<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/NCT03296345</url>
  </required_header>
  <id_info>
    <org_study_id>2010-010</org_study_id>
    <nct_id>NCT03296345</nct_id>
  </id_info>
  <brief_title>Adjuvant Low-dose Ketamine in Pediatric Sickle Cell Vaso-occlusive Crisis</brief_title>
  <acronym>AKTSS</acronym>
  <official_title>Adjuvant Low-dose Ketamine in Pediatric Sickle Cell Vaso-occlusive Crisis (AKTSS)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>UCSF Benioff Children's Hospital Oakland</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>UCSF Benioff Children's Hospital Oakland</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Acute vaso-occlusive episodes (VOEs) in sickle cell disease (SCD) are primarily managed with&#xD;
      opioids. Tolerance and hyperalgesia to opioids develops due to N-methyl-D-aspartate&#xD;
      (NMDA)-receptor mediated activation of the nociceptive system, and as a receptor antagonist,&#xD;
      ketamine mitigates this. Intravenous (IV) ketamine has demonstrated efficacy in reducing&#xD;
      post-operative, chronic, and cancer-related pain in pediatrics, as well as in reducing time&#xD;
      to pain control in the emergency department (ED) in adults. Limited studies suggest efficacy&#xD;
      in adult opioid-refractory SCD patients. This study is investigating the safety and&#xD;
      tolerability of adjuvant low-dose IV ketamine bolus for pediatric SCD VOE in the ED, as well&#xD;
      as its efficacy in improving pain control and reducing hospitalization.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In this cohort study, all consenting pediatric sickle-cell patients between 10 and 25 years&#xD;
      old who were cared for at UCSF Benioff Children's Hospital Oakland (UCSFBCHO) presenting to&#xD;
      the emergency department for VOC were enrolled in the study. Patients were compared to&#xD;
      themselves in a time series, pre and post exposure to the study intervention (low-dose&#xD;
      ketamine bolus at 0.2 mg/kg x 1 prior to second dose of IV opiate). The pediatric FACES pain&#xD;
      scale was used to measure pain scales at pre-designated time points in the ED per standard&#xD;
      nursing protocol (FACES for younger kids, visual analog scale in adolescents/young adults).&#xD;
      Opiate usage was summed in the ED, converted to mg/kg/hour of morphine equivalents (since&#xD;
      different opioids agents were given to different patients based on individual historical&#xD;
      efficacy, and since length of stay in the emergency room could affect total morphine&#xD;
      equivalents received), and compared between the pre and post-intervention groups. In&#xD;
      addition, length of stay, time to 50% pain control, presentation and discharge pain scores,&#xD;
      and likelihood of discharge from the ED were compared. Data was be collected via chart review&#xD;
      in the UCSFBCHO system by study investigators. Pre-intervention data from the past three&#xD;
      patient encounters (e.g., the mean of the mg/kg/hour of morphine equivalents used in the last&#xD;
      three patient encounters prior to receipt of ketamine) was compared to the post intervention&#xD;
      data. In addition, a survey, which is attached, was given to patients/families at the time of&#xD;
      the drug administration to attempt to discern if patients subjectively experienced&#xD;
      improvement in their pain and if they experienced any negative side effects due to the drug&#xD;
      administration. Monitoring for adverse events was recorded for each patient encounter.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>June 2016</start_date>
  <completion_date type="Actual">April 2018</completion_date>
  <primary_completion_date type="Actual">April 2018</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]</measure>
    <time_frame>18 months</time_frame>
    <description>The number of serious and minor adverse events was measured via patient-completed survey as well as by nurse and medical providers on presentation to the emergency department (ED). Serious adverse events are defined as cardiorespiratory events requiring intervention. Minor adverse events are defined as nausea/vomiting, emergence reaction (dysphoria; hallucinations; frightening dreams), and a sense of de-realization or &quot;dreamy&quot; sensation. Both study providers and patients themselves, via a survey that the parent and/or patient (based on age) fills out post receipt of ketamine, reported serious and minor adverse events.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Effect of Low-dose Ketamine (LDK) on Opioid Usage in the ED</measure>
    <time_frame>Up to one year prior and after LDK administration on day 1 of the study in the ED</time_frame>
    <description>Opioid usage for at least one but up to three prior patient visits in the last one year for each patient enrolled in the study was summarized, expressed as morphine equivalents in mg/kg/h, to account for different types of opioids used per patient preference, and then this was compared to the intervention group that received LDK. Percent change in opioid usage (expressed as morphine equivalents in mg/kg/h) is reported).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of Low-dose Ketamine on Pain Scores on Presentation to the ED</measure>
    <time_frame>Up to one year prior and on presentation to the ED after LDK administration</time_frame>
    <description>Patient pain scores at presentation for the enrolled encounters and for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. At least one but up to three prior visits were averaged and compared to the intervention visit. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of Low-dose Ketamine on Discharge Rates From the ED</measure>
    <time_frame>Up to one year prior to receipt of ketamine for the historical control arm/group and up to 18 months for the intervention arm/group</time_frame>
    <description>Percent discharge from the ED for intervention group and for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. Participants were assigned a &quot;0&quot; if discharged or &quot;1&quot; if not discharged.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Subjective Effect of Low Dose Ketamine on Pain Relief Assessed Via a Patient Survey</measure>
    <time_frame>after LDK administration on day 1 of the study in the ED</time_frame>
    <description>After receipt of LDK, patients and/or their parents, based on age, filled out a survey based on a Likert scale regarding their agreement (Strongly Disagree to Strongly Agree) with the following statements: Achieved faster pain relief with LDK, Achieved more complete pain relief with LDK, and Desire to receive LDK in a future vaso-occlusive crisis. There is also an area where patients could provide general comments regarding their experience in receiving LDK.&#xD;
