<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/NCT04454229</url>
  </required_header>
  <id_info>
    <org_study_id>PALACE1</org_study_id>
    <nct_id>NCT04454229</nct_id>
  </id_info>
  <brief_title>The Use of Penicillin Allergy Clinical Decision Rule to Enable Direct Oral Penicillin Challenge</brief_title>
  <acronym>PALACE</acronym>
  <official_title>The Use of Penicillin Allergy Clinical Decision Rule to Enable Direct Oral Penicillin Challenge - An International Multicenter Randomized Control Trial - The PALACE Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Austin Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Austin Health</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Whilst validated tools exist to enable inpatient penicillin assessment and de-labelling,&#xD;
      limited evidence is available regarding the safety and efficacy in the outpatient clinic. The&#xD;
      ability to deliver point-of-care penicillin allergy testing for a large cohort of patients,&#xD;
      without skin testing, will improve patient access to testing and utilization of preferred&#xD;
      penicillin antibiotics.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Patient-reported penicillin allergies result in poor health outcomes for patients and drive&#xD;
      inappropriate antibiotic prescribing, antimicrobial resistance and healthcare costs. Our&#xD;
      group has internally and externally validated a novel penicillin allergy clinician decision&#xD;
      rule (PEN-FAST) that is able to identify low risk penicillin allergies with a negative&#xD;
      predictive value of 96% (95%; 94-98%). Therefore, whilst validated tools exist to enable&#xD;
      inpatient penicillin assessment and de-labelling, limited evidence is available regarding the&#xD;
      safety and efficacy in the outpatient clinic. The ability to deliver point-of-care penicillin&#xD;
      allergy testing for a large cohort of patients, without skin testing, will improve patient&#xD;
      access to testing and utilization of preferred penicillin antibiotics.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 1, 2021</start_date>
  <completion_date type="Actual">December 2, 2022</completion_date>
  <primary_completion_date type="Actual">December 2, 2022</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>
    <intervention_model_description>Direct oral challenge in patients with PEN-Fast less than 3&#xD;
Eligible patients referred to the outpatient clinic reporting a penicillin allergy will be identified and assessed with a standard clinical history and the calculation of the PEN-FAST score. PEN-FAST is a three-point clinical assessment tool recently externally validated in a multicenter study, with a PEN-FAST score of &lt; 3 associated with 96.7% negative predictive value.&#xD;
Intervention:&#xD;
The patient will receive a single dose of oral penicillin, following baseline vital signs (i.e. temperature, heart rate, blood pressure, respiratory rate, skin check).&#xD;
Nursing staff will repeat vital signs as needed and after oral challenge while observing for signs of an immune mediated adverse reaction.&#xD;
If at any stage an antibiotic associated adverse event is noted, standard of care treatment is offered by the attending clinicians (ex. adrenalin for immediate hypersensitivity reaction).</intervention_model_description>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The difference in the proportion of positive oral challenges (i.e. immune-mediated reaction)</measure>
    <time_frame>up to 48H after oral challenge</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients referred to the outpatient allergy clinic that are eligible for intervention (i.e randomization) as per protocol [Eligibility to screened ratio]</measure>
    <time_frame>Before randomization</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Feasibility of recruitment defined as the proportion of patients consenting to participate in the study as per protocol from eligible patients. [Recruitment to eligibility ratio].</measure>
    <time_frame>Before randomization</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Feasibility of intervention delivery defined as the proportion of patients randomized to the intervention arm who had the intervention delivered as per protocol. [Intervention to recruitment ratio]</measure>
    <time_frame>Before randomization</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The proportion of patients with a penicillin allergy who experience an antibiotic associated immune mediated adverse event OR severe adverse drug reaction as per protocol definitions.</measure>
