<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/NCT04415892</url>
  </required_header>
  <id_info>
    <org_study_id>CCP19-3307-CIPN</org_study_id>
    <nct_id>NCT04415892</nct_id>
  </id_info>
  <brief_title>The Role of TRP Channels in CIPN</brief_title>
  <official_title>The Role of Transient Receptor Potential Channels in Chemotherapy-Induced Peripheral Neuropathic Pain.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Universitaire Ziekenhuizen KU Leuven</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Universitaire Ziekenhuizen KU Leuven</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>
      Part I:&#xD;
&#xD;
      Evaluating the increase in dermal blood flow upon topical application of cinnamaldehyde and&#xD;
      capsaicin on the fingers in healthy, male volunteers. In addition, the inter-period and&#xD;
      inter-hand reproducibility of the increase in dermal blood flow will be assessed.&#xD;
&#xD;
      Part II:&#xD;
&#xD;
      Evaluating the increase in dermal blood flow upon topical application of cinnamaldehyde and&#xD;
      capsaicin on the fingers in patients suffering from chemotherapy-induced peripheral&#xD;
      neuropathy compared to matched healthy volunteers.&#xD;
&#xD;
      Part III:&#xD;
&#xD;
      Evaluating the increase in dermal blood flow upon topical application of cinnamaldehyde and&#xD;
      capsaicin on the fingers in patients who are treated with paclitaxel or oxaliplatin.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The primary aim is to investigate whether paclitaxel and/or oxaliplatin alter TRP channel&#xD;
      functionality in vivo in human. TRP functionality can indirectly be assessed via dermal blood&#xD;
      flow changes which are part of the so-called neurogenic inflammation, induced upon TRP&#xD;
      activation. In vivo in human, TRP can be activated via topical application of cinnamaldehyde&#xD;
      or capsaicin on the skin.&#xD;
&#xD;
      In Part I of the study, the DBF changes upon topical application of cinnamaldehyde or&#xD;
      capsaicin on the fingers will be characterized, including inter-period and inter-hand&#xD;
      reproducibility.&#xD;
&#xD;
      In Part II, patients who are suffering from chronic CIPN after treatment with paclitaxel or&#xD;
      oxaliplatin are included. DBF changes upon cinnamaldehyde and capsaicin are compared to a&#xD;
      matched control group.&#xD;
&#xD;
      In Part III, DBF changes are assessed in patients prior to the first administration of&#xD;
      taxol/oxaliplatin and at regular points in time during the dosage regimen.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 1, 2019</start_date>
  <completion_date type="Anticipated">September 30, 2023</completion_date>
  <primary_completion_date type="Anticipated">September 1, 2023</primary_completion_date>
  <phase>N/A</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>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Characterization cinnamaldehyde</measure>
    <time_frame>Dermal blood flow response measured during 60 minutes post-application</time_frame>
    <description>The dermal blood flow response to topical application of cinnamaldehyde as assessed by LASCA on the fingers in healthy, male volunteers.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Inter-hand reproducibility cinnamaldehyde</measure>
    <time_frame>Dermal blood flow response measured simultaneously on both hands during 60 minutes post-application during study visit 1</time_frame>
    <description>The within subject inter-hand reproducibility of the dermal blood flow response to topical application of cinnamaldehyde as assessed by LASCA on the fingers in healthy, male volunteers</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Inter-period reproducibility cinnamaldehyde</measure>
    <time_frame>Interval of at least 5 days between both periods</time_frame>
    <description>The within subject inter-period reproducibility (i.e. assessing changes) of the dermal blood flow response to topical application of cinnamaldehyde as assessed by LASCA on the fingers in healthy, male volunteers</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Characterization capsaicin</measure>
    <time_frame>Dermal blood flow response measured during 60 minutes post-application</time_frame>
    <description>The dermal blood flow response to topical application of capsaicin as assessed by LASCA on the fingers in healthy, male volunteers</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Inter-hand reproducibility capsaicin</measure>