Count of Participants who agree or strongly agree for each question are reported.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of Low-dose Ketamine on Patient Pain Scores on Discharge From the ED/Admission to the Hospital</measure>
    <time_frame>At time of discharge from the ED/admission to the hospital (up to one year prior and after LDK administration)</time_frame>
    <description>Patient pain scores at time of discharge from the ED/admission to the hospital for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. At least one but up to three prior visits were averaged and compared to the intervention visit. Pain scores post receipt of ketamine are presented for the intervention group. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of Low-dose Ketamine on Percent Difference of Length of Stay (LOS) in the ED</measure>
    <time_frame>Up to one year prior to and after LDK administration on day 1 of the study in the ED</time_frame>
    <description>Length of stay (LOS) in minutes in the ED for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of Low-dose Ketamine on Time to 50% Pain Reduction</measure>
    <time_frame>Up to one year prior to and after LDK administration on day 1 of the study in the ED</time_frame>
    <description>Time to 50% pain reduction (pain reported 50% less than baseline) in minutes for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed as historical controls. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">62</enrollment>
  <condition>Sickle Cell Disease</condition>
  <condition>Vaso-Occlusive Crisis</condition>
  <arm_group>
    <arm_group_label>Intervention</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg. Pain scores were collected using the FACES scale currently in place. In consenting patients, chart review was performed with the following data collected: mg/kg/hour of morphine equivalents, pain scores on admission, during the encounter, and at discharge, the time to 50% pain reduction, and whether or not the patient was discharged.&#xD;
In addition, a survey, which is attached, was given to patients/families at the time of drug administration to determine if they experienced a subjective improvement in their pain and if they suffered any undue side effects due to drug administration.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Historical Control</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Patient data from at least one but up three patient encounters within the prior year were compared to their visit in which they were given adjuvant ketamine, using the outcome measures in the &quot;Intervention&quot; arm. Since this a historical control study, patients acted as their own controls in the above manner. Patients were allowed to re-enroll 4 weeks after presentation, which is typically considered a separate vaso-occlusive episode in the literature.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ketamine</intervention_name>
    <description>The intervention is IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs).</description>
    <arm_group_label>Intervention</arm_group_label>
    <other_name>Ketalar</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  All English-speaking, sickle cell patients who receive their care at UCSFBCHO in the&#xD;
             Department of Hematology who are 8-to-25-years-old presenting to the emergency&#xD;
             department for VOC were asked to enroll.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior adverse reaction to ketamine&#xD;
&#xD;
          -  Patients were asked during the consent process if they have ever received ketamine,&#xD;
             and if so, if they had any serious adverse reaction, such as difficulty breathing,&#xD;
             dysphoria, hallucinations, or allergic reaction. If they have, ketamine was not given&#xD;
             to these patients.&#xD;
&#xD;
          -  Patients who have received ketamine and experienced nausea or vomiting will be asked&#xD;
             if they wish to receive the medication. If they do not, they did not receive ketamine.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>10 Years</minimum_age>
    <maximum_age>25 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jonathan B Cooper-Sood, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children's Hospital and Research Center of Oakland</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UCSF Benioff Children's Hospital and Research Center Oakland</name>
      <address>
        <city>Oakland</city>
        <state>California</state>
        <zip>94609</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Neri CM, Pestieau SR, Darbari DS. Low-dose ketamine as a potential adjuvant therapy for painful vaso-occlusive crises in sickle cell disease. Paediatr Anaesth. 2013 Aug;23(8):684-9. doi: 10.1111/pan.12172. Epub 2013 Apr 9.</citation>
    <PMID>23565738</PMID>
  </reference>
  <reference>
    <citation>Tawfic QA, Faris AS, Eipe N. Sickle cell pain management: are we missing the role of pronociception and neuropathic pain? Paediatr Anaesth. 2013 Nov;23(11):1104-5. doi: 10.1111/pan.12269. No abstract available.</citation>
    <PMID>24088202</PMID>
  </reference>
  <reference>
    <citation>Jennings CA, Bobb BT, Noreika DM, Coyne PJ. Oral ketamine for sickle cell crisis pain refractory to opioids. J Pain Palliat Care Pharmacother. 2013 Jun;27(2):150-4. doi: 10.3109/15360288.2013.788599. Epub 2013 May 21.</citation>
    <PMID>23692261</PMID>
  </reference>
  <reference>
    <citation>Zempsky WT, Loiselle KA, Corsi JM, Hagstrom JN. Use of low-dose ketamine infusion for pediatric patients with sickle cell disease-related pain: a case series. Clin J Pain. 2010 Feb;26(2):163-7. doi: 10.1097/AJP.0b013e3181b511ab.</citation>
    <PMID>20090444</PMID>
  </reference>
  <reference>
    <citation>Riha H, Aaronson P, Schmidt A. Evaluation of analgesic effects of ketamine through sub-dissociative dosing in the ED. Am J Emerg Med. 2015 Jun;33(6):847-9. doi: 10.1016/j.ajem.2015.03.045. Epub 2015 Mar 25. No abstract available.</citation>
    <PMID>25865160</PMID>
  </reference>
  <reference>
    <citation>Beaudoin FL, Lin C, Guan W, Merchant RC. Low-dose ketamine improves pain relief in patients receiving intravenous opioids for acute pain in the emergency department: results of a randomized, double-blind, clinical trial. Acad Emerg Med. 2014 Nov;21(11):1193-202. doi: 10.1111/acem.12510.</citation>
    <PMID>25377395</PMID>
  </reference>
  <reference>
    <citation>Drake AB, Milne WK, Carpenter CR. Hot Off the Press: Subdissociative-dose Ketamine for Acute Pain in the Emergency Department. Acad Emerg Med. 2015 Jul;22(7):887-9. doi: 10.1111/acem.12705. Epub 2015 Jun 30. No abstract available.</citation>
