org_study_id>LTao-AEC/BC02-Ⅰ-healthy</org_study_id>
    <secondary_id>LTao</secondary_id>
    <nct_id>NCT03026972</nct_id>
  </id_info>
  <brief_title>A Phase ⅠStudy of the Recombinant Mycobacterium Tuberculosis Vaccine Freeze-dried</brief_title>
  <acronym>AEC/BC02</acronym>
  <official_title>A Phase ⅠStudy of the Human Body Tolerance Research of the Recombinant Mycobacterium Tuberculosis Vaccine Freeze-dried</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Shanghai Public Health Clinical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Beijing Simoonrecord Pharmaceutical Information Consulting Co.,Ltd</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Anhui Zhifei Longcom Biologic Pharmacy Co., Ltd.</source>
  <oversight_info>
    <has_dmc>No</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>
      There are four populations in Recombinant Mycobacterium tuberculosis Vaccine Freeze-dried&#xD;
      (AEC/BC02) phase I clinical research. The clinical study adopt open research design.&#xD;
&#xD;
      Population I have 25 subjects who received Tuberculin purified protein derivative(TB-PPD)&#xD;
      skin test and specific gamma-interferon (γ-IFN)detection whose results are both negative&#xD;
      ;Population II have 30 subjects who received Tuberculin purified protein derivative(TB-PPD)&#xD;
      and ESAT6-CFP10 skin test in different arms , specific gamma-interferon (γ-IFN) detection&#xD;
      whose results are all negative.We call polulation III as uninfected TB PPD positve&#xD;
      population.This group screened 30 subjects whose ESAT6-CFP10 skin test and specific&#xD;
      gamma-interferon (γ-IFN)detection results are both negative,but Tuberculin purified protein&#xD;
      derivative(TB-PPD) skin test positive.50 subjects whose three kinds of detection results are&#xD;
      all positive γ-IFN,TB-PPD and ESAT6-CFP10 ) are named as population IV.&#xD;
&#xD;
      After filtrating, injecting of population I start firstly.After ensure the safety of the&#xD;
      population I,the population II～polulation IV carry out in turn the implementation at the same&#xD;
      time.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Consider the safety of the inoculation,the trial is conducted in the following order:&#xD;
&#xD;
      Population I start firstly, polulation II～population IV is sarted when population I is&#xD;
      finished the entire immune and observation safety.Population II and population III should&#xD;
      proceed simultaneously,and these two kinds of population finish injecting the first doses of&#xD;
      placebo group after 4weeks,population IV start.&#xD;
&#xD;
      All participants of the placebo group and adjuvant group complete the first needle&#xD;
      intramuscular injection.5 subjects of Low-dose vaccine group are injected after being sure of&#xD;
      the security of placebo and adjucant groups after 3 days. When these low-dose vaccine&#xD;
      subjects is sure of safety in 2h,the rest of 5 subjects are injected.Each participant immune&#xD;
      one type of placebo, adjuvant or vaccination every two weeks, totally six stitches. In the&#xD;
      research, each subject receives only one dose of drug and cannot be subjected to experiments&#xD;
      about dose escalation.&#xD;
&#xD;
      The population Ⅰ subjects are received 6 needle times of placebo or low-dose adjuvant or&#xD;
      low-dose vaccine by haunch deep intramuscular injection to provide security basis. The&#xD;
      subjects should accept some physical examination during the clinical research. Vital signs&#xD;
      (breathing, pulse, blood pressure, body temperature) of each volunteer before each needle&#xD;
      injection and 30min; and local reaction of each volunteer at 30min after injection;routine&#xD;
      blood, routine urine, liver and kidney function, and ECG before first-dose,&#xD;
      third-dose,forth-dose and sixth-dose,7 days after the sixth needle injection; Female HCG is&#xD;
      tested before each needle injection and 7days after the sixth dose injected; chest X-ray&#xD;
      detection before the first injection and 7 days after the sixth needle injection. All&#xD;
      subjects should assess the changes of immunological indexes before the first injection, the&#xD;
      fourth time before injection and 7 days after the sixth needle injection. The specific&#xD;
      injection orders are as follows:&#xD;
&#xD;
      ①All the subjects of placebo group(5 cases) and low-dose adjuvant group(10 cases) will be&#xD;
      injected on the same day, the adjuvant group subjects should be injected after all the&#xD;
      placebo group completed and observed two hours safety;&#xD;
&#xD;
      ② All the subjects of low-dose vaccine (10 cases) will be injected on the third day if the&#xD;
      placebo group and adjuvant group subjects are observed safety.&#xD;
&#xD;
