<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/NCT03287375</url>
  </required_header>
  <id_info>
    <org_study_id>PIPAC-OPC2</org_study_id>
    <nct_id>NCT03287375</nct_id>
  </id_info>
  <brief_title>Treatment of Peritoneal Carcinomatosis With Pressurized IntraPeritoneal Aerosol Chemotherapy -</brief_title>
  <acronym>PIPAC-OPC2</acronym>
  <official_title>Treatment of Peritoneal Carcinomatosis With Pressurized IntraPeritoneal Aerosol - The PIPAC-OPC2 Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Michael Bau Mortensen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Odense University Hospital</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>
      This is a study, where the efficacy of Pressurized IntraPeritoneal Aerosol Chemotherapy&#xD;
      (PIPAC) against peritoneal metastases will be evaluated. Furthermore, this study will focus&#xD;
      on the best evaluation method, where both Quality of Life questionnaires, repeated histology,&#xD;
      cytology and MRI will be used.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patients with peritoneal metastases (PM) will be reviewed by the interdisciplinary tumor&#xD;
      board and included based on predefined in- and exclusion criteria. Eligible candidates with&#xD;
      primary colorectal or appendiceal cancers will be treated with intraperitoneal oxaliplatin&#xD;
      delivered by the PIPAC procedure, while patients with other primary cancers will be treated&#xD;
      with a combination of cisplatin and doxorubicin. Three PIPAC treatments will be scheduled in&#xD;
      intervals of 4-6 weeks (6-7 if combined with systemic chemotherapy). MRI and QoL&#xD;
      questionnaires will be performed at baseline and after three PIPAC treatments. If the&#xD;
      patients respond to the PIPAC treatment, further courses of PIPAC can be planned at the&#xD;
      tumour board meeting.&#xD;
&#xD;
      In brief, PIPAC is performed during a standard laparoscopy using two access ports, where the&#xD;
      magnitude of PM is evaluated using the Peritoneal Carcinosis Index and the Dutch 7 regions&#xD;
      count. Afterwards, the peritoneum is biopsied at different regions and peritoneal lavage&#xD;
      fluid is sent for cytology. Then, chemotherapy is aerosolised within the abdomen, and after&#xD;
      30 minutes, the aerosol has been absorbed by the peritoneum, and the patient is closed&#xD;
      according to departmental guidelines. The patients are expectedly discharged within 24 hours,&#xD;
      and will after each PIPAC treatment be screened for adverse events using the CTCAE and&#xD;
      Dindo-Clavien classification.&#xD;
&#xD;
      Amendment 23-03-2020:&#xD;
&#xD;
      Title Evaluation of the Peritoneal Regression Grading Score in biopsies from clips marked&#xD;
      peritoneal metastases compared to biopsies from the element with most malignant features&#xD;
      during repeated Pressurized IntraPeritoneal Aerosol Chemotherapy&#xD;
&#xD;
      Background Patients with peritoneal metastases (PM) may be treated with protocolled&#xD;
      Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) at Odense PIPAC Center by inclusion&#xD;
      in the prospective PIPAC-OPC2 study. The response evaluation is based on repeated biopsies&#xD;
      from clips marked PM elements retrieved during each PIPAC procedure. Histological regression&#xD;
      is categorized by the Peritoneal Regression Grading Score (PRGS). While the PRGS is&#xD;
      internationally validated and accepted, there is a lack of consensus regarding the biopsy&#xD;
      strategy during subsequent PIPAC procedures. As part of the PIPAC-OPC2 protocol, we define&#xD;
      the element with most malignant features in each of the four abdominal quadrants during the&#xD;
      first PIPAC procedure. We clips mark these elements to be able to take biopsies from the same&#xD;
      area during subsequent procedures, thus reducing sampling error. At other centres, the&#xD;
      biopsies are taken from those elements that are most suspicious of malignancy at visual&#xD;
      inspection during each PIPAC.&#xD;
&#xD;
      The question is whether the histological regression in repeated biopsies from clips marked&#xD;
      elements is influenced by fibrosis from the clips or dominated by scar tissue induced by the&#xD;
      biopsy per se. Moreover, it is possible that PMs may progress in unmarked areas, in spite of&#xD;
      regression in the marked areas. Hypothetically, this could lead to false positive regression,&#xD;
      thus overestimating the histological response to PIPAC.&#xD;
&#xD;
      Objective To investigate if the histologically assessed response to PIPAC is dependent on the&#xD;
      biopsy strategy: Biopsies taken from those areas that are most suspicious of malignancy at&#xD;
      visual inspection compared to re-biopsies of the same, clips marked PM elements during the&#xD;