    <PMID>26130219</PMID>
  </reference>
  <reference>
    <citation>Miller JP, Schauer SG, Ganem VJ, Bebarta VS. Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial. Am J Emerg Med. 2015 Mar;33(3):402-8. doi: 10.1016/j.ajem.2014.12.058. Epub 2015 Jan 7.</citation>
    <PMID>25624076</PMID>
  </reference>
  <reference>
    <citation>Uprety D, Baber A, Foy M. Ketamine infusion for sickle cell pain crisis refractory to opioids: a case report and review of literature. Ann Hematol. 2014 May;93(5):769-71. doi: 10.1007/s00277-013-1954-3. Epub 2013 Nov 15.</citation>
    <PMID>24232306</PMID>
  </reference>
  <reference>
    <citation>Tawfic QA, Faris AS, Kausalya R. The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease. J Pain Symptom Manage. 2014 Feb;47(2):334-40. doi: 10.1016/j.jpainsymman.2013.03.012. Epub 2013 Jul 12.</citation>
    <PMID>23856095</PMID>
  </reference>
  <reference>
    <citation>Ahern TL, Herring AA, Anderson ES, Madia VA, Fahimi J, Frazee BW. The first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED. Am J Emerg Med. 2015 Feb;33(2):197-201. doi: 10.1016/j.ajem.2014.11.010. Epub 2014 Nov 15.</citation>
    <PMID>25488336</PMID>
  </reference>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>January 9, 2017</study_first_submitted>
  <study_first_submitted_qc>September 23, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 28, 2017</study_first_posted>
  <results_first_submitted>November 17, 2020</results_first_submitted>
  <results_first_submitted_qc>March 25, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">April 20, 2021</results_first_posted>
  <last_update_submitted>March 25, 2021</last_update_submitted>
  <last_update_submitted_qc>March 25, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 20, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Ketamine</keyword>
  <keyword>Sickle Cell Disease</keyword>
  <keyword>Vaso-Occlusive Episode</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia, Sickle Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ketamine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 28, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/45/NCT03296345/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Study Participants</title>
          <description>Intervention: Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg.&#xD;
Ketamine: The intervention was IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs).&#xD;
Ultimately, 62 patient encounters were enrolled in the study.&#xD;
Historical Control: Patient data from at least one but up three patient encounters within the prior year were compared to their visit in which they were given adjuvant ketamine, using the outcome measures in the &quot;Intervention&quot; arm. Since this a historical control study, patients acted as their own controls in the above manner. Patients were allowed to re-enroll 4 weeks after presentation, which is typically considered a separate vaso-occlusive episode in the literature.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="62"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="62"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Study Participants</title>
          <description>Intervention: Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg.&#xD;
Ketamine: The intervention is IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs).</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="62"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="18.1" lower_limit="14" upper_limit="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="45"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="61"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Site of pain on presentation</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Back</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Extremity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Chest</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Whole body</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Abdomen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Other</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]</title>
        <description>The number of serious and minor adverse events was measured via patient-completed survey as well as by nurse and medical providers on presentation to the emergency department (ED). Serious adverse events are defined as cardiorespiratory events requiring intervention. Minor adverse events are defined as nausea/vomiting, emergence reaction (dysphoria; hallucinations; frightening dreams), and a sense of de-realization or &quot;dreamy&quot; sensation. Both study providers and patients themselves, via a survey that the parent and/or patient (based on age) fills out post receipt of ketamine, reported serious and minor adverse events.</description>
        <time_frame>18 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Intervention</title>
            <description>Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg.&#xD;
Ketamine: The intervention was IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs).&#xD;
Ultimately, 62 patient encounters were enrolled in the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]</title>
          <description>The number of serious and minor adverse events was measured via patient-completed survey as well as by nurse and medical providers on presentation to the emergency department (ED). Serious adverse events are defined as cardiorespiratory events requiring intervention. Minor adverse events are defined as nausea/vomiting, emergence reaction (dysphoria; hallucinations; frightening dreams), and a sense of de-realization or &quot;dreamy&quot; sensation. Both study providers and patients themselves, via a survey that the parent and/or patient (based on age) fills out post receipt of ketamine, reported serious and minor adverse events.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="62"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Serious adverse events</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Nausea/vomiting</title>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Emergence of emergence-like symptoms</title>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Dream-like/de-realized sensation</title>
                  <measurement_list>
                    <measurement group_id="O1" value="26"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Blurry vision</title>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Dizziness</title>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Floating sensation</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Heavy sensation</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Dry mouth</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No adverse event</title>
