<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/NCT03306550</url>
  </required_header>
  <id_info>
    <org_study_id>zz0908022</org_study_id>
    <nct_id>NCT03306550</nct_id>
  </id_info>
  <brief_title>Mechanism of Drug-drug Interaction Between Salvianolate Injection and Aspirin</brief_title>
  <official_title>Research on Mechanism of Drug-drug Interaction Between Salvianolate Injection and Aspirin Based on the Metabolic Enzyme and PK-PD Model</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Xiyuan Hospital of China Academy of Chinese Medical Sciences</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Xiyuan Hospital of China Academy of Chinese Medical Sciences</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 combination of anti-platelet medicine treatment and Chinese traditional medicine (TCM)&#xD;
      promoting blood circulation to removing blood stasis is widely used in treatment for&#xD;
      cardiovascular disease. However, the material foundation, effective mechanism and drug-drug&#xD;
      interaction is still not clear. In order to solve the puzzle of rational use of Joint&#xD;
      application by TCM and Western Medicine(WM),investigators conduct a research on mechanism of&#xD;
      drug-drug interaction between salvianolate injection and aspirin based on metabolic enzyme&#xD;
      and PK-PD model. This clinical trial contain three groups, aspirin group, salvianolate&#xD;
      injection group and combination (salvianolate injection+aspirin) group. Investigators collect&#xD;
      blood samples at special time points during post-administration.Investigators have already&#xD;
      find out the Salvianolate's pharmacokinetic characteristics in vivo and establish the&#xD;
      biological sample-testing analysis method in previous research. Depending on these results,&#xD;
      this clinical trial aim to explore the pharmacodynamics-pharmacokinetics(PK-PD)&#xD;
      characteristics of combination with Salvianolate and aspirin through biomarkers, blood&#xD;
      concentration. Finally clarify the TCM and WM material basis and mutual mechanism of drug&#xD;
      interaction and guide reasonable clinical prescription.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">October 10, 2017</start_date>
  <completion_date type="Anticipated">October 10, 2018</completion_date>
  <primary_completion_date type="Anticipated">April 10, 2018</primary_completion_date>
  <phase>N/A</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>Change of P-selection expression(platelet activation-dependent granule membrane) at different time points.</measure>
    <time_frame>Getting blood sample before taking medicine in the day 10 and after it in 15min、1h、2h、8h、24h</time_frame>
    <description>Use flow cytometric method to detect the P-selection expression on platelet at different time points. Analyse the influence of Asprin/Salvianolate on platelet interaction adhesion during drug concentration-time curves.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change of PAC-1 expression (platelet-associated complement) on the activated platelets at different time points.</measure>
    <time_frame>Getting blood sample before taking medicine in the day 10 and after it in 15min、1h、2h、8h、24h</time_frame>
    <description>Use flow cytometric method to detect the PAC-1 expression on platelet at different time points. Analyse the influence of Asprin/Salvianolate on platelet aggregation during drug concentration-time curves.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change of P2Y12 acceptor expression on platelets at different time points. (P2Y12 acceptor is a receptor for ADP(adenosine diphosphate) and ATP (adenosine triphosphate )coupled to G-proteins that inhibit the adenylyl cyclase second messenger system)</measure>
    <time_frame>Getting blood sample before taking medicine in the day 10 and after it in 15min、1h、2h、8h、24h</time_frame>
    <description>Use flow cytometric method to detect the P2Y12 acceptor expression on platelet at different time points. Analyse the influence of Asprin/Salvianolate on platelets aggregation activated by ADP or ATP during drug concentration-time curves.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change of PDE enzymes（phosphodiesterase）expression on platelet at different time points.</measure>
    <time_frame>Getting blood sample before taking medicine in the day 10 and after it in 15min、1h、2h、8h、24h</time_frame>
    <description>Use ELISA method to detect the PDE enzymes expression at different time points. Analyse the influence of Asprin/Salvianolate on platelets activated by PDE enzymes during drug concentration-time curves.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change of Aspirin esterase activity at different blood concentration of Asprin/Salvianolate</measure>
    <time_frame>Getting blood sample before taking aspirin in day 8 and day 9.In the day 10, getting blood sample before taking aspirin and after taking aspirin in 5min、15min、30min、45min、1h、2h、4h、8h、12h、24h</time_frame>
    <description>Conduct biological analysis by LC-MS/MS(liquid chromatography tandem mass spectrometry) to detect Aspirin and salicylic aspirin and salicylic acid:CSA/C(ASA+SA).The activity of combination arm and of the asprin arm is compared by t test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of Catechol-o-methyltransferase (COMT) activity at different blood concentration of Asprin/Salvianolate</measure>
    <time_frame>Getting blood sample before injection in day 8 and day 9.In the day 10, getting blood sample before injection and after injection in 5min、15min、30min、45min、1h、2h、4h、8h、12h、24h</time_frame>
    <description>COMT activity is the main metabolic enzymes of SAB.Use kit to detect COMT activity .</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">18</enrollment>
  <condition>Angina, Stable</condition>
  <arm_group>
    <arm_group_label>aspirin arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>only take aspirin (100mg,qd) orally for 10 days treatment course</description>
  </arm_group>