      second PIPAC procedure.&#xD;
&#xD;
      Number of patients Data from 131 consecutive patients included in the PIPAC-OPC1 or&#xD;
      PIPAC-OPC2 studies show that 67% had more than one PIPAC procedure. The mean PRGS was reduced&#xD;
      by 0.38 points (SD 0.65) from PIPAC 1 to PIPAC 2, based on re-biopsies from clips marked&#xD;
      elements.&#xD;
&#xD;
      With an alpha of 0.05 and a power of 0.80, 25 patients are needed to test the null hypothesis&#xD;
      of no difference between the two biopsy strategies. Patients are their own control.&#xD;
&#xD;
      Methods The present study is an amendment to the PIPAC-OPC2 study. To date, 101/137 patient&#xD;
      have been included. With an expected study termination of no more than 30% of the patients&#xD;
      before PIPAC 2, this amendment is feasible within the framework of the PIPAC-OPC2 study.&#xD;
&#xD;
      A clips marked element is defined as the area covered within two times the length of the&#xD;
      opened jaws of a biopsy forceps. An external surgical oncologist with vast experience of&#xD;
      staging cancer patients will define the PM element with most malignant features before&#xD;
      retrieval of biopsies during the second PIPAC procedure. Accordingly, biopsies will then be&#xD;
      taken from the clips marked elements and the defined element with most malignant features&#xD;
      (potentially same element). The pathologist will be blinded during the analyses of biopsies&#xD;
      from the second PIPAC procedure.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 1, 2016</start_date>
  <completion_date type="Actual">October 1, 2022</completion_date>
  <primary_completion_date type="Actual">February 1, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Cohorte study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of patients with major/complete histologic response (PRGS 1+2) peritoneal biopsies, within a series of three PIPAC procedures.</measure>
    <time_frame>4 years</time_frame>
    <description>Objective Tumor response will be evaluated by the Peritoneal Regression Grading Score based on repeated peritoneal biopsies during each PIPAC procedure.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients with improved Quality of Life (QoL)</measure>
    <time_frame>4 years</time_frame>
    <description>Based on EORTC QLQC30 questionnaire at baseline and after 3 PIPAC treatments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients where MRI is accurate in describing PM distribution and progressive/regressive disease</measure>
    <time_frame>4 years</time_frame>
    <description>Based on MRI of the abdomen at baseline and after 3 PIPAC treatments, it will be evaluated, whether MRI can detect PM and whether MRI can be used to evaluate progression/regression during PIPAC treatment. Comparative gold standard is laparoscopy including biopsies</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">143</enrollment>
  <condition>Peritoneum; Carcinomatosis</condition>
  <condition>Peritoneal Neoplasms</condition>
  <condition>Peritoneal Metastases</condition>
  <condition>Chemotherapy Effect</condition>
  <condition>Chemotherapeutic Toxicity</condition>
  <condition>Quality of Life</condition>
  <condition>Histologic Progression</condition>
  <arm_group>
    <arm_group_label>PIPAC</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Peritoneal metastases (PM) from colorectal or appendiceal cancer will be treated with Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) using oxaliplatin 92 mg/m2 in 150 ml dextrose. Peritoneal metastases (PM) from other GI or gynecologic cancers will be treated with Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) using cisplatin 7.5 mg/m2 in 150 ml saline combined with doxorubicin 1.5 mg/m2 in 50 ml saline. PIPAC is performed during a standard laparoscopy with a capnoperitoneum of 12 mmHg and the aerosolised chemotherapy will be nebulized at a maximum pressure of 200 PSI and a flow rate of 0.5 ml/min. There is no upper number of allowed PIPAC treatments, but they will be planned in series of 3 with 4-6 weeks interval (6-7 weeks if combined with systemic chemotherapy).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>PIPAC</intervention_name>
    <arm_group_label>PIPAC</arm_group_label>
    <other_name>Cisplatin</other_name>
    <other_name>Doxorubicin</other_name>
    <other_name>Oxaliplatin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histological or cytological verified gastrointestinal-, ovarian- or primary peritoneal&#xD;
             malignancy (based on tissue from the primary tumor and/or its metastases).&#xD;
&#xD;
          -  Ovarian cancer patients must be platinum resistant and have completed at least one&#xD;
             line of chemotherapy for platinum resistant disease.&#xD;
&#xD;