    <time_frame>Up to 48h after the drug challenge</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The proportion of patients with a penicillin allergy who experience an antibiotic associated non-immune mediated adverse event.</measure>
    <time_frame>Up to 48h after the drug challenge</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The proportion of patients that will respect the protocol (protocol compliance)</measure>
    <time_frame>Up to 48h after the drug challenge</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patient with positive Penicillin Skin Testing</measure>
    <time_frame>Up to 48h after the drug challenge</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with non-immune mediated positive oral provocation</measure>
    <time_frame>Up to 48h after the drug challenge</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with severe adverse reaction - anaphylaxis/death</measure>
    <time_frame>Up to 48h after the drug challenge</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time from randomization to delabelling</measure>
    <time_frame>Up to 48h after the drug challenge</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of appointments required for Penicillin delabelling</measure>
    <time_frame>Up to 48h after the drug challenge</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment with the Pre-Questionnaire and the 6 months follow-up Questionnaire</measure>
    <time_frame>Up to 6 months after the drug challenge</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">382</enrollment>
  <condition>Hypersensitivity, Immediate</condition>
  <condition>Hypersensitivity, Delayed</condition>
  <condition>Hypersensitivity Response</condition>
  <arm_group>
    <arm_group_label>Direct oral antibiotic challenge</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Direct oral antibiotic (penicillin) challenge in patients with PEN-Fast less than 3.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of care</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Standard of care: skin testing and, if negative, oral challenge.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Direct oral penicillin challenge</intervention_name>
    <description>The patient will receive a single dose of oral penicillin, following baseline vital signs.</description>
    <arm_group_label>Direct oral antibiotic challenge</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Standard of care</intervention_name>
    <description>Routine management as per the treating clinicians that include skin prick and intradermal beta-lactam testing, followed by oral penicillin challenge in the setting of negative skin testing.</description>
    <arm_group_label>Standard of care</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adult patients referred to the outpatient allergy clinic for a penicillin allergy&#xD;
             history;&#xD;
&#xD;
          2. Willing and able to give consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patient age is &lt; 18 years;&#xD;
&#xD;
          2. Patients with a PEN-FAST score less than 3&#xD;
&#xD;
          3. Pregnancy;&#xD;
&#xD;
          4. Any other illness that, in the investigator's judgement, will substantially increase&#xD;
             the risk associated with subject's participation in this study;&#xD;
&#xD;
          5. Patients with history of type A adverse drug reaction, drug-associated anaphylaxis,&#xD;
             idiopathic urticaria/anaphylaxis, mastocytosis, serum sickness, blistering skin&#xD;
             eruption or acute interstitial nephritis;&#xD;
&#xD;
          6. Patients where the allergy history was not able to be confirmed with patient;&#xD;
&#xD;
          7. Patients on concurrent antihistamine therapy;&#xD;
&#xD;
          8. Patients receiving more than stress dose steroids (i.e. &gt; 50mg QID hydrocortisone [or&#xD;
             steroid equivalent]).&#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>Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vanderbilt University Medical Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Austin Health</name>
      <address>
        <city>Heidelberg</city>
        <state>Victoria</state>
        <zip>3084</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Peter MacCallum Cancer Center</name>
      <address>
        <city>Melbourne</city>
        <state>Victoria</state>
        <zip>3000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Melbourne Hospital</name>
      <address>
        <city>Melbourne</city>
        <state>Victoria</state>
        <zip>3000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>McGill University Health Centre (MUHC)</name>
      <address>
        <city>Montreal</city>
        <state>Quebec</state>