                  <measurement_list>
                    <measurement group_id="O1" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Effect of Low-dose Ketamine (LDK) on Opioid Usage in the ED</title>
        <description>Opioid usage for at least one but up to three prior patient visits in the last one year for each patient enrolled in the study was summarized, expressed as morphine equivalents in mg/kg/h, to account for different types of opioids used per patient preference, and then this was compared to the intervention group that received LDK. Percent change in opioid usage (expressed as morphine equivalents in mg/kg/h) is reported).</description>
        <time_frame>Up to one year prior and after LDK administration on day 1 of the study in the ED</time_frame>
        <population>62 enrolled patient-encounters were compared to their prior visits individually. At least one but up to three prior visits were averaged and compared to the intervention visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Intervention</title>
            <description>Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg.&#xD;
Ketamine: The intervention was IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs).&#xD;
Ultimately, 62 patient encounters were enrolled in the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Effect of Low-dose Ketamine (LDK) on Opioid Usage in the ED</title>
          <description>Opioid usage for at least one but up to three prior patient visits in the last one year for each patient enrolled in the study was summarized, expressed as morphine equivalents in mg/kg/h, to account for different types of opioids used per patient preference, and then this was compared to the intervention group that received LDK. Percent change in opioid usage (expressed as morphine equivalents in mg/kg/h) is reported).</description>
          <population>62 enrolled patient-encounters were compared to their prior visits individually. At least one but up to three prior visits were averaged and compared to the intervention visit.</population>
          <units>percent change</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="62"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-15" lower_limit="-28" upper_limit="-2.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.004</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>-15</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-28</ci_lower_limit>
            <ci_upper_limit>-2.3</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Effect of Low-dose Ketamine on Pain Scores on Presentation to the ED</title>
        <description>Patient pain scores at presentation for the enrolled encounters and for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. At least one but up to three prior visits were averaged and compared to the intervention visit. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain).</description>
        <time_frame>Up to one year prior and on presentation to the ED after LDK administration</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Intervention</title>
            <description>Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg.&#xD;
Ketamine: The intervention was IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs).&#xD;
Ultimately, 62 patient encounters were enrolled in the study.</description>
          </group>
          <group group_id="O2">
            <title>Historical Control</title>
            <description>Patient data from at least one but up three patient encounters within the prior year were compared to their visit in which they were given adjuvant ketamine, using the outcome measures in the &quot;Intervention&quot; arm. Since this a historical control study, patients acted as their own controls in the above manner. Patients were allowed to re-enroll 4 weeks after presentation, which is typically considered a separate vaso-occlusive episode in the literature.</description>
          </group>
        </group_list>
        <measure>
          <title>Effect of Low-dose Ketamine on Pain Scores on Presentation to the ED</title>
          <description>Patient pain scores at presentation for the enrolled encounters and for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. At least one but up to three prior visits were averaged and compared to the intervention visit. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain).</description>
          <units>Score on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="62"/>
                <count group_id="O2" value="62"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.23" lower_limit="8.98" upper_limit="9.47"/>
                    <measurement group_id="O2" value="9.08" lower_limit="8.83" upper_limit="9.34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.38</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Effect of Low-dose Ketamine on Discharge Rates From the ED</title>
        <description>Percent discharge from the ED for intervention group and for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. Participants were assigned a &quot;0&quot; if discharged or &quot;1&quot; if not discharged.</description>
        <time_frame>Up to one year prior to receipt of ketamine for the historical control arm/group and up to 18 months for the intervention arm/group</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Intervention</title>
            <description>Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg.&#xD;
Ketamine: The intervention was IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs).&#xD;
Ultimately, 62 patient encounters were enrolled in the study.</description>
          </group>
          <group group_id="O2">
            <title>Historical Control</title>
            <description>Patient data from at least one but up three patient encounters within the prior year were compared to their visit in which they were given adjuvant ketamine, using the outcome measures in the &quot;Intervention&quot; arm. Since this a historical control study, patients acted as their own controls in the above manner. Patients were allowed to re-enroll 4 weeks after presentation, which is typically considered a separate vaso-occlusive episode in the literature.</description>
          </group>
        </group_list>
        <measure>
          <title>Effect of Low-dose Ketamine on Discharge Rates From the ED</title>
          <description>Percent discharge from the ED for intervention group and for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. Participants were assigned a &quot;0&quot; if discharged or &quot;1&quot; if not discharged.</description>
