<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/NCT02230566</url>
  </required_header>
  <id_info>
    <org_study_id>UX003-CL301</org_study_id>
    <nct_id>NCT02230566</nct_id>
  </id_info>
  <brief_title>A Phase 3 Study of UX003 Recombinant Human Betaglucuronidase (rhGUS) Enzyme Replacement Therapy in Patients With Mucopolysaccharidosis Type 7 (MPS 7)</brief_title>
  <official_title>A Randomized, Placebo-Controlled, Blind-Start, Single-Crossover Phase 3 Study to Assess the Efficacy and Safety of UX003 rhGUS Enzyme Replacement Therapy in Patients With MPS 7</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ultragenyx Pharmaceutical Inc</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Ultragenyx Pharmaceutical Inc</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The Phase 3 study will use a novel randomized, intra-subject placebo-controlled, single&#xD;
      crossover design, referred to as Blind Start, to evaluate the safety and efficacy of UX003.&#xD;
      The Blind Start is a novel design whereby participants will be randomized to 1 of 4 groups,&#xD;
      each representing a different treatment sequence, and will cross over to UX003 at different&#xD;
      pre-defined time points in a blinded manner. All groups will receive a minimum of 24 weeks&#xD;
      treatment with 4 mg/kg UX003 every other week (QOW).&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>December 2014</start_date>
  <completion_date type="Actual">May 2016</completion_date>
  <primary_completion_date type="Actual">May 2016</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>Yes</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>European Union (EU) and Rest of World: Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate (DS) at UX003 Treatment Week 24</measure>
    <time_frame>Baseline (defined as the average of all assessments prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
    <description>Baseline was defined as the average of all assessments prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect was subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Percent change from baseline in uGAG DS was analyzed by generalized estimating equation (GEE) modeling based on observed data. The GEE model included included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable.&#xD;
In the United States (US), this was considered a secondary outcome measure. Per guidance from the Food and Drug Administration (FDA), no primary efficacy variable was declared in the US. Efficacy was to be based on the totality of the clinical data on a per participant basis.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Multi-Domain Responder Index (MDRI) Score at UX003 Treatment Week 24</measure>
    <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
    <description>MDRI score, calculated as the total response score at UX003 Treatment Week 24 across 6 domains: 6-Minute Walk Test, forced vital capacity predicted value, shoulder flexion, visual acuity, and Bruininks-Oseretsky Test of Motor Proficiency fine motor and gross motor capacity. For each domain, a minimally important difference (MID) was pre-specified. Changes from before treatment (baseline) to 24 weeks after treatment in each domain variable were scored against pre-specified MIDs. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) An improvement or decline ≥ MID was scored either as a +1 or -1, respectively, and a change &lt;MID was scored as 0. The integration of benefit occurred by summing the responses (-1, +1, 0) across all 6 domain variables to derive the MDRI score, with a range of -6 (greatest possible decline) to +6 (greatest possible improvement).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in 6-Minute Walk Test (6MWT) at UX003 Treatment Week 24</measure>
    <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
    <description>The total distance walked (in meters) in a 6-minute period was measured. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) A positive change from Baseline indicates improvement. Change from baseline in 6MWT was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Pulmonary Function Testing: Percentage of Predicted Forced Vital Capacity (FVC%Pred) at UX003 Treatment Week 24</measure>
    <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
    <description>Spirometry was administered to participants who did not require invasive ventilatory support or have a tracheostomy and measured percentage of predicted FVC. The percent predicted values were calculated after testing using published normative data. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) No GEE analysis was performed for FVC due to the limitation of the sample size.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Pulmonary Function Testing: Maximum Ventilatory Ventilation (MVV) at UX003 Treatment Week 24</measure>
    <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
    <description>Spirometry was administered to participants who did not require invasive ventilatory support or have a tracheostomy to measure MVV. The percent predicted values were calculated after testing using published normative data. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Shoulder Flexion and Extension Maximum Range of Motion at UX003 Treatment Week 24</measure>
    <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
    <description>Goniometry was used to measure (in degrees) the maximum passive shoulder range of motion in both flexion and extension. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in shoulder flexion-left was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Uncorrected Visual Acuity at UX003 Treatment Week 24</measure>
    <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
    <description>Visual acuity was measured (corrected and uncorrected) using a standard eye chart and recorded for each eye independently. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. The change in the number of lines from pre-treatment baseline to 24 weeks of treatment was evaluated. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) A positive change from baseline indicates improvement. Change from baseline in uncorrected visual acuity was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) Scores at UX003 Treatment Week 24</measure>
    <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
    <description>BOT-2 was administered to evaluate treatment-related changes in 4 domains assessing both fine and gross motor function: balance (score 0 to 37), fine motor precision (score 0 to 41), manual dexterity (score 0 to 45), and running speed/agility (score 0 to 52). Higher scores indicate more motor proficiency; a positive change from baseline indicates improvement. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in BOT-2 was analyzed by GEE modeling based on observed data. The GEE model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale at UX003 Treatment Week 24</measure>