    <time_frame>Dermal blood flow response measured simultaneously on both hands during 60 minutes post-application during study visit 3</time_frame>
    <description>The within subject inter-hand reproducibility of the dermal blood flow response to topical application of capsaicin as assessed by LASCA on the fingers in healthy, male volunteers.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Inter-period reproducibility capsaicin</measure>
    <time_frame>Interval of at least 5 days between both periods</time_frame>
    <description>The within subject inter-period reproducibility (i.e. assessing changes) of the dermal blood flow response to topical application of capsaicin as assessed by LASCA on the fingers in healthy, male volunteers.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>DBF patients compared to healthy volunteers</measure>
    <time_frame>Dermal blood flow measured in patients who are suffering from CIPN 1 to 12 months after the last administration of paclitaxel or oxaliplatin.</time_frame>
    <description>The dermal blood flow changes upon topical application of cinnamaldehyde and capsaicin in patients suffering from chemotherapy-induced peripheral neuropathy compared to matched healthy volunteers.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>DBF in patients before, during and after chemotherapeutic treatment</measure>
    <time_frame>Dermal blood flow measured prior to the first, or within 5 days after administration of paclitaxel or oxaliplatin</time_frame>
    <description>The dermal blood flow changes upon topical application of cinnamaldehyde and capsaicin in patients prior to, during and after treatment with either paclitaxel or oxaliplatin.</description>
  </primary_outcome>
  <number_of_arms>7</number_of_arms>
  <enrollment type="Anticipated">240</enrollment>
  <condition>Chemotherapy-induced Peripheral Neuropathy</condition>
  <arm_group>
    <arm_group_label>Healthy volunteers</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Young, healthy male volunteers to characterize the DBF changes upon cinnamaldehyde and capsaicin, including the reproducibility.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Paclitaxel Patients</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Group of patients after treatment with paclitaxel.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Paclitaxel Controls</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Group of healthy volunteers, matched for sex, age and BMI with the group of Paclitaxel Patients.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Oxaliplatin Patients</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Group of patients after treatment with oxaliplatin.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Oxaliplatin Controls</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Group of healthy volunteers, matched for sex, age and BMI with the group of Oxaliplatin Patients.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Longitudinal Paclitaxel Patients</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Group of patients who are treated with paclitaxel.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Longitudinal Oxaliplatin Patients</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Group of patients who are treated with oxaliplatin.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Cinnamaldehyde and capsaicin</intervention_name>
    <description>Topical application of cinnamaldehyde and capsaicin on the fingers</description>
    <arm_group_label>Healthy volunteers</arm_group_label>
    <arm_group_label>Longitudinal Oxaliplatin Patients</arm_group_label>
    <arm_group_label>Longitudinal Paclitaxel Patients</arm_group_label>
    <arm_group_label>Oxaliplatin Controls</arm_group_label>
    <arm_group_label>Oxaliplatin Patients</arm_group_label>
    <arm_group_label>Paclitaxel Controls</arm_group_label>
    <arm_group_label>Paclitaxel Patients</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria Healthy volunteers:&#xD;
&#xD;
          1. Subject is a white male ≥18 and ≤45 years of age.&#xD;
&#xD;
          2. Subject is a non-smoker for at least 6 months prior to the start of the study.&#xD;
&#xD;
          3. Subject has a body mass index between 18-30 kg/m².&#xD;
&#xD;
          4. Subject is judged to be in good health on the basis of medical history, physical&#xD;
             examination and vital signs.&#xD;
&#xD;
          5. Subject understands the procedures and agrees to participate in the study by giving&#xD;
