<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/NCT01732471</url>
  </required_header>
  <id_info>
    <org_study_id>EMR 700773_510</org_study_id>
    <nct_id>NCT01732471</nct_id>
  </id_info>
  <brief_title>Phase 3 Open-label Study to Evaluate the Response and Safety of Kuvan® in Subjects With Phenylketonuria</brief_title>
  <official_title>A Phase III Non-comparative Open-label Clinical Study to Evaluate the Response to and Safety of Kuvan (Sapropterin Dihydrochloride) After 6 Weeks of Treatment in Patients of 4 to 18 Years of Age With Phenylketonuria Who Have Elevated Blood Phenylalanine Levels</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Merck KGaA, Darmstadt, Germany</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Merck KGaA, Darmstadt, Germany</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an open-label, non-comparative, Phase 3 study to evaluate the degree, frequency of&#xD;
      response and safety of Kuvan® (sapropterin dihydrochloride) in subjects aged 4 to 18 years&#xD;
      who have phenylketonuria and with elevated blood phenylalanine level of greater than or equal&#xD;
      to 450 micromole per liter.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>November 2012</start_date>
  <completion_date type="Actual">October 2013</completion_date>
  <primary_completion_date type="Actual">October 2013</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of Participants With Response to Kuvan® (Sapropterin Dihydrochloride) Treatment</measure>
    <time_frame>Day 8</time_frame>
    <description>Response to Kuvan® (sapropterin dihydrochloride) treatment was defined as a reduction in blood phenylalanine levels of greater than or equal to 30% at Day 8 as compared to baseline.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Overall Population</measure>
    <time_frame>Baseline, Day 8</time_frame>
    <description>Percent change in blood phenylalanine levels after 8-day Kuvan® therapy (response test period) was calculated as (blood phenylalanine level at Day 8 minus blood phenylalanine level at baseline)*100/ blood phenylalanine level at baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Sub-population of Responders</measure>
    <time_frame>Baseline, Day 8</time_frame>
    <description>Percent change in blood phenylalanine levels after 8-day Kuvan® therapy (response test period) was calculated as (blood phenylalanine level at Day 8 minus blood phenylalanine level at baseline)*100/ blood phenylalanine level at baseline.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in Overall Safety Population</measure>
    <time_frame>Baseline up to Week 11</time_frame>
    <description>An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">90</enrollment>
  <condition>Phenylketonuria</condition>
  <arm_group>
    <arm_group_label>Kuvan®</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Kuvan®</intervention_name>
    <description>Kuvan® (sapropterin dihydrochloride) will be administered orally at a dose of 20 milligram per kilogram per day (mg/kg/day) once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment will be continued at the same dose for further 6 weeks.</description>
    <arm_group_label>Kuvan®</arm_group_label>
    <other_name>Sapropterin dihydrochloride</other_name>
    <other_name>6R-BH4 tetrahydrobiopterin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Willing and able to provide written informed consent (for children under 18 years old&#xD;
             the parent[s]/guardians give informed consent, subjects 14-17 years old give&#xD;
             additionally their own written informed consent)&#xD;
&#xD;
          -  Age of 4 - 18 years, inclusive&#xD;
&#xD;
          -  Confirmed clinical and biochemical hyperphenylalaninemia due to phenylketonuria&#xD;
             documented by past medical history with at least 2 blood phenylalanine level greater&#xD;
             than or equal to 400 micromole per liter obtained in 2 separate occasions&#xD;
&#xD;
          -  Blood phenylalanine level at screening greater than or equal to 450 micromole per&#xD;
             liter (mean of two measurements)&#xD;
&#xD;
          -  For women of childbearing potential, a negative urine pregnancy test is required at&#xD;
             screening and willingness to use a highly effective method of contraception is&#xD;
             required while participating in the study&#xD;
&#xD;
          -  Subject and/or the parent/guardian willing and able to comply with study procedures&#xD;
&#xD;
          -  Subject and/or the parent/guardian willing to continue current diet unchanged during&#xD;
             the 8 days response test and to adapt the diet according to phenylalanine therapeutic&#xD;
             target range during the 6 week treatment period&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subject already assessed for responsiveness to sapropterin dihydrochloride or other&#xD;
             tetrahydrobiopterin (BH4)&#xD;
&#xD;
          -  Used any investigational agent other than Kuvan® (sapropterin dihydrochloride) within&#xD;
             30 days of screening, or required any investigational agent or vaccine prior to&#xD;
             completion of all scheduled study assessments&#xD;
&#xD;
          -  Pregnant or breastfeeding, or considering pregnancy&#xD;
&#xD;
          -  Concurrent disease or conditions that would interfere with study participation or&#xD;
             safety (for example, seizure disorder, asthma or other condition requiring oral or&#xD;
             parenteral corticosteroid administration, insulin-dependent diabetes, or organ&#xD;
             transplantation recipient)&#xD;
&#xD;
          -  Concurrent use of required concomitant treatment with any drug known to inhibit folate&#xD;
             synthesis (for example, methotrexate), levodopa, phosphodiesterase type-5 (PDE-5)&#xD;
             inhibitors (such as, sildenafil, vardenafil or tadalafil), medications that are known&#xD;
             to affect nitric oxide synthesis metabolism or action&#xD;
&#xD;
          -  Any conditions, that, in the view of the Principal Investigator renders the subject at&#xD;
             high risk for failure to comply with treatment or to complete the study&#xD;
&#xD;
          -  Clinical diagnosis of primary BH4 deficiency&#xD;
&#xD;
          -  Known hypersensitivity to Kuvan® (sapropterin dihydrochloride) or its excipients or to&#xD;
             other approved or non-approved formulation of tetrabiopterin&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>4 Years</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Please contact Merck KGaA Communication Center</name>
      <address>
        <city>Darmstadt</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>July 2014</verification_date>
  <study_first_submitted>November 19, 2012</study_first_submitted>