          <units>percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="62"/>
                <count group_id="O2" value="62"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="33"/>
                    <measurement group_id="O2" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>0.58</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Subjective Effect of Low Dose Ketamine on Pain Relief Assessed Via a Patient Survey</title>
        <description>After receipt of LDK, patients and/or their parents, based on age, filled out a survey based on a Likert scale regarding their agreement (Strongly Disagree to Strongly Agree) with the following statements: Achieved faster pain relief with LDK, Achieved more complete pain relief with LDK, and Desire to receive LDK in a future vaso-occlusive crisis. There is also an area where patients could provide general comments regarding their experience in receiving LDK.&#xD;
Count of Participants who agree or strongly agree for each question are reported.</description>
        <time_frame>after LDK administration on day 1 of the study in the ED</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Intervention</title>
            <description>Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg.&#xD;
Ketamine: The intervention was IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs).&#xD;
Ultimately, 62 patient encounters were enrolled in the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Subjective Effect of Low Dose Ketamine on Pain Relief Assessed Via a Patient Survey</title>
          <description>After receipt of LDK, patients and/or their parents, based on age, filled out a survey based on a Likert scale regarding their agreement (Strongly Disagree to Strongly Agree) with the following statements: Achieved faster pain relief with LDK, Achieved more complete pain relief with LDK, and Desire to receive LDK in a future vaso-occlusive crisis. There is also an area where patients could provide general comments regarding their experience in receiving LDK.&#xD;
Count of Participants who agree or strongly agree for each question are reported.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="62"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Achieved faster pain relief?</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Achieved more complete pain relief?</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Desire to receive LDK in the future?</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="49"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Effect of Low-dose Ketamine on Patient Pain Scores on Discharge From the ED/Admission to the Hospital</title>
        <description>Patient pain scores at time of discharge from the ED/admission to the hospital for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. At least one but up to three prior visits were averaged and compared to the intervention visit. Pain scores post receipt of ketamine are presented for the intervention group. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain).</description>
        <time_frame>At time of discharge from the ED/admission to the hospital (up to one year prior and after LDK administration)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Intervention</title>
            <description>Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg.&#xD;
Ketamine: The intervention was IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs).&#xD;
Ultimately, 62 patient encounters were enrolled in the study.</description>
          </group>
          <group group_id="O2">
            <title>Historical Control</title>
            <description>Patient data from at least one but up three patient encounters within the prior year were compared to their visit in which they were given adjuvant ketamine, using the outcome measures in the &quot;Intervention&quot; arm. Since this a historical control study, patients acted as their own controls in the above manner. Patients were allowed to re-enroll 4 weeks after presentation, which is typically considered a separate vaso-occlusive episode in the literature.</description>
          </group>
        </group_list>
        <measure>
          <title>Effect of Low-dose Ketamine on Patient Pain Scores on Discharge From the ED/Admission to the Hospital</title>
          <description>Patient pain scores at time of discharge from the ED/admission to the hospital for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. At least one but up to three prior visits were averaged and compared to the intervention visit. Pain scores post receipt of ketamine are presented for the intervention group. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain).</description>
          <units>Score on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="62"/>
                <count group_id="O2" value="62"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.15" lower_limit="6.61" upper_limit="7.68"/>
                    <measurement group_id="O2" value="7.26" lower_limit="6.84" upper_limit="7.68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>A Wilcoxon sign-rank, given non parametric data, was used to compare the intervention and historical control groups for statistical significance, while a student's t-test was used to estimate effect size</non_inferiority_desc>
            <p_value>0.76</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Effect of Low-dose Ketamine on Percent Difference of Length of Stay (LOS) in the ED</title>
        <description>Length of stay (LOS) in minutes in the ED for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed.</description>
        <time_frame>Up to one year prior to and after LDK administration on day 1 of the study in the ED</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Intervention</title>
            <description>Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg.&#xD;
Ketamine: The intervention was IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs).&#xD;
Ultimately, 62 patient encounters were enrolled in the study.</description>
          </group>
          <group group_id="O2">
            <title>Historical Control</title>
            <description>Patient data from at least one but up three patient encounters within the prior year were compared to their visit in which they were given adjuvant ketamine, using the outcome measures in the &quot;Intervention&quot; arm. Since this a historical control study, patients acted as their own controls in the above manner. Patients were allowed to re-enroll 4 weeks after presentation, which is typically considered a separate vaso-occlusive episode in the literature.</description>
          </group>
        </group_list>
        <measure>