      ③The clinical study of population Ⅱ and population Ⅲ will be carried out 3 days later if the&#xD;
      low-dose vaccine group subjects of the population Ⅰ are observed safety; Each subject&#xD;
      inoculates a dose of drug every two weeks, a total of six agents. In conclusion, the result&#xD;
      of the Phase I Clinical Study of population I evaluate safety of different dose of&#xD;
      Recombinant Mycobacterium tuberculosis Vaccine Freeze-dried(AEC/BCO2) in different&#xD;
      population, but also provide a safe basis for the Phase I Clinical Study.&#xD;
&#xD;
      The populationⅠsubjects are injected the first needle injection and observe safety after 3&#xD;
      days and then conducted clinical research population Ⅱ and Ⅲ in Phase I Clinical. The study&#xD;
      population Ⅱ/Ⅲ will be injected to a placebo or adjuvant or vaccination and collect any&#xD;
      adverse events and serious adverse events to evaluate its safety during the period of&#xD;
      clinical research.When the above two kinds of population are injected first doses of placebo&#xD;
      after 4 weeks,the low-dose group of population IV proceed.High-dose group of population IV&#xD;
      conduct trial after the low-dose group injected first dose of placebo later 1 week.&#xD;
&#xD;
      The 30 subjects of study population Ⅱand 30 subjects of population III who meet the inclusion&#xD;
      criteria and do not accord with standard of exclusion are divided into placebo&#xD;
      group,high-dose adjuvant group and high-dose vaccine group, each group has 10&#xD;
      participants.The 50 subjects of population IV are invidided into low-dose group and high-dose&#xD;
      group,each group of 25 subjects.The Low-dose group consiste of 5 placebo subjects,10 adjuvant&#xD;
      subjects and 10 vaccine subjects.The high-dose grouping is same as low-dose group.Every&#xD;
      subject must accept some physical examination during the clinical research,and all the items&#xD;
      of physical examination are as same as population I. Specific injection orders are as&#xD;
      follows:&#xD;
&#xD;
      ①Population II and population III should proceed simultaneously,and these two kinds of&#xD;
      population finish injecting the first doses of placebo group after 4weeks,population IV&#xD;
      start;&#xD;
&#xD;
      ②High-dose group of population IV conduct trial after the low-dose group injected first dose&#xD;
      of placebo later 1 week;&#xD;
&#xD;
      ③Every pupolation are injected placebo and adjuvant firstly;5 subjects of Low-dose vaccine&#xD;
      group are injected after being sure of the security of placebo and adjucant groups after 3&#xD;
      days. When these low-dose vaccine subjects is sure of safety in 2h,the rest of 5 subjects are&#xD;
      injected.&#xD;
&#xD;
      All subjects are vaccinated once every two weeks, a total of six times vaccination.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 16, 2018</start_date>
  <completion_date type="Actual">October 30, 2019</completion_date>
  <primary_completion_date type="Actual">September 4, 2018</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The number of participants with Adverse Events after coxal muscle injection</measure>
    <time_frame>Up to a week after the sixth time injection</time_frame>
    <description>The adverse events observed mainly from laboratory examination(including vital signs/routine blood/routingurine/Liver and kidney fuction/Electrocardiograghy and Chest X-ray detection),skin reactivity and local reaction after drug injection.Vital signs(breathing,pulse,blood pressure,body temperature) of each volunteer before each dose injection,and 30min after injection.Routine blood,routine urine,liver and kidney function,and ECG before first dose,third dose,sixth dose,and 7 days after the sixth time injection;skin reactivity and local reaction of rach volunteer at 30min before and after every injection.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Laboratory markers of immunity</measure>
    <time_frame>Up to a week after the sixth time injection</time_frame>
    <description>Evaluation of IFN-γand antibody level of before and after the immune,intracellular cytokine staining in blood .</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">25</enrollment>
  <condition>Tuberculosis</condition>
  <arm_group>