  <study_first_submitted_qc>November 19, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 22, 2012</study_first_posted>
  <results_first_submitted>June 24, 2014</results_first_submitted>
  <results_first_submitted_qc>July 25, 2014</results_first_submitted_qc>
  <results_first_posted type="Estimate">July 28, 2014</results_first_posted>
  <last_update_submitted>July 25, 2014</last_update_submitted>
  <last_update_submitted_qc>July 25, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">July 28, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>EMR 700733_510, Genetic disorder, Phenylketonuria, phenylalanine, Kuvan, sapropterin dihydrochloride</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Phenylketonurias</mesh_term>
  </condition_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Kuvan®</title>
          <description>Kuvan® (sapropterin dihydrochloride) was administered orally at a dose of 20 milligram per kilogram per day (mg/kg/day) once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment was continued at the same dose for further 6 weeks.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="90"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="89"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Intention to Treat (ITT) population included all participants who had efficacy assessment result from at least 1 visit except for the inclusion visit.</population>
      <group_list>
        <group group_id="B1">
          <title>Kuvan®</title>
          <description>Kuvan® (sapropterin dihydrochloride) was administered orally at a dose of 20 mg/kg/day once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment was continued at the same dose for further 6 weeks.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="90"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9.59" spread="4.09"/>
                  </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="41"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="49"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Participants With Response to Kuvan® (Sapropterin Dihydrochloride) Treatment</title>
        <description>Response to Kuvan® (sapropterin dihydrochloride) treatment was defined as a reduction in blood phenylalanine levels of greater than or equal to 30% at Day 8 as compared to baseline.</description>
        <time_frame>Day 8</time_frame>
        <population>Overall (ITT) population included all participants who had efficacy assessment result from at least 1 visit except for the inclusion visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Kuvan®</title>
            <description>Kuvan® (sapropterin dihydrochloride) was administered orally at a dose of 20 mg/kg/day once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment was continued at the same dose for further 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants With Response to Kuvan® (Sapropterin Dihydrochloride) Treatment</title>
          <description>Response to Kuvan® (sapropterin dihydrochloride) treatment was defined as a reduction in blood phenylalanine levels of greater than or equal to 30% at Day 8 as compared to baseline.</description>
          <population>Overall (ITT) population included all participants who had efficacy assessment result from at least 1 visit except for the inclusion visit.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="90"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="33.3" lower_limit="23.7" upper_limit="44.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Overall Population</title>
        <description>Percent change in blood phenylalanine levels after 8-day Kuvan® therapy (response test period) was calculated as (blood phenylalanine level at Day 8 minus blood phenylalanine level at baseline)*100/ blood phenylalanine level at baseline.</description>
        <time_frame>Baseline, Day 8</time_frame>
        <population>Overall (ITT) population included all participants who had efficacy assessment result from at least 1 visit except for the inclusion visit.</population>
        <group_list>
          <group group_id="O1">
            <title>Kuvan®</title>
            <description>Kuvan® (sapropterin dihydrochloride) was administered orally at a dose of 20 mg/kg/day once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment was continued at the same dose for further 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Overall Population</title>
          <description>Percent change in blood phenylalanine levels after 8-day Kuvan® therapy (response test period) was calculated as (blood phenylalanine level at Day 8 minus blood phenylalanine level at baseline)*100/ blood phenylalanine level at baseline.</description>
          <population>Overall (ITT) population included all participants who had efficacy assessment result from at least 1 visit except for the inclusion visit.</population>
          <units>percent change</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="90"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-14.14" spread="28.35"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Sub-population of Responders</title>
        <description>Percent change in blood phenylalanine levels after 8-day Kuvan® therapy (response test period) was calculated as (blood phenylalanine level at Day 8 minus blood phenylalanine level at baseline)*100/ blood phenylalanine level at baseline.</description>
        <time_frame>Baseline, Day 8</time_frame>
        <population>Sub-population of responders included participants with reduction in blood phenylalanine levels of greater than or equal to 30% at Day 8 as compared to baseline.</population>
        <group_list>
          <group group_id="O1">
            <title>Kuvan®</title>
            <description>Kuvan® (sapropterin dihydrochloride) was administered orally at a dose of 20 mg/kg/day once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment was continued at the same dose for further 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Sub-population of Responders</title>
          <description>Percent change in blood phenylalanine levels after 8-day Kuvan® therapy (response test period) was calculated as (blood phenylalanine level at Day 8 minus blood phenylalanine level at baseline)*100/ blood phenylalanine level at baseline.</description>
          <population>Sub-population of responders included participants with reduction in blood phenylalanine levels of greater than or equal to 30% at Day 8 as compared to baseline.</population>
          <units>percent change</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-44.25" spread="15.13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in Overall Safety Population</title>
        <description>An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.</description>
        <time_frame>Baseline up to Week 11</time_frame>