          <title>Effect of Low-dose Ketamine on Percent Difference of Length of Stay (LOS) in the ED</title>
          <description>Length of stay (LOS) in minutes in the ED for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed.</description>
          <units>LOS in minutes</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="62"/>
                <count group_id="O2" value="62"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="273.5" lower_limit="241.3" upper_limit="305.6"/>
                    <measurement group_id="O2" value="217.3" lower_limit="200.0" upper_limit="234.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Effect of Low-dose Ketamine on Time to 50% Pain Reduction</title>
        <description>Time to 50% pain reduction (pain reported 50% less than baseline) in minutes for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed as historical controls. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain).</description>
        <time_frame>Up to one year prior to and after LDK administration on day 1 of the study in the ED</time_frame>
        <population>16 participants reported a 50% pain reduction, and those 16 participants were included in the analysis of time to 50% pain reduction.</population>
        <group_list>
          <group group_id="O1">
            <title>Intervention</title>
            <description>Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg.&#xD;
Ketamine: The intervention was IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs).&#xD;
Ultimately, 62 patient encounters were enrolled in the study.</description>
          </group>
          <group group_id="O2">
            <title>Historical Control</title>
            <description>Patient data from at least one but up three patient encounters within the prior year were compared to their visit in which they were given adjuvant ketamine, using the outcome measures in the &quot;Intervention&quot; arm. Since this a historical control study, patients acted as their own controls in the above manner.</description>
          </group>
        </group_list>
        <measure>
          <title>Effect of Low-dose Ketamine on Time to 50% Pain Reduction</title>
          <description>Time to 50% pain reduction (pain reported 50% less than baseline) in minutes for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed as historical controls. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain).</description>
          <population>16 participants reported a 50% pain reduction, and those 16 participants were included in the analysis of time to 50% pain reduction.</population>
          <units>time to 50% pain reduction in minutes</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="116.1" lower_limit="111.6" upper_limit="220.6"/>
                    <measurement group_id="O2" value="167.3" lower_limit="117.0" upper_limit="217.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>18 months</time_frame>
      <desc>Serious adverse events were defined per protocol as reaction to intervention causing cardiorespiratory compromise requiring medical intervention.</desc>
      <group_list>
        <group group_id="E1">
          <title>Intervention</title>
          <description>Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg.&#xD;
Ketamine: The intervention was IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs).&#xD;
Ultimately, 62 patient encounters were enrolled in the study.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="62"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="62"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="42" subjects_at_risk="62"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurry vision</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="62"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea/vomiting</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="62"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Emergence of emergence-like symptoms</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="62"/>
              </event>
              <event>
                <sub_title>Dream-like/de-realized sensation</sub_title>
                <counts group_id="E1" subjects_affected="26" subjects_at_risk="62"/>
              </event>
              <event>
                <sub_title>Floating sensation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="62"/>
              </event>
              <event>
                <sub_title>Heavy sensation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="62"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="62"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="62"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Given the study design (non-blinded, non-randomized), the effect of LDK on opioid usage and other secondary outcomes cannot be definitively associated with LDK itself given the possibility of a placebo effect.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Jonathan Bryan Cooper-Sood, MD</name_or_title>
      <organization>Valley Children's Hospital</organization>
      <phone>559-353-3000</phone>
      <email>coopersoodj@usacs.com</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03296345
org study id: 2010-010
nct id: NCT03296345
lead sponsor: 
has dmc: Yes
Acute vaso-occlusive episodes (VOEs) in sickle cell disease (SCD) are primarily managed with
      opioids. Tolerance and hyperalgesia to opioids develops due to N-methyl-D-aspartate
      (NMDA)-receptor mediated activation of the nociceptive system, and as a receptor antagonist,
      ketamine mitigates this. Intravenous (IV) ketamine has demonstrated efficacy in reducing
      post-operative, chronic, and cancer-related pain in pediatrics, as well as in reducing time
      to pain control in the emergency department (ED) in adults. Limited studies suggest efficacy
      in adult opioid-refractory SCD patients. This study is investigating the safety and
      tolerability of adjuvant low-dose IV ketamine bolus for pediatric SCD VOE in the ED, as well
      as its efficacy in improving pain control and reducing hospitalization.
In this cohort study, all consenting pediatric sickle-cell patients between 10 and 25 years
      old who were cared for at UCSF Benioff Children's Hospital Oakland (UCSFBCHO) presenting to
      the emergency department for VOC were enrolled in the study. Patients were compared to
      themselves in a time series, pre and post exposure to the study intervention (low-dose
      ketamine bolus at 0.2 mg/kg x 1 prior to second dose of IV opiate). The pediatric FACES pain
      scale was used to measure pain scales at pre-designated time points in the ED per standard
      nursing protocol (FACES for younger kids, visual analog scale in adolescents/young adults).
