<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/NCT03291080</url>
  </required_header>
  <id_info>
    <org_study_id>INV500</org_study_id>
    <nct_id>NCT03291080</nct_id>
  </id_info>
  <brief_title>Oral Liquid 13-cis-retinoic Acid (13-CRA)</brief_title>
  <acronym>My-CRA</acronym>
  <official_title>Relative Bioavailability and Comparative Pharmacokinetics of 13-CRA Oral Liquid and Extracted Capsule Formulations: a Randomised, Open Label, Multi-dose, Cross-over Clinical Trial in Patients Requiring Treatment Cycles of 13-CRA.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Nova Laboratories Limited</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Nova Laboratories Limited</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      An open label, randomised, multiple dose, cross-over relative bioavailability and&#xD;
      pharmacokinetics trial of a novel oral liquid and capsule formulations of 13-CRA administered&#xD;
      to patients from 0 months - &lt; 21 years.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      All patients requiring at least two cycles of 13-CRA therapy will be eligible for recruitment&#xD;
      into the trial.&#xD;
&#xD;
      13-CRA will be prescribed to patients according to local treatment protocols at each clinical&#xD;
      site. The dose administered will be 200mg/m2/day for both test and reference product.&#xD;
      Patients with a body weight of ≤12kg will receive a dose of 160 mg/m2/day.&#xD;
&#xD;
      The pharmacokinetics of 13-CRA liquid (test product) and extracted from capsule (reference&#xD;
      product) will be evaluated over two months. Prior to the initiation of 13-CRA treatment as&#xD;
      part of the trial, patients will be randomised to receive either liquid or capsule&#xD;
      formulation in &quot;My-CRA month 1&quot;. The patients will then cross-over to the alternative&#xD;
      formulation in &quot;My-CRA month 2&quot;. The patients on the trial who require further treatment will&#xD;
      revert to standard therapy i.e. 13-CRA extracted from capsules according to local practice.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 17, 2018</start_date>
  <completion_date type="Actual">September 12, 2019</completion_date>
  <primary_completion_date type="Actual">September 12, 2019</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Relative Bioavailability</measure>
    <time_frame>On day 1 and 14 of treatment</time_frame>
    <description>Relative bioavailability (Area under the curve) of 13-CRA administered as oral liquid (test) and extracted capsule (reference) formulations.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximum Plasma Concentration (Cmax)</measure>
    <time_frame>On day 1 and 14 of treatment</time_frame>
    <description>Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Maximum Concentration (Tmax)</measure>
    <time_frame>On day 1 and 14 of treatment</time_frame>
    <description>Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area Under Plasma Concentration Time Curve (AUC) Metabolite</measure>
    <time_frame>On day 1 and 14 of treatment</time_frame>
    <description>Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation- metabolite 4-oxo-13-cisRA</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax (ng/mL)- Metabolite</measure>
    <time_frame>On day 1 and 14 of treatment</time_frame>
    <description>Pharmacokinetic parameter for metabolite 4-oxo-13-cisRA PK</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>T Max of Metabolite</measure>
    <time_frame>On day 1 and 14 of treatment</time_frame>
    <description>T max for metabolite -4-oxo-13-cisRA PK</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Neuroblastoma</condition>
  <arm_group>
    <arm_group_label>Liquid</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral liquid formulation of 13-Cis Retinoic Acid - test product.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Capsule</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Isotretinoin capsules (13-CRA extracted per standard of care)- reference product.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Liquid 13-Cis Retinoic Acid</intervention_name>
    <description>Liquid 13-Cis Retinoic Acid</description>
    <arm_group_label>Liquid</arm_group_label>
    <other_name>Isotretinoin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Extracted capsules 13-CRA</intervention_name>
    <description>Extracted capsules 13-CRA</description>
    <arm_group_label>Capsule</arm_group_label>
    <other_name>Isotretinoin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female aged from 0 years to &lt; 21 years of age.&#xD;
&#xD;
          2. Patient with high risk neuroblastoma, or unresectable, unfavourable histology&#xD;
             intermediate risk neuroblastoma the latter age ≥ 18 months at diagnosis&#xD;
&#xD;
          3. Patient who is scheduled to receive at least two treatment cycles of 13-CRA.&#xD;
&#xD;
          4. Patient who cannot swallow 13-CRA capsules (i.e. requires extraction of 13-CRA from&#xD;
             the capsules).&#xD;
&#xD;
          5. Negative pregnancy test for females of child-bearing potential before initiation of&#xD;
             treatment, and sexually active patients and partners agreeing to undertake adequate&#xD;
             contraceptive measures (see section 4.5).&#xD;
&#xD;
          6. Provision of a single or double lumen central venous catheter for sampling (i.e.&#xD;
             already in place).&#xD;
&#xD;
          7. Parent(s)/legal guardian able and willing to provide written informed consent for the&#xD;