    <arm_group_label>Population I</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Population I has 25 subjects,and it is considered as Tuberculin purified protein derivative(TB-PPD) skin test and specific gamma-interferon (γ-IFN) detection result all negative.Population I are coxal muscle injection of placebo or low dose adjuvant or low dose vaccine.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Population II</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Population II is considered as Tuberculin purified protein derivative(TB-PPD) skin test , ESAT6-CFP10 skin test and specific gamma-interferon (γ-IFN) detection result all negative.It has 30 subjects.Population II are coxal muscle injection of placebo or high dose adjuvant or high dose vaccine.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Population III</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Population III is considered as ESAT6-CFP10 skin test and specific gamma-interferon (γ-IFN) detection result negive,but Tuberculin purified protein derivative(TB-PPD) skin test positive.Population IV is needed 30 subjects.These subjects are coxal muscle injection of placebo or high dose adjuvant or high dose vaccine.This arm is uninfected TB PPD positve population.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Population IV</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Population IV is considered as Tuberculin purified protein derivative(TB-PPD) skin test and ESAT6-CFP10 skin test and specific gamma-interferon (γ-IFN) detection result all positive.We are called latent infection population,and need to screen 50 subjects through these three selection method.Population III are coxal muscle injection of placebo or adjuvant( including low dose adjuvant or high dose adjuvant) or vaccine(including low dose vaccine high dose vaccine).</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>The placebo drug contains 20mg mannitol and 10 millimole(mM) phosphate buffer(PB).population I～population IV are coxal muscle injection of placebo.</description>
    <arm_group_label>Population I</arm_group_label>
    <arm_group_label>Population II</arm_group_label>
    <arm_group_label>Population III</arm_group_label>
    <arm_group_label>Population IV</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Low dose adjuvant</intervention_name>
    <description>Population I and polulation IV are coxal muscle injection of low dose adjuvant.</description>
    <arm_group_label>Population I</arm_group_label>
    <arm_group_label>Population IV</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>High dose adjuvant</intervention_name>
    <description>Population II ,Population III and Population IV are coxal muscle injection of high dose adjuvant.</description>
    <arm_group_label>Population II</arm_group_label>
    <arm_group_label>Population III</arm_group_label>
    <arm_group_label>Population IV</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Low dose vaccine</intervention_name>
    <description>Population I and population IV are coxal muscle injection of low dose vaccine.</description>
    <arm_group_label>Population I</arm_group_label>
    <arm_group_label>Population IV</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>High dose vaccine</intervention_name>
    <description>Population II,population III and population IV are coxal muscle injection of high dose vaccine .</description>
    <arm_group_label>Population II</arm_group_label>
    <arm_group_label>Population III</arm_group_label>
    <arm_group_label>Population IV</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Agreed to participate in the test and sign the informed consent;&#xD;
&#xD;
          -  Subjects should comply with the requirements of the clinical trial protocol and be&#xD;
             followed;&#xD;
&#xD;
          -  Aged form 18-45 years old . Body mass index should be in the range of 18-30. Body Mass&#xD;
             Index BMI: weight (Kg)/ [height (m)*height (m)];&#xD;
&#xD;
          -  Physical condition: body temperatue, blood pressure, heart rate and respiratory status&#xD;
             are normal minor abnormalities but no abnormal symptoms and signs;&#xD;
&#xD;
          -  Lab test including blood, urine, liver and kidney function are normal minor&#xD;
             abnormalities but no abnormal symptoms and signs;&#xD;
&#xD;
          -  ECG,X-ray chest radiograph are normal minor abnormalities but no abnormal symptoms and&#xD;
             signs;&#xD;
&#xD;
          -  Subjects have no history of tuberculosis;&#xD;
&#xD;
          -  Subjects have no acute or chronic disease, acute infectious diseases, dermatoses or&#xD;
             skin allergy caused by various reasons;&#xD;
&#xD;
          -  Subject have not participated in other clinical drug trials or inoculated against&#xD;
             other prophylactic and immune globulin in the nearly 3 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Suffering from other serious disease, e.g. tumor, autoimmune disease, progressive&#xD;
             atherosclerosis, diabetes accompanied with complications, chronic obstructive&#xD;
             pulmonary disease(COPD) needing oxygen therapy, acute or progressive liver or kidney&#xD;
             disease, congestive heart failure, etc;&#xD;
&#xD;
          -  Subjects were a history of TB;&#xD;
&#xD;
          -  Subjects are immune dysfunction or abnormal, e.g. patients receive immunosuppressive&#xD;