          -  Radiological, histological or cytological evidence of PC.&#xD;
&#xD;
          -  No indication for CRS and HIPEC (according to National Guidelines).&#xD;
&#xD;
          -  Performance status 0-1.&#xD;
&#xD;
          -  No more than a single extra-peritoneal metastasis.&#xD;
&#xD;
          -  Age &gt; 18 years.&#xD;
&#xD;
          -  Females must be post-menopausal&#xD;
&#xD;
          -  Written informed consent must be obtained according to the local Ethics Committee&#xD;
             requirements.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Symptomatic small bowel obstruction (i.e. total parenteral nutrition, nasogastric&#xD;
             tube).&#xD;
&#xD;
          -  Previous treatment with maximum cumulative doses of doxorubicin, daunorubicin,&#xD;
             epirubicin, idarubicin, and/or other anthracyclines and anthracenediones.&#xD;
&#xD;
          -  A history of allergic reaction to platinum containing compounds or doxorubicin.&#xD;
&#xD;
          -  Renal impairment, defined as GFR &lt; 40 ml/min, (Cockcroft-Gault Equation).&#xD;
&#xD;
          -  Myocardial insufficiency, defined as NYHA class &gt; 2.&#xD;
&#xD;
          -  Impaired liver function defined as bilirubin ≥ 1.5 x UNL (upper normal limit).&#xD;
&#xD;
          -  Inadequate hematological function defined as ANC ≤ 1.5 x 109/l and platelets ≤ 100&#xD;
             x109/l.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Department of Surgery, Odense University Hospital</name>
      <address>
        <city>Odense</city>
        <zip>5000</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <reference>
    <citation>Solass W, Kerb R, Murdter T, Giger-Pabst U, Strumberg D, Tempfer C, Zieren J, Schwab M, Reymond MA. Intraperitoneal chemotherapy of peritoneal carcinomatosis using pressurized aerosol as an alternative to liquid solution: first evidence for efficacy. Ann Surg Oncol. 2014 Feb;21(2):553-9. doi: 10.1245/s10434-013-3213-1. Epub 2013 Sep 5.</citation>
    <PMID>24006094</PMID>
  </reference>
  <reference>
    <citation>Tempfer CB, Celik I, Solass W, Buerkle B, Pabst UG, Zieren J, Strumberg D, Reymond MA. Activity of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with cisplatin and doxorubicin in women with recurrent, platinum-resistant ovarian cancer: preliminary clinical experience. Gynecol Oncol. 2014 Feb;132(2):307-11. doi: 10.1016/j.ygyno.2013.11.022. Epub 2013 Nov 23.</citation>
    <PMID>24275155</PMID>
  </reference>
  <reference>
    <citation>Solass W, Giger-Pabst U, Zieren J, Reymond MA. Pressurized intraperitoneal aerosol chemotherapy (PIPAC): occupational health and safety aspects. Ann Surg Oncol. 2013 Oct;20(11):3504-11. doi: 10.1245/s10434-013-3039-x. Epub 2013 Jun 14.</citation>
    <PMID>23765417</PMID>
  </reference>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>September 2, 2017</study_first_submitted>
  <study_first_submitted_qc>September 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 19, 2017</study_first_posted>
  <last_update_submitted>October 5, 2022</last_update_submitted>
  <last_update_submitted_qc>October 5, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Odense University Hospital</investigator_affiliation>
    <investigator_full_name>Michael Bau Mortensen</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Peritoneal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cisplatin</mesh_term>
    <mesh_term>Doxorubicin</mesh_term>
    <mesh_term>Oxaliplatin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Publications and presentations will be based on patient data, but the database is not open to other researchers.</ipd_description>
  </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/NCT03287375
org study id: PIPAC-OPC2
nct id: NCT03287375
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This is a study, where the efficacy of Pressurized IntraPeritoneal Aerosol Chemotherapy
      (PIPAC) against peritoneal metastases will be evaluated. Furthermore, this study will focus
      on the best evaluation method, where both Quality of Life questionnaires, repeated histology,
      cytology and MRI will be used.
Patients with peritoneal metastases (PM) will be reviewed by the interdisciplinary tumor
      board and included based on predefined in- and exclusion criteria. Eligible candidates with
      primary colorectal or appendiceal cancers will be treated with intraperitoneal oxaliplatin
      delivered by the PIPAC procedure, while patients with other primary cancers will be treated
      with a combination of cisplatin and doxorubicin. Three PIPAC treatments will be scheduled in
      intervals of 4-6 weeks (6-7 if combined with systemic chemotherapy). MRI and QoL
      questionnaires will be performed at baseline and after three PIPAC treatments. If the
      patients respond to the PIPAC treatment, further courses of PIPAC can be planned at the
      tumour board meeting.