             written informed consent.&#xD;
&#xD;
          6. Subject is matched to the patient groups for sex, age and BMI (only part II).&#xD;
&#xD;
        Inclusion Criteria Patients of Part II:&#xD;
&#xD;
          1. Subject is a white male or female ≥18 and ≤70 years of age.&#xD;
&#xD;
          2. Subject is a non-smoker for at least 6 months prior to the start of the study.&#xD;
&#xD;
          3. Subject has a BMI between 18-35 kg/m².&#xD;
&#xD;
          4. Subject has a history of treatment with one of the following chemotherapeutic agents:&#xD;
&#xD;
               -  Paclitaxel&#xD;
&#xD;
               -  Oxaliplatin&#xD;
&#xD;
          5. Subject suffers from peripheral neuropathy grade 1, 2 or 3 according to the Total&#xD;
             Neuropathy Score (clinical version). Grade 1 correlates to a score of 1-7, grade 2 to&#xD;
             a score of 8-14 and grade 3 to a score of 15-21(10-12).&#xD;
&#xD;
          6. Subject suffers from neuropathic symptoms in the upper limbs.&#xD;
&#xD;
          7. Discontinuation or termination of therapy with the chemotherapeutic agent occurred &gt;1&#xD;
             month and &lt; 1 year ago.&#xD;
&#xD;
          8. Subject understands the procedures and agrees to participate in the study by giving&#xD;
             written informed consent.&#xD;
&#xD;
        Inclusion Criteria for patients of Part III&#xD;
&#xD;
          1. Subject is a white male or female ≥18 and ≤75 years of age.&#xD;
&#xD;
          2. Subject is a non-smoker for at least 6 months prior to the start of the study.&#xD;
&#xD;
          3. Subject has a BMI between 18-35 kg/m².&#xD;
&#xD;
          4. Subject will receive treatment with paclitaxel or oxaliplatin in the near future.&#xD;
&#xD;
          5. Subject understands the procedures and agrees to participate in the study by giving&#xD;
             written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Subject has eczema, scleroderma, psoriasis, dermatitis, or keloids, tumors, ulcers,&#xD;
             burns, flaps or grafts on their fingers or any other abnormality of the skin which, in&#xD;
             the opinion of the investigator may interfere with the study assessments.&#xD;
&#xD;
          2. Subject has excessive hair growth on the fingers.&#xD;
&#xD;
          3. Subject cannot avoid excessive tanning (any exposure to sunlight or a tanning bed&#xD;
             which would cause a sunburn reaction) throughout the study.&#xD;
&#xD;
          4. Subject has a history of significant severe (drug) allergies.&#xD;
&#xD;
          5. Subject uses any prescription or non-prescription drugs on a regular basis which, in&#xD;
             the investigator's opinion, might confound the results of the study.&#xD;
&#xD;
          6. Subject currently uses lotions, oils, depilatory preparations, makeup, or other&#xD;
             topical treatments on the fingers on a regular basis which cannot be discontinued for&#xD;
             the duration of the study.&#xD;
&#xD;
          7. Subject is unable to refrain from drinking alcohol 24 hours prior to each study visit,&#xD;
             is currently a regular user of any illicit drugs, or has a history of drug (including&#xD;
             alcohol) abuse.&#xD;
&#xD;
          8. Subject is unable to refrain from drinking caffeinated beverages (e.g. coffee, tea,&#xD;
             cola, …) 24 hours prior to each study visit. Subject is unable to limit their intake&#xD;
             of caffeinated beverages to ≤4 cups a day throughout the study.&#xD;
&#xD;
          9. Subject has any of the following vital sign measurements at screening after at least&#xD;
             10 minutes of supine rest: Heart Rate &lt;40 or &gt;100 beats/min, Diastolic Blood Pressure&#xD;
             &lt;50 or &gt;90 mmHg, Systolic Blood Pressure &lt;90 or &gt;140 mmHg.&#xD;
&#xD;
         10. Subject is currently participating or has been involved in testing an investigational&#xD;
             drug in another clinical study within the last 4 weeks.&#xD;
&#xD;
         11. Subject is in a situation or has a condition which, in the opinion of the&#xD;
             investigator, may interfere with safe and optimal participation in the study.&#xD;
&#xD;
         12. Subject has a history of any illness or disorder which, in the investigator's opinion,&#xD;
             might confound the results of the study.&#xD;
&#xD;
         13. Subject suffered from peripheral neuropathy prior to the chemotherapeutic treatment&#xD;
             (Only for patients).&#xD;