             agents or immunosuppressive agents, receive immunoglobulin preparations outsider the&#xD;
             gastrointestinal or blood products within 3 months, extracted plasma or infected by&#xD;
             immunodeficiency virus or related disease;&#xD;
&#xD;
          -  Mentally or physically disabled,and have family history of convulsions, epilepsy,&#xD;
             encephalopathy or mental illness.&#xD;
&#xD;
          -  Subjects have took part in other clinical trials in the nearly 3 months,or vacinated&#xD;
             any prophylactic;&#xD;
&#xD;
          -  Allergic constitution, e.g. patients have allergic history to two or more kinds of&#xD;
             drugs or food, or drug components;&#xD;
&#xD;
          -  Substance abuse， drug or alcohol abuse;&#xD;
&#xD;
          -  Pregnant or breast feeding female;&#xD;
&#xD;
          -  people have birth plan during study or in six moons after entire immune;&#xD;
&#xD;
          -  Any other cases that may influence the test evaluation.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Shuihua Lu</last_name>
    <role>Principal Investigator</role>
    <affiliation>Shanghai Public Health Clinical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Shanghai Public Health clinical Center</name>
      <address>
        <city>Shanghai</city>
        <state>Shanghai</state>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
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    <citation>Halperin SA, Van Nest G, Smith B, Abtahi S, Whiley H, Eiden JJ. A phase I study of the safety and immunogenicity of recombinant hepatitis B surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide adjuvant. Vaccine. 2003 Jun 2;21(19-20):2461-7. doi: 10.1016/s0264-410x(03)00045-8.</citation>
    <PMID>12744879</PMID>
  </reference>
  <reference>
    <citation>Jones TR, Obaldia N 3rd, Gramzinski RA, Charoenvit Y, Kolodny N, Kitov S, Davis HL, Krieg AM, Hoffman SL. Synthetic oligodeoxynucleotides containing CpG motifs enhance immunogenicity of a peptide malaria vaccine in Aotus monkeys. Vaccine. 1999 Aug 6;17(23-24):3065-71. doi: 10.1016/s0264-410x(99)00145-0.</citation>
    <PMID>10462241</PMID>
  </reference>
  <reference>
    <citation>Tokunaga T, Yamamoto H, Shimada S, Abe H, Fukuda T, Fujisawa Y, Furutani Y, Yano O, Kataoka T, Sudo T, et al. Antitumor activity of deoxyribonucleic acid fraction from Mycobacterium bovis BCG. I. Isolation, physicochemical characterization, and antitumor activity. J Natl Cancer Inst. 1984 Apr;72(4):955-62.</citation>
    <PMID>6200641</PMID>
  </reference>
  <reference>
    <citation>Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature. 1995 Apr 6;374(6522):546-9. doi: 10.1038/374546a0.</citation>
    <PMID>7700380</PMID>
  </reference>
  <reference>
    <citation>Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T, Endres S, Hartmann G. Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol. 2002 May 1;168(9):4531-7. doi: 10.4049/jimmunol.168.9.4531.</citation>
    <PMID>11970999</PMID>
  </reference>
  <reference>
    <citation>Thomas LJ, Hammond RA, Forsberg EM, Geoghegan-Barek KM, Karalius BH, Marsh HC Jr, Rittershaus CW. Co-administration of a CpG adjuvant (VaxImmune, CPG 7909) with CETP vaccines increased immunogenicity in rabbits and mice. Hum Vaccin. 2009 Feb;5(2):79-84. doi: 10.4161/hv.5.2.6521. Epub 2009 Mar 1.</citation>
    <PMID>18670196</PMID>
  </reference>
  <reference>
    <citation>Chen L, Xu M, Wang ZY, Chen BW, Du WX, Su C, Shen XB, Zhao AH, Dong N, Wang YJ, Wang GZ. The development and preliminary evaluation of a new Mycobacterium tuberculosis vaccine comprising Ag85b, HspX and CFP-10:ESAT-6 fusion protein with CpG DNA and aluminum hydroxide adjuvants. FEMS Immunol Med Microbiol. 2010 Jun 1;59(1):42-52. doi: 10.1111/j.1574-695X.2010.00660.x. Epub 2010 Feb 17.</citation>
    <PMID>20298499</PMID>
  </reference>
  <verification_date>December 2019</verification_date>
  <study_first_submitted>January 12, 2017</study_first_submitted>
  <study_first_submitted_qc>January 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 20, 2017</study_first_posted>
  <last_update_submitted>March 9, 2022</last_update_submitted>
  <last_update_submitted_qc>March 9, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 24, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Safety</keyword>
  <keyword>Tolerance</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vaccines</mesh_term>
  </intervention_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/NCT03026972
org study id: LTao-AEC/BC02-Ⅰ-healthy
secondary id: LTao
nct id: NCT03026972
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
There are four populations in Recombinant Mycobacterium tuberculosis Vaccine Freeze-dried
      (AEC/BC02) phase I clinical research. The clinical study adopt open research design.