             patient to take part in the trial.&#xD;
&#xD;
          8. Where applicable, the patient should assent to undergo blood sampling for&#xD;
             pharmacokinetic purposes and to allow physiological measurements to be made.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any clinically significant medical condition or abnormality, which, in the opinion of&#xD;
             the investigator, might compromise the safety of the patient or which might interfere&#xD;
             with the trial.&#xD;
&#xD;
          2. Diagnosis of high-risk neuroblastoma (HRNBL) which is currently being treated on the&#xD;
             SIOPEN HRNBL trial (patients who have exited this trial will be eligible).&#xD;
&#xD;
          3. Known allergy to 13-CRA or any of the excipients.&#xD;
&#xD;
          4. Inadequate contraception measures in females of childbearing age.&#xD;
&#xD;
          5. Receiving concomitant treatment with tetracyclines.&#xD;
&#xD;
        Prior to each cycle:&#xD;
&#xD;
          1. Total bilirubin ≤ 1.5 x normal, and (SGPT) ALT ≤ 5 x normal. Veno-occlusive disease if&#xD;
             present, should be stable or improving.&#xD;
&#xD;
          2. Skin toxicity no greater than CTCAE Grade 1(10)&#xD;
&#xD;
          3. Serum triglycerides &lt;5.65mmol/L.&#xD;
&#xD;
          4. No haematuria and / or proteinuria on urinalysis.&#xD;
&#xD;
          5. Serum calcium ≤ 2.9mmol/L.&#xD;
&#xD;
          6. Serum creatinine based on age / gender as follows:&#xD;
&#xD;
             Age Maximum Serum Creatinine µmol/L Male Female 1 month to &lt; 6 months 35 35 6 months&#xD;
             to &lt; 1 year 44 44 1 to &lt; 2 years 53 53 2 to &lt; 6 years 70 70 6 to &lt; 10 years 88 88 10&#xD;
             to &lt; 13 years 106 106 13 to &lt; 16 years 132 124&#xD;
&#xD;
             ≥ 16 years 150 124&#xD;
&#xD;
          7. Patients with a seizure disorder must be well controlled and taking anticonvulsants.&#xD;
             CNS toxicity &lt; grade 2 (CTCAE).&#xD;
&#xD;
        Withdrawal Criteria:&#xD;
&#xD;
          1. Positive pregnancy test - pregnancy testing will be undertaken before treatment&#xD;
             commences and routinely before each course of treatment in females of childbearing&#xD;
             potential. If a patient is found to be pregnant during the trial, the next course of&#xD;
             treatment will not be given until the pregnancy has been discussed with the treating&#xD;
             clinician, and the patient will be withdrawn from the trial whether or not treatment&#xD;
             is continued.&#xD;
&#xD;
          2. Request of the patient, for any reason.&#xD;
&#xD;
          3. Discretion of the investigator.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>21 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hussain Mulla, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Nova Laboratories Limited</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Bruce Morland</name>
      <address>
        <city>Birmingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dr Antony Ng</name>
      <address>
        <city>Bristol</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dr Amos Burke</name>
      <address>
        <city>Cambridge</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mark Brougham</name>
      <address>
        <city>Edinburgh</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dr Martin Elliott</name>
      <address>
        <city>Leeds</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dr Guiseppe Barone</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dr Guy Makin</name>
      <address>
        <city>Manchester</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dr Madhumita Dandapani</name>
      <address>
        <city>Nottingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kate Wheeler</name>
      <address>
        <city>Oxford</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sucheta Vaidya</name>
      <address>
        <city>Sutton</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>July 19, 2017</study_first_submitted>
  <study_first_submitted_qc>September 19, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 25, 2017</study_first_posted>
  <results_first_submitted>May 27, 2021</results_first_submitted>
  <results_first_submitted_qc>September 22, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">October 19, 2021</results_first_posted>
  <last_update_submitted>September 22, 2021</last_update_submitted>
  <last_update_submitted_qc>September 22, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 19, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuroblastoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tretinoin</mesh_term>
    <mesh_term>Isotretinoin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>December 8, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/80/NCT03291080/Prot_000.pdf</document_url>
    </provided_document>
    <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>October 19, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/80/NCT03291080/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>First Oral Liquid, Then Capsule</title>
          <description>Oral liquid formulation of 13-Cis Retinoic Acid (test product) in the first cycle. Then extracted 13-CRA capsule (reference product) in the second cycle.</description>
        </group>
        <group group_id="P2">
          <title>First Capsule, Then Oral Liquid</title>