&#xD;
         14. Subject has (a history of) diabetes mellitus, amyloidosis, vitamin B deficiency or any&#xD;
             other medical disorder that, in the investigator's opinion, may cause peripheral&#xD;
             neuropathy (only for Part II and III).&#xD;
&#xD;
         15. Subject has (a history of) a lesion in the central nervous system that is known to&#xD;
             possibly cause neuropathic pain: e.g. spinal cord injury, infarction localized in the&#xD;
             brainstem or thalamus, syringomyelia, multiple sclerosis, or any other disorder of the&#xD;
             CNS that, in the investigator's opinion, may cause neuropathic pain (only for Part II&#xD;
             and III).&#xD;
&#xD;
         16. Subject has a history of treatment with bortezomib, vincristine, or any other compound&#xD;
             that, in the investigator's opinion, may cause neuropathic pain (only for Part II and&#xD;
             III).&#xD;
&#xD;
         17. Subject did not develop neuropathy after treatment with epirubicine-cyclofosfamide&#xD;
             (only for the paclitaxel group in Part III).&#xD;
&#xD;
         18. Subject has a family history of peripheral neuropathy (only for Part II and III).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jan de Hoon, MD, PhD, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Center for Clinical Pharmacology</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Heleen Marynissen, MD</last_name>
    <phone>+3216347014</phone>
    <email>heleen.marynissen@uzleuven.be</email>
  </overall_contact>
  <location>
    <facility>
      <name>KU Leuven</name>
      <address>
        <city>Leuven</city>
        <state>Vlaams-Brabant</state>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Heleen Marynissen</last_name>
      <phone>+3216342201</phone>
      <email>heleen.marynissen@uzleuven.be</email>
    </contact>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>May 20, 2020</study_first_submitted>
  <study_first_submitted_qc>June 2, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 4, 2020</study_first_posted>
  <last_update_submitted>July 6, 2022</last_update_submitted>
  <last_update_submitted_qc>July 6, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 11, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Cinnamaldehyde</keyword>
  <keyword>Capsaicin</keyword>
  <keyword>Dermal Blood Flow</keyword>
  <keyword>Fingers</keyword>
  <keyword>Human</keyword>
  <keyword>Reproducibility</keyword>
  <keyword>Paclitaxel</keyword>
  <keyword>Oxaliplatin</keyword>
  <keyword>Peripheral Neuropathy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Peripheral Nervous System Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cinnamaldehyde</mesh_term>
    <mesh_term>Capsaicin</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/NCT04415892
org study id: CCP19-3307-CIPN
nct id: NCT04415892
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Part I:

      Evaluating the increase in dermal blood flow upon topical application of cinnamaldehyde and
      capsaicin on the fingers in healthy, male volunteers. In addition, the inter-period and
      inter-hand reproducibility of the increase in dermal blood flow will be assessed.

      Part II:

      Evaluating the increase in dermal blood flow upon topical application of cinnamaldehyde and
      capsaicin on the fingers in patients suffering from chemotherapy-induced peripheral
      neuropathy compared to matched healthy volunteers.

      Part III:

      Evaluating the increase in dermal blood flow upon topical application of cinnamaldehyde and
      capsaicin on the fingers in patients who are treated with paclitaxel or oxaliplatin.
The primary aim is to investigate whether paclitaxel and/or oxaliplatin alter TRP channel
      functionality in vivo in human. TRP functionality can indirectly be assessed via dermal blood
      flow changes which are part of the so-called neurogenic inflammation, induced upon TRP
      activation. In vivo in human, TRP can be activated via topical application of cinnamaldehyde
      or capsaicin on the skin.

      In Part I of the study, the DBF changes upon topical application of cinnamaldehyde or
      capsaicin on the fingers will be characterized, including inter-period and inter-hand
      reproducibility.

      In Part II, patients who are suffering from chronic CIPN after treatment with paclitaxel or
      oxaliplatin are included. DBF changes upon cinnamaldehyde and capsaicin are compared to a
      matched control group.