      Population I have 25 subjects who received Tuberculin purified protein derivative(TB-PPD)
      skin test and specific gamma-interferon (γ-IFN)detection whose results are both negative
      ;Population II have 30 subjects who received Tuberculin purified protein derivative(TB-PPD)
      and ESAT6-CFP10 skin test in different arms , specific gamma-interferon (γ-IFN) detection
      whose results are all negative.We call polulation III as uninfected TB PPD positve
      population.This group screened 30 subjects whose ESAT6-CFP10 skin test and specific
      gamma-interferon (γ-IFN)detection results are both negative,but Tuberculin purified protein
      derivative(TB-PPD) skin test positive.50 subjects whose three kinds of detection results are
      all positive γ-IFN,TB-PPD and ESAT6-CFP10 ) are named as population IV.

      After filtrating, injecting of population I start firstly.After ensure the safety of the
      population I,the population II～polulation IV carry out in turn the implementation at the same
      time.
Consider the safety of the inoculation,the trial is conducted in the following order:

      Population I start firstly, polulation II～population IV is sarted when population I is
      finished the entire immune and observation safety.Population II and population III should
      proceed simultaneously,and these two kinds of population finish injecting the first doses of
      placebo group after 4weeks,population IV start.

      All participants of the placebo group and adjuvant group complete the first needle
      intramuscular injection.5 subjects of Low-dose vaccine group are injected after being sure of
      the security of placebo and adjucant groups after 3 days. When these low-dose vaccine
      subjects is sure of safety in 2h,the rest of 5 subjects are injected.Each participant immune
      one type of placebo, adjuvant or vaccination every two weeks, totally six stitches. In the
      research, each subject receives only one dose of drug and cannot be subjected to experiments
      about dose escalation.

      The population Ⅰ subjects are received 6 needle times of placebo or low-dose adjuvant or
      low-dose vaccine by haunch deep intramuscular injection to provide security basis. The
      subjects should accept some physical examination during the clinical research. Vital signs
      (breathing, pulse, blood pressure, body temperature) of each volunteer before each needle
      injection and 30min; and local reaction of each volunteer at 30min after injection;routine
      blood, routine urine, liver and kidney function, and ECG before first-dose,
      third-dose,forth-dose and sixth-dose,7 days after the sixth needle injection; Female HCG is
      tested before each needle injection and 7days after the sixth dose injected; chest X-ray
      detection before the first injection and 7 days after the sixth needle injection. All
      subjects should assess the changes of immunological indexes before the first injection, the
      fourth time before injection and 7 days after the sixth needle injection. The specific
      injection orders are as follows:

      ①All the subjects of placebo group(5 cases) and low-dose adjuvant group(10 cases) will be
      injected on the same day, the adjuvant group subjects should be injected after all the
      placebo group completed and observed two hours safety;

      ② All the subjects of low-dose vaccine (10 cases) will be injected on the third day if the
      placebo group and adjuvant group subjects are observed safety.