  <arm_group>
    <arm_group_label>salvianolate injection arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>only inject salvianolate(200mg+5%Glucose Injection 250ml，iv) for 10 days treatment course</description>
  </arm_group>
  <arm_group>
    <arm_group_label>aspirin and salvianolate injection arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>take aspirin (100mg,qd) orally and inject salvianolate(200mg+5%Glucose Injection 250ml，iv) for 10 days treatment course</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>salvianolate injection</intervention_name>
    <description>The main ingredient of salvianolate injection is salvianolic acid B(SAB) which is extracted from the root of red salvia. Red salvia is used in traditional Chinese Medicine. It could promote blood circulation to removing blood stasis,which is clinically effective in treatment for cardiovascular disease.</description>
    <arm_group_label>aspirin and salvianolate injection arm</arm_group_label>
    <arm_group_label>salvianolate injection arm</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aspirin Tablet</intervention_name>
    <description>Anti-platelet medicine treatment and Chinese traditional medicine (TCM) promoting blood circulation to removing blood stasis is widely used in treatment for cardiovascular disease.</description>
    <arm_group_label>aspirin and salvianolate injection arm</arm_group_label>
    <arm_group_label>aspirin arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Meet the diagnostic criteria of coronary heart disease.&#xD;
&#xD;
          2. Meet the diagnostic criteria of stable angina pectoris.&#xD;
&#xD;
          3. Meet the diagnostic criteria of syndrome of blood stasis.&#xD;
&#xD;
          4. Angina in grade I-II according to Canadian cardiovascular society (CCS).&#xD;
&#xD;
          5. It could be enrolled if the subject taking aspirin or salvianolate injection with one&#xD;
             month regularly。&#xD;
&#xD;
          6. The subjects were informed and voluntarily signed informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Severe heart disease (acute myocardial infarction of acute myocardial infarction in 6&#xD;
             months), severe cardiopulmonary dysfunction (eg: cardiac function II)&#xD;
&#xD;
          2. Poorly controlled hypertension(systolic pressure &gt;160mmHg or diastolic pressure&#xD;
             &gt;100mmHg).&#xD;
&#xD;
          3. Diabetics.&#xD;
&#xD;
          4. Severe primary diseases such as liver and renal hematopoietic system damage. Such&#xD;
             as:liver function（ALT≥2×ULN、AST≥2×ULN）,kidney function（Cr&gt;1.0×ULN) or nervous and&#xD;
             mental disorder.&#xD;
&#xD;
          5. Pregnant, breast-feeding and menstrual women, or women planning pregnancy within 3&#xD;
             months.&#xD;
&#xD;
          6. Subjects who participated in clinical trials in recent 3 months.&#xD;
&#xD;
          7. Subjects who took surgery treatment or had hemorrhagic tendency in recent 4 weeks.&#xD;
&#xD;
          8. Subjects who had drug allergy history or with allergic constitution.&#xD;
&#xD;
          9. Subjects who has mental or physical disorders.&#xD;
&#xD;
         10. Subjects who had bad compliance or is not suitable for this clinical trial by&#xD;
             investigator's judgement&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>35 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Rui Li, MD,Phd</last_name>
    <phone>0086+01062835651</phone>
    <email>crystal005@163.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>wantong Zhang, MD</last_name>
  </overall_contact_backup>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>September 4, 2017</study_first_submitted>
  <study_first_submitted_qc>October 9, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 11, 2017</study_first_posted>
  <last_update_submitted>October 9, 2017</last_update_submitted>
  <last_update_submitted_qc>October 9, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">October 11, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>drug-drug interaction</keyword>
  <keyword>Asprin</keyword>
  <keyword>salvianolate injection</keyword>
  <keyword>PK-PD model</keyword>
  <keyword>metabolic enzymes</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Angina, Stable</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aspirin</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/NCT03306550
org study id: zz0908022
nct id: NCT03306550
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
The combination of anti-platelet medicine treatment and Chinese traditional medicine (TCM)
      promoting blood circulation to removing blood stasis is widely used in treatment for
      cardiovascular disease. However, the material foundation, effective mechanism and drug-drug
      interaction is still not clear. In order to solve the puzzle of rational use of Joint
      application by TCM and Western Medicine(WM),investigators conduct a research on mechanism of
      drug-drug interaction between salvianolate injection and aspirin based on metabolic enzyme
      and PK-PD model. This clinical trial contain three groups, aspirin group, salvianolate
      injection group and combination (salvianolate injection+aspirin) group. Investigators collect
      blood samples at special time points during post-administration.Investigators have already
      find out the Salvianolate's pharmacokinetic characteristics in vivo and establish the
      biological sample-testing analysis method in previous research. Depending on these results,
      this clinical trial aim to explore the pharmacodynamics-pharmacokinetics(PK-PD)
      characteristics of combination with Salvianolate and aspirin through biomarkers, blood
      concentration. Finally clarify the TCM and WM material basis and mutual mechanism of drug
      interaction and guide reasonable clinical prescription.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change of P-selection expression(platelet activation-dependent granule membrane) at different time points.