      Opiate usage was summed in the ED, converted to mg/kg/hour of morphine equivalents (since
      different opioids agents were given to different patients based on individual historical
      efficacy, and since length of stay in the emergency room could affect total morphine
      equivalents received), and compared between the pre and post-intervention groups. In
      addition, length of stay, time to 50% pain control, presentation and discharge pain scores,
      and likelihood of discharge from the ED were compared. Data was be collected via chart review
      in the UCSFBCHO system by study investigators. Pre-intervention data from the past three
      patient encounters (e.g., the mean of the mg/kg/hour of morphine equivalents used in the last
      three patient encounters prior to receipt of ketamine) was compared to the post intervention
      data. In addition, a survey, which is attached, was given to patients/families at the time of
      the drug administration to attempt to discern if patients subjectively experienced
      improvement in their pain and if they experienced any negative side effects due to the drug
      administration. Monitoring for adverse events was recorded for each patient encounter.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Treatment-Emergent Adverse Events [Safety and Tolerability]
time frame: 18 months
description: The number of serious and minor adverse events was measured via patient-completed survey as well as by nurse and medical providers on presentation to the emergency department (ED). Serious adverse events are defined as cardiorespiratory events requiring intervention. Minor adverse events are defined as nausea/vomiting, emergence reaction (dysphoria; hallucinations; frightening dreams), and a sense of de-realization or "dreamy" sensation. Both study providers and patients themselves, via a survey that the parent and/or patient (based on age) fills out post receipt of ketamine, reported serious and minor adverse events.
measure: Effect of Low-dose Ketamine (LDK) on Opioid Usage in the ED
time frame: Up to one year prior and after LDK administration on day 1 of the study in the ED
description: Opioid usage for at least one but up to three prior patient visits in the last one year for each patient enrolled in the study was summarized, expressed as morphine equivalents in mg/kg/h, to account for different types of opioids used per patient preference, and then this was compared to the intervention group that received LDK. Percent change in opioid usage (expressed as morphine equivalents in mg/kg/h) is reported).
measure: Effect of Low-dose Ketamine on Pain Scores on Presentation to the ED
time frame: Up to one year prior and on presentation to the ED after LDK administration
description: Patient pain scores at presentation for the enrolled encounters and for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. At least one but up to three prior visits were averaged and compared to the intervention visit. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain).
measure: Effect of Low-dose Ketamine on Discharge Rates From the ED
time frame: Up to one year prior to receipt of ketamine for the historical control arm/group and up to 18 months for the intervention arm/group
description: Percent discharge from the ED for intervention group and for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. Participants were assigned a "0" if discharged or "1" if not discharged.
measure: Subjective Effect of Low Dose Ketamine on Pain Relief Assessed Via a Patient Survey
time frame: after LDK administration on day 1 of the study in the ED
description: After receipt of LDK, patients and/or their parents, based on age, filled out a survey based on a Likert scale regarding their agreement (Strongly Disagree to Strongly Agree) with the following statements: Achieved faster pain relief with LDK, Achieved more complete pain relief with LDK, and Desire to receive LDK in a future vaso-occlusive crisis. There is also an area where patients could provide general comments regarding their experience in receiving LDK.
Count of Participants who agree or strongly agree for each question are reported.
measure: Effect of Low-dose Ketamine on Patient Pain Scores on Discharge From the ED/Admission to the Hospital
time frame: At time of discharge from the ED/admission to the hospital (up to one year prior and after LDK administration)
description: Patient pain scores at time of discharge from the ED/admission to the hospital for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed. At least one but up to three prior visits were averaged and compared to the intervention visit. Pain scores post receipt of ketamine are presented for the intervention group. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain).
measure: Effect of Low-dose Ketamine on Percent Difference of Length of Stay (LOS) in the ED
time frame: Up to one year prior to and after LDK administration on day 1 of the study in the ED
description: Length of stay (LOS) in minutes in the ED for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed.
measure: Effect of Low-dose Ketamine on Time to 50% Pain Reduction
time frame: Up to one year prior to and after LDK administration on day 1 of the study in the ED
description: Time to 50% pain reduction (pain reported 50% less than baseline) in minutes for at least one but up to three visits prior to receipt of ketamine in the last one year, were assessed as historical controls. Pain was assessed using the faces pain scale which consists of a series of line diagrams of faces with expressions of increasing distress. The score ranges from 0 (no pain) to 10 (the worst pain).
arm group label: Intervention
arm group type: Active Comparator
description: Prior to the second dose of IV opiates, the experiment was to give patients a single IV bolus of ketamine at the dose of 0.2 mg/kg. Pain scores were collected using the FACES scale currently in place. In consenting patients, chart review was performed with the following data collected: mg/kg/hour of morphine equivalents, pain scores on admission, during the encounter, and at discharge, the time to 50% pain reduction, and whether or not the patient was discharged.