      In Part III, DBF changes are assessed in patients prior to the first administration of
      taxol/oxaliplatin and at regular points in time during the dosage regimen.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: None (Open Label)
measure: Characterization cinnamaldehyde
time frame: Dermal blood flow response measured during 60 minutes post-application
description: The dermal blood flow response to topical application of cinnamaldehyde as assessed by LASCA on the fingers in healthy, male volunteers.
measure: Inter-hand reproducibility cinnamaldehyde
time frame: Dermal blood flow response measured simultaneously on both hands during 60 minutes post-application during study visit 1
description: The within subject inter-hand reproducibility of the dermal blood flow response to topical application of cinnamaldehyde as assessed by LASCA on the fingers in healthy, male volunteers
measure: Inter-period reproducibility cinnamaldehyde
time frame: Interval of at least 5 days between both periods
description: The within subject inter-period reproducibility (i.e. assessing changes) of the dermal blood flow response to topical application of cinnamaldehyde as assessed by LASCA on the fingers in healthy, male volunteers
measure: Characterization capsaicin
time frame: Dermal blood flow response measured during 60 minutes post-application
description: The dermal blood flow response to topical application of capsaicin as assessed by LASCA on the fingers in healthy, male volunteers
measure: Inter-hand reproducibility capsaicin
time frame: Dermal blood flow response measured simultaneously on both hands during 60 minutes post-application during study visit 3
description: The within subject inter-hand reproducibility of the dermal blood flow response to topical application of capsaicin as assessed by LASCA on the fingers in healthy, male volunteers.
measure: Inter-period reproducibility capsaicin
time frame: Interval of at least 5 days between both periods
description: The within subject inter-period reproducibility (i.e. assessing changes) of the dermal blood flow response to topical application of capsaicin as assessed by LASCA on the fingers in healthy, male volunteers.
measure: DBF patients compared to healthy volunteers
time frame: Dermal blood flow measured in patients who are suffering from CIPN 1 to 12 months after the last administration of paclitaxel or oxaliplatin.
description: The dermal blood flow changes upon topical application of cinnamaldehyde and capsaicin in patients suffering from chemotherapy-induced peripheral neuropathy compared to matched healthy volunteers.
measure: DBF in patients before, during and after chemotherapeutic treatment
time frame: Dermal blood flow measured prior to the first, or within 5 days after administration of paclitaxel or oxaliplatin
description: The dermal blood flow changes upon topical application of cinnamaldehyde and capsaicin in patients prior to, during and after treatment with either paclitaxel or oxaliplatin.
arm group label: Healthy volunteers
arm group type: Other
description: Young, healthy male volunteers to characterize the DBF changes upon cinnamaldehyde and capsaicin, including the reproducibility.
arm group label: Paclitaxel Patients
arm group type: Other
description: Group of patients after treatment with paclitaxel.
arm group label: Paclitaxel Controls
arm group type: Other
description: Group of healthy volunteers, matched for sex, age and BMI with the group of Paclitaxel Patients.
arm group label: Oxaliplatin Patients
arm group type: Other
description: Group of patients after treatment with oxaliplatin.
arm group label: Oxaliplatin Controls
arm group type: Other
description: Group of healthy volunteers, matched for sex, age and BMI with the group of Oxaliplatin Patients.
arm group label: Longitudinal Paclitaxel Patients
arm group type: Other
description: Group of patients who are treated with paclitaxel.
arm group label: Longitudinal Oxaliplatin Patients
arm group type: Other
description: Group of patients who are treated with oxaliplatin.
intervention type: Other
intervention name: Cinnamaldehyde and capsaicin
description: Topical application of cinnamaldehyde and capsaicin on the fingers
arm group label: Healthy volunteers
arm group label: Longitudinal Oxaliplatin Patients
arm group label: Longitudinal Paclitaxel Patients
arm group label: Oxaliplatin Controls
arm group label: Oxaliplatin Patients
arm group label: Paclitaxel Controls
arm group label: Paclitaxel Patients
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Jan de Hoon, MD, PhD, MSc
role: Principal Investigator
affiliation: Center for Clinical Pharmacology
last name: Heleen Marynissen, MD
phone: +3216347014
email: heleen.marynissen@uzleuven.be
facility: 
status: Recruiting
contact: 
country: Belgium
responsible party type: Sponsor
mesh term: Peripheral Nervous System Diseases
mesh term: Cinnamaldehyde
mesh term: Capsaicin
sharing ipd: No