        <population>Overall safety population included all participants who received at least 1 dose of investigational medicinal product.</population>
        <group_list>
          <group group_id="O1">
            <title>Kuvan®</title>
            <description>Kuvan® (sapropterin dihydrochloride) was administered orally at a dose of 20 mg/kg/day once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment was continued at the same dose for further 6 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in Overall Safety Population</title>
          <description>An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.</description>
          <population>Overall safety population included all participants who received at least 1 dose of investigational medicinal product.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="90"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>AEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Baseline up to Week 11</time_frame>
      <desc>An AE is any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. An SAE is an AE resulting in any of following outcomes:death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.</desc>
      <group_list>
        <group group_id="E1">
          <title>Kuvan®</title>
          <description>Kuvan® (sapropterin dihydrochloride) was administered orally at a dose of 20 mg/kg/day once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment was continued at the same dose for further 6 weeks.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (16.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Upper limb fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA (16.0)</default_vocab>
        <default_assessment>Non-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="23" subjects_at_risk="90"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Myopia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </event>
              <event>
                <sub_title>Faeces pale</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </event>
              <event>
                <sub_title>Gastroduodenitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Oral herpes</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Heat stroke</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Iodine deficiency</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Haematuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </event>
              <event>
                <sub_title>Leukocyturia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </event>
              <event>
                <sub_title>Phenylketonuria</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="90"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Dysmenorrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </event>
              <event>
                <sub_title>Genital labial adhesions</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </event>
              <event>
                <sub_title>Respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="90"/>
              </event>
              <event>
                <sub_title>Respiratory tract infection viral</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="90"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin odour abnormal</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Retinal vascular disorder</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="90"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="90"/>
              </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>All written or oral publications and/or information related to Study and/or results of Study should be submitted at first in writing to Sponsor at least 30 working days for publication and 15 working days for brief review, abstract before planned date of submission. If Sponsor is filing a patent application on Study results, Sponsor can delay its authorization for publication/communication of Study results to Investigator and/or Research Centre until date of international registration of patent.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Merck KGaA Communication Center</name_or_title>
      <organization>Merck Serono, a division of Merck KGaA</organization>
      <phone>+49-6151-72-5200</phone>
      <email>service@merckgroup.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/NCT01732471
org study id: EMR 700773_510
nct id: NCT01732471
lead sponsor: 
has dmc: No
This is an open-label, non-comparative, Phase 3 study to evaluate the degree, frequency of
      response and safety of Kuvan® (sapropterin dihydrochloride) in subjects aged 4 to 18 years
      who have phenylketonuria and with elevated blood phenylalanine level of greater than or equal
      to 450 micromole per liter.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Percentage of Participants With Response to Kuvan® (Sapropterin Dihydrochloride) Treatment
time frame: Day 8
description: Response to Kuvan® (sapropterin dihydrochloride) treatment was defined as a reduction in blood phenylalanine levels of greater than or equal to 30% at Day 8 as compared to baseline.
measure: Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Overall Population
time frame: Baseline, Day 8
description: Percent change in blood phenylalanine levels after 8-day Kuvan® therapy (response test period) was calculated as (blood phenylalanine level at Day 8 minus blood phenylalanine level at baseline)*100/ blood phenylalanine level at baseline.
measure: Percent Change From Baseline in Blood Phenylalanine Levels at Day 8 in Sub-population of Responders
time frame: Baseline, Day 8
description: Percent change in blood phenylalanine levels after 8-day Kuvan® therapy (response test period) was calculated as (blood phenylalanine level at Day 8 minus blood phenylalanine level at baseline)*100/ blood phenylalanine level at baseline.
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) in Overall Safety Population
time frame: Baseline up to Week 11
description: An adverse event (AE) was defined as any new untoward medical occurrences/worsening of pre-existing medical condition without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect.
arm group label: Kuvan®
arm group type: Experimental
intervention type: Drug
intervention name: Kuvan®
description: Kuvan® (sapropterin dihydrochloride) will be administered orally at a dose of 20 milligram per kilogram per day (mg/kg/day) once daily for 8 days. If there is 30 percent (%) decrease in blood phenylalanine levels from baseline at the end of Day 8, then treatment will be continued at the same dose for further 6 weeks.
arm group label: Kuvan®
other name: Sapropterin dihydrochloride
other name: 6R-BH4 tetrahydrobiopterin
criteria: 
gender: All
minimum age: 4 Years
maximum age: 18 Years
healthy volunteers: No
facility: 
country: Germany
responsible party type: Sponsor
mesh term: Phenylketonurias
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 