      In brief, PIPAC is performed during a standard laparoscopy using two access ports, where the
      magnitude of PM is evaluated using the Peritoneal Carcinosis Index and the Dutch 7 regions
      count. Afterwards, the peritoneum is biopsied at different regions and peritoneal lavage
      fluid is sent for cytology. Then, chemotherapy is aerosolised within the abdomen, and after
      30 minutes, the aerosol has been absorbed by the peritoneum, and the patient is closed
      according to departmental guidelines. The patients are expectedly discharged within 24 hours,
      and will after each PIPAC treatment be screened for adverse events using the CTCAE and
      Dindo-Clavien classification.

      Amendment 23-03-2020:

      Title Evaluation of the Peritoneal Regression Grading Score in biopsies from clips marked
      peritoneal metastases compared to biopsies from the element with most malignant features
      during repeated Pressurized IntraPeritoneal Aerosol Chemotherapy

      Background Patients with peritoneal metastases (PM) may be treated with protocolled
      Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) at Odense PIPAC Center by inclusion
      in the prospective PIPAC-OPC2 study. The response evaluation is based on repeated biopsies
      from clips marked PM elements retrieved during each PIPAC procedure. Histological regression
      is categorized by the Peritoneal Regression Grading Score (PRGS). While the PRGS is
      internationally validated and accepted, there is a lack of consensus regarding the biopsy
      strategy during subsequent PIPAC procedures. As part of the PIPAC-OPC2 protocol, we define
      the element with most malignant features in each of the four abdominal quadrants during the
      first PIPAC procedure. We clips mark these elements to be able to take biopsies from the same
      area during subsequent procedures, thus reducing sampling error. At other centres, the
      biopsies are taken from those elements that are most suspicious of malignancy at visual
      inspection during each PIPAC.

      The question is whether the histological regression in repeated biopsies from clips marked
      elements is influenced by fibrosis from the clips or dominated by scar tissue induced by the
      biopsy per se. Moreover, it is possible that PMs may progress in unmarked areas, in spite of
      regression in the marked areas. Hypothetically, this could lead to false positive regression,
      thus overestimating the histological response to PIPAC.

      Objective To investigate if the histologically assessed response to PIPAC is dependent on the
      biopsy strategy: Biopsies taken from those areas that are most suspicious of malignancy at
      visual inspection compared to re-biopsies of the same, clips marked PM elements during the
      second PIPAC procedure.

      Number of patients Data from 131 consecutive patients included in the PIPAC-OPC1 or
      PIPAC-OPC2 studies show that 67% had more than one PIPAC procedure. The mean PRGS was reduced
      by 0.38 points (SD 0.65) from PIPAC 1 to PIPAC 2, based on re-biopsies from clips marked
      elements.

      With an alpha of 0.05 and a power of 0.80, 25 patients are needed to test the null hypothesis
      of no difference between the two biopsy strategies. Patients are their own control.

      Methods The present study is an amendment to the PIPAC-OPC2 study. To date, 101/137 patient
      have been included. With an expected study termination of no more than 30% of the patients
      before PIPAC 2, this amendment is feasible within the framework of the PIPAC-OPC2 study.