          <description>13-CRA capsules extracted per standard of care (reference product) in the first cycle. Then oral liquid formulation of 13-CRA (test product) in the second cycle.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>First Cycle (2 Weeks)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Washout (2 Weeks)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Second Cylcle (2 Weeks)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Liquid First</title>
          <description>Oral liquid formulation of 13-Cis Retinoic Acid (test product) administered in Cycle 1, then 13-CRA extracted capsules (reference product) administered in Cycle 2. The daily dose in each cycle was 200mg per m^2 (in 2 divided doses), reduced to 160 mg per m^2 if weight &lt; 12 kg</description>
        </group>
        <group group_id="B2">
          <title>Extracted Capsule First</title>
          <description>13-CRA extracted capsules (reference product) administered in Cycle 1, then oral liquid formulation of 13-Cis Retinoic Acid (test product) administered in Cycle 2. The daily dose in each cycle was 200mg per m^2 (in 2 divided doses), reduced to 160 mg per m^2 if weight &lt; 12 kg</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="11"/>
            <count group_id="B2" value="9"/>
            <count group_id="B3" value="20"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="20"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </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="4"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Race</title>
              <category_list>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian or Asian British</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Other</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Height</title>
          <units>Metre</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0.974" spread="0.113"/>
                    <measurement group_id="B2" value="1.062" spread="0.21"/>
                    <measurement group_id="B3" value="1.009" spread="0.163"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Weight</title>
          <units>Kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14.66" spread="3.47"/>
                    <measurement group_id="B2" value="18.96" spread="9.09"/>
                    <measurement group_id="B3" value="16.3" spread="6.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Relative Bioavailability</title>
        <description>Relative bioavailability (Area under the curve) of 13-CRA administered as oral liquid (test) and extracted capsule (reference) formulations.</description>
        <time_frame>On day 1 and 14 of treatment</time_frame>
        <population>Relative bioavailability - AUC (h.ng/mL)</population>
        <group_list>
          <group group_id="O1">
            <title>13-CRA Oral Liquid</title>
            <description>Oral liquid formulation - test product</description>
          </group>
          <group group_id="O2">
            <title>13-CRA Extracted Capsule</title>
            <description>Oral liquid formulation - reference product</description>
          </group>
        </group_list>
        <measure>
          <title>Relative Bioavailability</title>
          <description>Relative bioavailability (Area under the curve) of 13-CRA administered as oral liquid (test) and extracted capsule (reference) formulations.</description>
          <population>Relative bioavailability - AUC (h.ng/mL)</population>
          <units>(h.ng/mL)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10009.0" spread="3672.97"/>
                    <measurement group_id="O2" value="6075.9" spread="2090.66"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Maximum Plasma Concentration (Cmax)</title>
        <description>Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation</description>
        <time_frame>On day 1 and 14 of treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>13-CRA Oral Liquid</title>
            <description>Oral liquid formulation - test product</description>
          </group>
          <group group_id="O2">
            <title>13-CRA Extracted Capsule</title>
            <description>Extracted Capsules- reference product</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Plasma Concentration (Cmax)</title>
          <description>Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation</description>
          <units>(ng/mL)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1237.6" spread="662.67"/>
                    <measurement group_id="O2" value="748.2" spread="379.28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Maximum Concentration (Tmax)</title>
        <description>Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation</description>
        <time_frame>On day 1 and 14 of treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>13-CRA Oral Liquid</title>
            <description>Oral liquid formulation - test product</description>
          </group>
          <group group_id="O2">
            <title>13-CRA Extracted Capsule</title>
            <description>Extracted Capsules- reference product</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Maximum Concentration (Tmax)</title>
          <description>Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation</description>
          <units>(h)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.2" spread="0.76"/>
                    <measurement group_id="O2" value="3.0" spread="0.76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Area Under Plasma Concentration Time Curve (AUC) Metabolite</title>
        <description>Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation- metabolite 4-oxo-13-cisRA</description>