      ③The clinical study of population Ⅱ and population Ⅲ will be carried out 3 days later if the
      low-dose vaccine group subjects of the population Ⅰ are observed safety; Each subject
      inoculates a dose of drug every two weeks, a total of six agents. In conclusion, the result
      of the Phase I Clinical Study of population I evaluate safety of different dose of
      Recombinant Mycobacterium tuberculosis Vaccine Freeze-dried(AEC/BCO2) in different
      population, but also provide a safe basis for the Phase I Clinical Study.

      The populationⅠsubjects are injected the first needle injection and observe safety after 3
      days and then conducted clinical research population Ⅱ and Ⅲ in Phase I Clinical. The study
      population Ⅱ/Ⅲ will be injected to a placebo or adjuvant or vaccination and collect any
      adverse events and serious adverse events to evaluate its safety during the period of
      clinical research.When the above two kinds of population are injected first doses of placebo
      after 4 weeks,the low-dose group of population IV proceed.High-dose group of population IV
      conduct trial after the low-dose group injected first dose of placebo later 1 week.

      The 30 subjects of study population Ⅱand 30 subjects of population III who meet the inclusion
      criteria and do not accord with standard of exclusion are divided into placebo
      group,high-dose adjuvant group and high-dose vaccine group, each group has 10
      participants.The 50 subjects of population IV are invidided into low-dose group and high-dose
      group,each group of 25 subjects.The Low-dose group consiste of 5 placebo subjects,10 adjuvant
      subjects and 10 vaccine subjects.The high-dose grouping is same as low-dose group.Every
      subject must accept some physical examination during the clinical research,and all the items
      of physical examination are as same as population I. Specific injection orders are as
      follows:

      ①Population II and population III should proceed simultaneously,and these two kinds of
      population finish injecting the first doses of placebo group after 4weeks,population IV
      start;

      ②High-dose group of population IV conduct trial after the low-dose group injected first dose
      of placebo later 1 week;

      ③Every pupolation are injected placebo and adjuvant firstly;5 subjects of Low-dose vaccine
      group are injected after being sure of the security of placebo and adjucant groups after 3
      days. When these low-dose vaccine subjects is sure of safety in 2h,the rest of 5 subjects are
      injected.