time frame: Getting blood sample before taking medicine in the day 10 and after it in 15min、1h、2h、8h、24h
description: Use flow cytometric method to detect the P-selection expression on platelet at different time points. Analyse the influence of Asprin/Salvianolate on platelet interaction adhesion during drug concentration-time curves.
measure: Change of PAC-1 expression (platelet-associated complement) on the activated platelets at different time points.
time frame: Getting blood sample before taking medicine in the day 10 and after it in 15min、1h、2h、8h、24h
description: Use flow cytometric method to detect the PAC-1 expression on platelet at different time points. Analyse the influence of Asprin/Salvianolate on platelet aggregation during drug concentration-time curves.
measure: Change of P2Y12 acceptor expression on platelets at different time points. (P2Y12 acceptor is a receptor for ADP(adenosine diphosphate) and ATP (adenosine triphosphate )coupled to G-proteins that inhibit the adenylyl cyclase second messenger system)
time frame: Getting blood sample before taking medicine in the day 10 and after it in 15min、1h、2h、8h、24h
description: Use flow cytometric method to detect the P2Y12 acceptor expression on platelet at different time points. Analyse the influence of Asprin/Salvianolate on platelets aggregation activated by ADP or ATP during drug concentration-time curves.
measure: Change of PDE enzymes（phosphodiesterase）expression on platelet at different time points.
time frame: Getting blood sample before taking medicine in the day 10 and after it in 15min、1h、2h、8h、24h
description: Use ELISA method to detect the PDE enzymes expression at different time points. Analyse the influence of Asprin/Salvianolate on platelets activated by PDE enzymes during drug concentration-time curves.
measure: Change of Aspirin esterase activity at different blood concentration of Asprin/Salvianolate
time frame: Getting blood sample before taking aspirin in day 8 and day 9.In the day 10, getting blood sample before taking aspirin and after taking aspirin in 5min、15min、30min、45min、1h、2h、4h、8h、12h、24h
description: Conduct biological analysis by LC-MS/MS(liquid chromatography tandem mass spectrometry) to detect Aspirin and salicylic aspirin and salicylic acid:CSA/C(ASA+SA).The activity of combination arm and of the asprin arm is compared by t test.
measure: Change of Catechol-o-methyltransferase (COMT) activity at different blood concentration of Asprin/Salvianolate
time frame: Getting blood sample before injection in day 8 and day 9.In the day 10, getting blood sample before injection and after injection in 5min、15min、30min、45min、1h、2h、4h、8h、12h、24h
description: COMT activity is the main metabolic enzymes of SAB.Use kit to detect COMT activity .
arm group label: aspirin arm
arm group type: Active Comparator
description: only take aspirin (100mg,qd) orally for 10 days treatment course
arm group label: salvianolate injection arm
arm group type: Active Comparator
description: only inject salvianolate(200mg+5%Glucose Injection 250ml，iv) for 10 days treatment course
arm group label: aspirin and salvianolate injection arm
arm group type: Experimental
description: take aspirin (100mg,qd) orally and inject salvianolate(200mg+5%Glucose Injection 250ml，iv) for 10 days treatment course
intervention type: Drug
intervention name: salvianolate injection
description: The main ingredient of salvianolate injection is salvianolic acid B(SAB) which is extracted from the root of red salvia. Red salvia is used in traditional Chinese Medicine. It could promote blood circulation to removing blood stasis,which is clinically effective in treatment for cardiovascular disease.
arm group label: aspirin and salvianolate injection arm
arm group label: salvianolate injection arm
intervention type: Drug
intervention name: Aspirin Tablet
description: Anti-platelet medicine treatment and Chinese traditional medicine (TCM) promoting blood circulation to removing blood stasis is widely used in treatment for cardiovascular disease.
arm group label: aspirin and salvianolate injection arm
arm group label: aspirin arm
criteria: 
gender: All
minimum age: 35 Years
maximum age: 65 Years
healthy volunteers: No
last name: Rui Li, MD,Phd
phone: 0086+01062835651
email: crystal005@163.com
last name: wantong Zhang, MD
responsible party type: Sponsor
mesh term: Angina, Stable
mesh term: Aspirin