      A clips marked element is defined as the area covered within two times the length of the
      opened jaws of a biopsy forceps. An external surgical oncologist with vast experience of
      staging cancer patients will define the PM element with most malignant features before
      retrieval of biopsies during the second PIPAC procedure. Accordingly, biopsies will then be
      taken from the clips marked elements and the defined element with most malignant features
      (potentially same element). The pathologist will be blinded during the analyses of biopsies
      from the second PIPAC procedure.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Cohorte study
primary purpose: Treatment
masking: None (Open Label)
measure: Number of patients with major/complete histologic response (PRGS 1+2) peritoneal biopsies, within a series of three PIPAC procedures.
time frame: 4 years
description: Objective Tumor response will be evaluated by the Peritoneal Regression Grading Score based on repeated peritoneal biopsies during each PIPAC procedure.
measure: Number of patients with improved Quality of Life (QoL)
time frame: 4 years
description: Based on EORTC QLQC30 questionnaire at baseline and after 3 PIPAC treatments
measure: Number of patients where MRI is accurate in describing PM distribution and progressive/regressive disease
time frame: 4 years
description: Based on MRI of the abdomen at baseline and after 3 PIPAC treatments, it will be evaluated, whether MRI can detect PM and whether MRI can be used to evaluate progression/regression during PIPAC treatment. Comparative gold standard is laparoscopy including biopsies
arm group label: PIPAC
arm group type: Experimental
description: Peritoneal metastases (PM) from colorectal or appendiceal cancer will be treated with Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) using oxaliplatin 92 mg/m2 in 150 ml dextrose. Peritoneal metastases (PM) from other GI or gynecologic cancers will be treated with Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) using cisplatin 7.5 mg/m2 in 150 ml saline combined with doxorubicin 1.5 mg/m2 in 50 ml saline. PIPAC is performed during a standard laparoscopy with a capnoperitoneum of 12 mmHg and the aerosolised chemotherapy will be nebulized at a maximum pressure of 200 PSI and a flow rate of 0.5 ml/min. There is no upper number of allowed PIPAC treatments, but they will be planned in series of 3 with 4-6 weeks interval (6-7 weeks if combined with systemic chemotherapy).
intervention type: Drug
intervention name: PIPAC
arm group label: PIPAC
other name: Cisplatin
other name: Doxorubicin
other name: Oxaliplatin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: Denmark
citation: Solass W, Kerb R, Murdter T, Giger-Pabst U, Strumberg D, Tempfer C, Zieren J, Schwab M, Reymond MA. Intraperitoneal chemotherapy of peritoneal carcinomatosis using pressurized aerosol as an alternative to liquid solution: first evidence for efficacy. Ann Surg Oncol. 2014 Feb;21(2):553-9. doi: 10.1245/s10434-013-3213-1. Epub 2013 Sep 5.
PMID: 24006094
citation: Tempfer CB, Celik I, Solass W, Buerkle B, Pabst UG, Zieren J, Strumberg D, Reymond MA. Activity of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with cisplatin and doxorubicin in women with recurrent, platinum-resistant ovarian cancer: preliminary clinical experience. Gynecol Oncol. 2014 Feb;132(2):307-11. doi: 10.1016/j.ygyno.2013.11.022. Epub 2013 Nov 23.
PMID: 24275155
citation: Solass W, Giger-Pabst U, Zieren J, Reymond MA. Pressurized intraperitoneal aerosol chemotherapy (PIPAC): occupational health and safety aspects. Ann Surg Oncol. 2013 Oct;20(11):3504-11. doi: 10.1245/s10434-013-3039-x. Epub 2013 Jun 14.
PMID: 23765417
responsible party type: Sponsor-Investigator
investigator affiliation: Odense University Hospital
investigator full name: Michael Bau Mortensen
investigator title: Professor
mesh term: Carcinoma
mesh term: Peritoneal Neoplasms
mesh term: Cisplatin
mesh term: Doxorubicin
mesh term: Oxaliplatin
sharing ipd: No
ipd description: Publications and presentations will be based on patient data, but the database is not open to other researchers.