        <time_frame>On day 1 and 14 of treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>13-CRA Oral Liquid</title>
            <description>Oral liquid formulation - test product</description>
          </group>
          <group group_id="O2">
            <title>13-CRA Extracted Capsule</title>
            <description>Oral liquid formulation - reference product</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under Plasma Concentration Time Curve (AUC) Metabolite</title>
          <description>Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation- metabolite 4-oxo-13-cisRA</description>
          <units>(h*ng/mL)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="38462.3" spread="18913.60"/>
                    <measurement group_id="O2" value="23312.7" spread="10947.59"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Cmax (ng/mL)- Metabolite</title>
        <description>Pharmacokinetic parameter for metabolite 4-oxo-13-cisRA PK</description>
        <time_frame>On day 1 and 14 of treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>13-CRA Oral Liquid</title>
            <description>Oral liquid formulation - test product</description>
          </group>
          <group group_id="O2">
            <title>13-CRA Extracted Capsule</title>
            <description>Extracted Capsules- reference product</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax (ng/mL)- Metabolite</title>
          <description>Pharmacokinetic parameter for metabolite 4-oxo-13-cisRA PK</description>
          <units>(ng/mL)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3366.2" spread="1648.08"/>
                    <measurement group_id="O2" value="2039.1" spread="952.23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>T Max of Metabolite</title>
        <description>T max for metabolite -4-oxo-13-cisRA PK</description>
        <time_frame>On day 1 and 14 of treatment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>13-CRA Oral Liquid</title>
            <description>Oral liquid formulation - test product</description>
          </group>
          <group group_id="O2">
            <title>13-CRA Extracted Capsule</title>
            <description>Extracted Capsules- reference product</description>
          </group>
        </group_list>
        <measure>
          <title>T Max of Metabolite</title>
          <description>T max for metabolite -4-oxo-13-cisRA PK</description>
          <units>(h)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.1" spread="1.16"/>
                    <measurement group_id="O2" value="6.9" spread="1.16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Through study completion, an average of 2 months.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>13-CRA Oral Liquid</title>
          <description>Oral liquid formulation - test product</description>
        </group>
        <group group_id="E2">
          <title>13-CRA Extracted Capsule</title>
          <description>Oral liquid formulation - reference product</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (12.1)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <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="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Haematemesis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="20"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Hypersensitivity</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Respiratory syncitial virus infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Enteric neuropathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute Kidney Injury</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA (12.1)</default_vocab>
        <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="18" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="20"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Chapped Lips</sub_title>
                <counts group_id="E1" events="9" subjects_affected="8" subjects_at_risk="20"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="20"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="7" subjects_affected="6" subjects_at_risk="20"/>
                <counts group_id="E2" events="6" subjects_affected="5" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="20"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="10" subjects_affected="8" subjects_at_risk="20"/>
                <counts group_id="E2" events="8" subjects_affected="6" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Swelling face</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Dry Skin</sub_title>
                <counts group_id="E1" events="8" subjects_affected="8" subjects_at_risk="20"/>
                <counts group_id="E2" events="12" subjects_affected="10" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Skin exfoliation</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="20"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>
    <point_of_contact>
      <name_or_title>Dr Hussain Mulla</name_or_title>
      <organization>Nova Laboratories</organization>
      <phone>+44 (0) 116 223 0100</phone>
      <email>hussain.mulla@novalabs.co.uk</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/NCT03291080
org study id: INV500
nct id: NCT03291080
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
An open label, randomised, multiple dose, cross-over relative bioavailability and
      pharmacokinetics trial of a novel oral liquid and capsule formulations of 13-CRA administered
      to patients from 0 months - < 21 years.