In addition, a survey, which is attached, was given to patients/families at the time of drug administration to determine if they experienced a subjective improvement in their pain and if they suffered any undue side effects due to drug administration.
arm group label: Historical Control
arm group type: No Intervention
description: Patient data from at least one but up three patient encounters within the prior year were compared to their visit in which they were given adjuvant ketamine, using the outcome measures in the "Intervention" arm. Since this a historical control study, patients acted as their own controls in the above manner. Patients were allowed to re-enroll 4 weeks after presentation, which is typically considered a separate vaso-occlusive episode in the literature.
intervention type: Drug
intervention name: Ketamine
description: The intervention is IV low-dose bolus ketamine as an adjuvant to standard therapy (IV opiates and NSAIDs).
arm group label: Intervention
other name: Ketalar
criteria: 
gender: All
minimum age: 10 Years
maximum age: 25 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Jonathan B Cooper-Sood, MD
role: Principal Investigator
affiliation: Children's Hospital and Research Center of Oakland
facility: 
country: United States
citation: Neri CM, Pestieau SR, Darbari DS. Low-dose ketamine as a potential adjuvant therapy for painful vaso-occlusive crises in sickle cell disease. Paediatr Anaesth. 2013 Aug;23(8):684-9. doi: 10.1111/pan.12172. Epub 2013 Apr 9.
PMID: 23565738
citation: Tawfic QA, Faris AS, Eipe N. Sickle cell pain management: are we missing the role of pronociception and neuropathic pain? Paediatr Anaesth. 2013 Nov;23(11):1104-5. doi: 10.1111/pan.12269. No abstract available.
PMID: 24088202
citation: Jennings CA, Bobb BT, Noreika DM, Coyne PJ. Oral ketamine for sickle cell crisis pain refractory to opioids. J Pain Palliat Care Pharmacother. 2013 Jun;27(2):150-4. doi: 10.3109/15360288.2013.788599. Epub 2013 May 21.
PMID: 23692261
citation: Zempsky WT, Loiselle KA, Corsi JM, Hagstrom JN. Use of low-dose ketamine infusion for pediatric patients with sickle cell disease-related pain: a case series. Clin J Pain. 2010 Feb;26(2):163-7. doi: 10.1097/AJP.0b013e3181b511ab.
PMID: 20090444
citation: Riha H, Aaronson P, Schmidt A. Evaluation of analgesic effects of ketamine through sub-dissociative dosing in the ED. Am J Emerg Med. 2015 Jun;33(6):847-9. doi: 10.1016/j.ajem.2015.03.045. Epub 2015 Mar 25. No abstract available.
PMID: 25865160
citation: Beaudoin FL, Lin C, Guan W, Merchant RC. Low-dose ketamine improves pain relief in patients receiving intravenous opioids for acute pain in the emergency department: results of a randomized, double-blind, clinical trial. Acad Emerg Med. 2014 Nov;21(11):1193-202. doi: 10.1111/acem.12510.
PMID: 25377395
citation: Drake AB, Milne WK, Carpenter CR. Hot Off the Press: Subdissociative-dose Ketamine for Acute Pain in the Emergency Department. Acad Emerg Med. 2015 Jul;22(7):887-9. doi: 10.1111/acem.12705. Epub 2015 Jun 30. No abstract available.
PMID: 26130219
citation: Miller JP, Schauer SG, Ganem VJ, Bebarta VS. Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial. Am J Emerg Med. 2015 Mar;33(3):402-8. doi: 10.1016/j.ajem.2014.12.058. Epub 2015 Jan 7.
PMID: 25624076
citation: Uprety D, Baber A, Foy M. Ketamine infusion for sickle cell pain crisis refractory to opioids: a case report and review of literature. Ann Hematol. 2014 May;93(5):769-71. doi: 10.1007/s00277-013-1954-3. Epub 2013 Nov 15.
PMID: 24232306
citation: Tawfic QA, Faris AS, Kausalya R. The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease. J Pain Symptom Manage. 2014 Feb;47(2):334-40. doi: 10.1016/j.jpainsymman.2013.03.012. Epub 2013 Jul 12.
PMID: 23856095
citation: Ahern TL, Herring AA, Anderson ES, Madia VA, Fahimi J, Frazee BW. The first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED. Am J Emerg Med. 2015 Feb;33(2):197-201. doi: 10.1016/j.ajem.2014.11.010. Epub 2014 Nov 15.
PMID: 25488336
responsible party type: Sponsor
mesh term: Anemia, Sickle Cell
mesh term: Ketamine
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Given the study design (non-blinded, non-randomized), the effect of LDK on opioid usage and other secondary outcomes cannot be definitively associated with LDK itself given the possibility of a placebo effect.
point of contact: 