        <zip>H3G 1A4</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Canada</country>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Trubiano JA, Vogrin S, Chua KYL, Bourke J, Yun J, Douglas A, Stone CA, Yu R, Groenendijk L, Holmes NE, Phillips EJ. Development and Validation of a Penicillin Allergy Clinical Decision Rule. JAMA Intern Med. 2020 May 1;180(5):745-752. doi: 10.1001/jamainternmed.2020.0403.</citation>
    <PMID>32176248</PMID>
  </results_reference>
  <results_reference>
    <citation>Devchand M, Urbancic KF, Khumra S, Douglas AP, Smibert O, Cohen E, Sutherland M, Phillips EJ, Trubiano JA. Pathways to improved antibiotic allergy and antimicrobial stewardship practice: The validation of a beta-lactam antibiotic allergy assessment tool. J Allergy Clin Immunol Pract. 2019 Mar;7(3):1063-1065.e5. doi: 10.1016/j.jaip.2018.07.048. Epub 2018 Aug 29.</citation>
    <PMID>30172019</PMID>
  </results_reference>
  <results_reference>
    <citation>Trubiano JA, Smibert O, Douglas A, Devchand M, Lambros B, Holmes NE, Chua KY, Phillips EJ, Slavin MA. The Safety and Efficacy of an Oral Penicillin Challenge Program in Cancer Patients: A Multicenter Pilot Study. Open Forum Infect Dis. 2018 Nov 17;5(12):ofy306. doi: 10.1093/ofid/ofy306. eCollection 2018 Dec.</citation>
    <PMID>30547046</PMID>
  </results_reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>June 25, 2020</study_first_submitted>
  <study_first_submitted_qc>June 29, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 1, 2020</study_first_posted>
  <last_update_submitted>March 2, 2023</last_update_submitted>
  <last_update_submitted_qc>March 2, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>McGill University Health Centre/Research Institute of the McGill University Health Centre</investigator_affiliation>
    <investigator_full_name>Ana Copaescu</investigator_full_name>
    <investigator_title>Physician-Scientist Immunology and Allergy</investigator_title>
  </responsible_party>
  <keyword>penicillin</keyword>
  <keyword>Low Risk allergy</keyword>
  <keyword>direct oral challenge</keyword>
  <keyword>standard of care</keyword>
  <keyword>outpatient clinic</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypersensitivity</mesh_term>
    <mesh_term>Hypersensitivity, Immediate</mesh_term>
    <mesh_term>Hypersensitivity, Delayed</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Penicillins</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 10, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/29/NCT04454229/SAP_002.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT04454229
org study id: PALACE1
nct id: NCT04454229
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Whilst validated tools exist to enable inpatient penicillin assessment and de-labelling,
      limited evidence is available regarding the safety and efficacy in the outpatient clinic. The
      ability to deliver point-of-care penicillin allergy testing for a large cohort of patients,
      without skin testing, will improve patient access to testing and utilization of preferred
      penicillin antibiotics.
Patient-reported penicillin allergies result in poor health outcomes for patients and drive
      inappropriate antibiotic prescribing, antimicrobial resistance and healthcare costs. Our
      group has internally and externally validated a novel penicillin allergy clinician decision
      rule (PEN-FAST) that is able to identify low risk penicillin allergies with a negative
      predictive value of 96% (95%; 94-98%). Therefore, whilst validated tools exist to enable
      inpatient penicillin assessment and de-labelling, limited evidence is available regarding the
      safety and efficacy in the outpatient clinic. The ability to deliver point-of-care penicillin
      allergy testing for a large cohort of patients, without skin testing, will improve patient
      access to testing and utilization of preferred penicillin antibiotics.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Direct oral challenge in patients with PEN-Fast less than 3
Eligible patients referred to the outpatient clinic reporting a penicillin allergy will be identified and assessed with a standard clinical history and the calculation of the PEN-FAST score. PEN-FAST is a three-point clinical assessment tool recently externally validated in a multicenter study, with a PEN-FAST score of < 3 associated with 96.7% negative predictive value.
Intervention:
The patient will receive a single dose of oral penicillin, following baseline vital signs (i.e. temperature, heart rate, blood pressure, respiratory rate, skin check).
Nursing staff will repeat vital signs as needed and after oral challenge while observing for signs of an immune mediated adverse reaction.