All patients requiring at least two cycles of 13-CRA therapy will be eligible for recruitment
      into the trial.

      13-CRA will be prescribed to patients according to local treatment protocols at each clinical
      site. The dose administered will be 200mg/m2/day for both test and reference product.
      Patients with a body weight of ≤12kg will receive a dose of 160 mg/m2/day.

      The pharmacokinetics of 13-CRA liquid (test product) and extracted from capsule (reference
      product) will be evaluated over two months. Prior to the initiation of 13-CRA treatment as
      part of the trial, patients will be randomised to receive either liquid or capsule
      formulation in "My-CRA month 1". The patients will then cross-over to the alternative
      formulation in "My-CRA month 2". The patients on the trial who require further treatment will
      revert to standard therapy i.e. 13-CRA extracted from capsules according to local practice.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Other
masking: None (Open Label)
measure: Relative Bioavailability
time frame: On day 1 and 14 of treatment
description: Relative bioavailability (Area under the curve) of 13-CRA administered as oral liquid (test) and extracted capsule (reference) formulations.
measure: Maximum Plasma Concentration (Cmax)
time frame: On day 1 and 14 of treatment
description: Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation
measure: Time to Maximum Concentration (Tmax)
time frame: On day 1 and 14 of treatment
description: Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation
measure: Area Under Plasma Concentration Time Curve (AUC) Metabolite
time frame: On day 1 and 14 of treatment
description: Pharmacokinetic parameter for 13 CRA extracted capsules versus oral liquid formulation- metabolite 4-oxo-13-cisRA
measure: Cmax (ng/mL)- Metabolite
time frame: On day 1 and 14 of treatment
description: Pharmacokinetic parameter for metabolite 4-oxo-13-cisRA PK
measure: T Max of Metabolite
time frame: On day 1 and 14 of treatment
description: T max for metabolite -4-oxo-13-cisRA PK
arm group label: Liquid
arm group type: Experimental
description: Oral liquid formulation of 13-Cis Retinoic Acid - test product.
arm group label: Capsule
arm group type: Experimental
description: Isotretinoin capsules (13-CRA extracted per standard of care)- reference product.
intervention type: Drug
intervention name: Liquid 13-Cis Retinoic Acid
description: Liquid 13-Cis Retinoic Acid
arm group label: Liquid
other name: Isotretinoin
intervention type: Drug
intervention name: Extracted capsules 13-CRA
description: Extracted capsules 13-CRA
arm group label: Capsule
other name: Isotretinoin
criteria: 
gender: All
minimum age: N/A
maximum age: 21 Years
healthy volunteers: No
last name: Hussain Mulla, PhD
role: Study Director
affiliation: Nova Laboratories Limited
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Neuroblastoma
mesh term: Tretinoin
mesh term: Isotretinoin
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 