      All subjects are vaccinated once every two weeks, a total of six times vaccination.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: The number of participants with Adverse Events after coxal muscle injection
time frame: Up to a week after the sixth time injection
description: The adverse events observed mainly from laboratory examination(including vital signs/routine blood/routingurine/Liver and kidney fuction/Electrocardiograghy and Chest X-ray detection),skin reactivity and local reaction after drug injection.Vital signs(breathing,pulse,blood pressure,body temperature) of each volunteer before each dose injection,and 30min after injection.Routine blood,routine urine,liver and kidney function,and ECG before first dose,third dose,sixth dose,and 7 days after the sixth time injection;skin reactivity and local reaction of rach volunteer at 30min before and after every injection.
measure: Laboratory markers of immunity
time frame: Up to a week after the sixth time injection
description: Evaluation of IFN-γand antibody level of before and after the immune,intracellular cytokine staining in blood .
arm group label: Population I
arm group type: Experimental
description: Population I has 25 subjects,and it is considered as Tuberculin purified protein derivative(TB-PPD) skin test and specific gamma-interferon (γ-IFN) detection result all negative.Population I are coxal muscle injection of placebo or low dose adjuvant or low dose vaccine.
arm group label: Population II
arm group type: Experimental
description: Population II is considered as Tuberculin purified protein derivative(TB-PPD) skin test , ESAT6-CFP10 skin test and specific gamma-interferon (γ-IFN) detection result all negative.It has 30 subjects.Population II are coxal muscle injection of placebo or high dose adjuvant or high dose vaccine.
arm group label: Population III
arm group type: Experimental
description: Population III is considered as ESAT6-CFP10 skin test and specific gamma-interferon (γ-IFN) detection result negive,but Tuberculin purified protein derivative(TB-PPD) skin test positive.Population IV is needed 30 subjects.These subjects are coxal muscle injection of placebo or high dose adjuvant or high dose vaccine.This arm is uninfected TB PPD positve population.
arm group label: Population IV
arm group type: Experimental
description: Population IV is considered as Tuberculin purified protein derivative(TB-PPD) skin test and ESAT6-CFP10 skin test and specific gamma-interferon (γ-IFN) detection result all positive.We are called latent infection population,and need to screen 50 subjects through these three selection method.Population III are coxal muscle injection of placebo or adjuvant( including low dose adjuvant or high dose adjuvant) or vaccine(including low dose vaccine high dose vaccine).
intervention type: Biological
intervention name: Placebo
description: The placebo drug contains 20mg mannitol and 10 millimole(mM) phosphate buffer(PB).population I～population IV are coxal muscle injection of placebo.
arm group label: Population I
arm group label: Population II
arm group label: Population III
arm group label: Population IV
intervention type: Biological
intervention name: Low dose adjuvant
description: Population I and polulation IV are coxal muscle injection of low dose adjuvant.
arm group label: Population I
arm group label: Population IV
intervention type: Biological
intervention name: High dose adjuvant
description: Population II ,Population III and Population IV are coxal muscle injection of high dose adjuvant.
arm group label: Population II
arm group label: Population III
arm group label: Population IV
intervention type: Biological
intervention name: Low dose vaccine
description: Population I and population IV are coxal muscle injection of low dose vaccine.
arm group label: Population I
arm group label: Population IV
intervention type: Biological
intervention name: High dose vaccine
description: Population II,population III and population IV are coxal muscle injection of high dose vaccine .
arm group label: Population II
arm group label: Population III
arm group label: Population IV
criteria: 
gender: All
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Shuihua Lu
role: Principal Investigator
affiliation: Shanghai Public Health Clinical Center
facility: 
country: China
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PMID: 15297066
citation: Halperin SA, Van Nest G, Smith B, Abtahi S, Whiley H, Eiden JJ. A phase I study of the safety and immunogenicity of recombinant hepatitis B surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide adjuvant. Vaccine. 2003 Jun 2;21(19-20):2461-7. doi: 10.1016/s0264-410x(03)00045-8.
PMID: 12744879
citation: Jones TR, Obaldia N 3rd, Gramzinski RA, Charoenvit Y, Kolodny N, Kitov S, Davis HL, Krieg AM, Hoffman SL. Synthetic oligodeoxynucleotides containing CpG motifs enhance immunogenicity of a peptide malaria vaccine in Aotus monkeys. Vaccine. 1999 Aug 6;17(23-24):3065-71. doi: 10.1016/s0264-410x(99)00145-0.
PMID: 10462241
citation: Tokunaga T, Yamamoto H, Shimada S, Abe H, Fukuda T, Fujisawa Y, Furutani Y, Yano O, Kataoka T, Sudo T, et al. Antitumor activity of deoxyribonucleic acid fraction from Mycobacterium bovis BCG. I. Isolation, physicochemical characterization, and antitumor activity. J Natl Cancer Inst. 1984 Apr;72(4):955-62.
PMID: 6200641
citation: Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature. 1995 Apr 6;374(6522):546-9. doi: 10.1038/374546a0.
PMID: 7700380
citation: Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T, Endres S, Hartmann G. Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol. 2002 May 1;168(9):4531-7. doi: 10.4049/jimmunol.168.9.4531.
PMID: 11970999
citation: Thomas LJ, Hammond RA, Forsberg EM, Geoghegan-Barek KM, Karalius BH, Marsh HC Jr, Rittershaus CW. Co-administration of a CpG adjuvant (VaxImmune, CPG 7909) with CETP vaccines increased immunogenicity in rabbits and mice. Hum Vaccin. 2009 Feb;5(2):79-84. doi: 10.4161/hv.5.2.6521. Epub 2009 Mar 1.
PMID: 18670196
citation: Chen L, Xu M, Wang ZY, Chen BW, Du WX, Su C, Shen XB, Zhao AH, Dong N, Wang YJ, Wang GZ. The development and preliminary evaluation of a new Mycobacterium tuberculosis vaccine comprising Ag85b, HspX and CFP-10:ESAT-6 fusion protein with CpG DNA and aluminum hydroxide adjuvants. FEMS Immunol Med Microbiol. 2010 Jun 1;59(1):42-52. doi: 10.1111/j.1574-695X.2010.00660.x. Epub 2010 Feb 17.
PMID: 20298499
responsible party type: Sponsor
mesh term: Tuberculosis
mesh term: Vaccines
sharing ipd: No