If at any stage an antibiotic associated adverse event is noted, standard of care treatment is offered by the attending clinicians (ex. adrenalin for immediate hypersensitivity reaction).
primary purpose: Diagnostic
masking: None (Open Label)
measure: The difference in the proportion of positive oral challenges (i.e. immune-mediated reaction)
time frame: up to 48H after oral challenge
measure: Proportion of patients referred to the outpatient allergy clinic that are eligible for intervention (i.e randomization) as per protocol [Eligibility to screened ratio]
time frame: Before randomization
measure: Feasibility of recruitment defined as the proportion of patients consenting to participate in the study as per protocol from eligible patients. [Recruitment to eligibility ratio].
time frame: Before randomization
measure: Feasibility of intervention delivery defined as the proportion of patients randomized to the intervention arm who had the intervention delivered as per protocol. [Intervention to recruitment ratio]
time frame: Before randomization
measure: The proportion of patients with a penicillin allergy who experience an antibiotic associated immune mediated adverse event OR severe adverse drug reaction as per protocol definitions.
time frame: Up to 48h after the drug challenge
measure: The proportion of patients with a penicillin allergy who experience an antibiotic associated non-immune mediated adverse event.
time frame: Up to 48h after the drug challenge
measure: The proportion of patients that will respect the protocol (protocol compliance)
time frame: Up to 48h after the drug challenge
measure: Proportion of patient with positive Penicillin Skin Testing
time frame: Up to 48h after the drug challenge
measure: Proportion of patients with non-immune mediated positive oral provocation
time frame: Up to 48h after the drug challenge
measure: Proportion of patients with severe adverse reaction - anaphylaxis/death
time frame: Up to 48h after the drug challenge
measure: Time from randomization to delabelling
time frame: Up to 48h after the drug challenge
measure: Number of appointments required for Penicillin delabelling
time frame: Up to 48h after the drug challenge
measure: Assessment with the Pre-Questionnaire and the 6 months follow-up Questionnaire
time frame: Up to 6 months after the drug challenge
arm group label: Direct oral antibiotic challenge
arm group type: Experimental
description: Direct oral antibiotic (penicillin) challenge in patients with PEN-Fast less than 3.
arm group label: Standard of care
arm group type: Active Comparator
description: Standard of care: skin testing and, if negative, oral challenge.
intervention type: Other
intervention name: Direct oral penicillin challenge
description: The patient will receive a single dose of oral penicillin, following baseline vital signs.
arm group label: Direct oral antibiotic challenge
intervention type: Other
intervention name: Standard of care
description: Routine management as per the treating clinicians that include skin prick and intradermal beta-lactam testing, followed by oral penicillin challenge in the setting of negative skin testing.
arm group label: Standard of care
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Australia
country: Canada
country: United States
citation: Trubiano JA, Vogrin S, Chua KYL, Bourke J, Yun J, Douglas A, Stone CA, Yu R, Groenendijk L, Holmes NE, Phillips EJ. Development and Validation of a Penicillin Allergy Clinical Decision Rule. JAMA Intern Med. 2020 May 1;180(5):745-752. doi: 10.1001/jamainternmed.2020.0403.
PMID: 32176248
citation: Devchand M, Urbancic KF, Khumra S, Douglas AP, Smibert O, Cohen E, Sutherland M, Phillips EJ, Trubiano JA. Pathways to improved antibiotic allergy and antimicrobial stewardship practice: The validation of a beta-lactam antibiotic allergy assessment tool. J Allergy Clin Immunol Pract. 2019 Mar;7(3):1063-1065.e5. doi: 10.1016/j.jaip.2018.07.048. Epub 2018 Aug 29.
PMID: 30172019
citation: Trubiano JA, Smibert O, Douglas A, Devchand M, Lambros B, Holmes NE, Chua KY, Phillips EJ, Slavin MA. The Safety and Efficacy of an Oral Penicillin Challenge Program in Cancer Patients: A Multicenter Pilot Study. Open Forum Infect Dis. 2018 Nov 17;5(12):ofy306. doi: 10.1093/ofid/ofy306. eCollection 2018 Dec.
PMID: 30547046
responsible party type: Principal Investigator
investigator affiliation: McGill University Health Centre/Research Institute of the McGill University Health Centre
investigator full name: Ana Copaescu
investigator title: Physician-Scientist Immunology and Allergy
mesh term: Hypersensitivity
mesh term: Hypersensitivity, Immediate
mesh term: Hypersensitivity, Delayed
mesh term: Penicillins
provided document: 