    <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
    <description>The PedsQL 18-item scale is comprised of 3 dimensions: general fatigue (6 items), sleep/rest fatigue (6 items) and cognitive fatigue (6 items). Each item has a 5-point Likert response scale that is reverse scored and transformed to a 0 to 100 scale with higher scores indicating less fatigue. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in PedsQL total fatigue score was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and ≥1 post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Individual Clinical Response (ICR) Responders at UX003 Treatment Week 24</measure>
    <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
    <description>Percentage of participants who were ICR responders based on MID criteria at Week 24. At the Randomization visit, the physician queried the participant or parent/caregiver about signs and symptoms of MPS VII that interfered most with the participant's daily life. Answers were mapped to an appropriate clinical outcome measure (e.g., difficulty walking could map to the 6MWT; breathing problems to FVC). The clinical outcome ranked with the highest impact on daily life that could be reliably completed by the participant and met a threshold level of impairment was selected as the ICR for that participant. ICR response was assessed based on a positive change (according to pre-specified MID criteria) of each participant's ICR. Agresti-Coull confidence interval with nominal coverage ≥ 95%.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Impactful Clinical Problem Total Score at UX003 Treatment Week 24</measure>
    <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
    <description>The 3 most impactful clinical problems as reported by the subject/parent/caregiver during the Clinical Problem Evaluation were scored on a Likert scale from 1 (very little problem) to 7 (an extreme amount) at randomization and post-randomization visits. At post-randomization visits, each clinical problem was again scored for impact on daily activities. Total scores ranged from 3 to 21; lower scores reflect less impact on daily life. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) The change from baseline up to UX003 Treatment Week 24 were analyzed by GEE modeling, including baseline value, and the post-UX003 initiation treatment week as a categorical variable. The covariance structure within participants is assumed to be exchangeable.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>MPS 7</condition>
  <condition>Sly Syndrome</condition>
  <condition>Mucopolysaccharidosis</condition>
  <condition>MPS VII</condition>
  <arm_group>
    <arm_group_label>Group A: 4 mg/kg UX003</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>4 mg/kg UX003 QOW through Week 46</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group B: 8 Weeks Placebo then 4 mg/kg UX003</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Placebo QOW for the first 8 weeks followed by 4 mg/kg UX003 QOW through Week 46</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group C: 16 Weeks Placebo then 4 mg/kg UX003</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Placebo QOW for the first 16 weeks followed by 4 mg/kg UX003 QOW through Week 46</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group D: 24 Weeks Placebo then 4 mg/kg UX003</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Placebo QOW for the first 24 weeks followed by 4 mg/kg UX003 QOW through Week 46</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>UX003</intervention_name>
    <description>UX003 is a sterile concentrate formulation of rhGUS for intravenous infusion</description>
    <arm_group_label>Group A: 4 mg/kg UX003</arm_group_label>
    <arm_group_label>Group B: 8 Weeks Placebo then 4 mg/kg UX003</arm_group_label>
    <arm_group_label>Group C: 16 Weeks Placebo then 4 mg/kg UX003</arm_group_label>
    <arm_group_label>Group D: 24 Weeks Placebo then 4 mg/kg UX003</arm_group_label>
    <other_name>recombinant human beta-glucuronidase</other_name>
    <other_name>rh-β-glucuronidase</other_name>
    <other_name>rhGUS</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo consisting of the UX003 formulation buffer (without rhGUS)</description>
    <arm_group_label>Group B: 8 Weeks Placebo then 4 mg/kg UX003</arm_group_label>
    <arm_group_label>Group C: 16 Weeks Placebo then 4 mg/kg UX003</arm_group_label>
    <arm_group_label>Group D: 24 Weeks Placebo then 4 mg/kg UX003</arm_group_label>
    <other_name>Reference therapy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Confirmed diagnosis of MPS 7 based on leukocyte or fibroblast glucuronidase enzyme&#xD;
             assay or genetic testing.&#xD;
&#xD;
          -  Elevated urinary glycosaminoglycan (uGAG) excretion at a minimum of 3-fold over the&#xD;
             mean normal for age (at Screening).&#xD;
&#xD;
          -  Apparent clinical signs of lysosomal storage disease as judged by the Investigator,&#xD;
             including at least one of the following: enlarged liver and spleen, joint limitations,&#xD;
             airway obstruction or pulmonary problems, limitation of mobility while still&#xD;
             ambulatory.&#xD;
&#xD;
          -  Aged 5 - 35 years, inclusive.&#xD;
&#xD;
          -  Willing and able to provide written informed consent, or in the case of subjects under&#xD;
             the age of 18 (or 16 years, depending on the region), provide written assent (if&#xD;
             required) and written informed consent by a legally authorized representative after&#xD;
             the nature of the study has been explained, and prior to any research-related&#xD;
             procedures.&#xD;
&#xD;
          -  Sexually active subjects must be willing to use acceptable highly effective methods of&#xD;
             contraception while participating in the study and for 30 days following the last&#xD;
             dose.&#xD;
&#xD;
          -  Females of childbearing potential must have a negative pregnancy test at Screening and&#xD;
             be willing to have additional pregnancy tests during the study. Females considered not&#xD;
             of childbearing potential include those who have not experienced menarche, or have had&#xD;
             tubal ligation at least one year prior to Screening, or who have had total&#xD;
             hysterectomy.&#xD;
&#xD;
          -  Naïve to treatment with UX003.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Undergone a successful bone marrow or stem cell transplant or has any degree of&#xD;
             detectable chimaerism with donor cells.&#xD;
&#xD;
          -  Major surgery within 3 months prior to study entry or planned major surgery during the&#xD;
             study that may not allow safe participation in the study.&#xD;
&#xD;
          -  Presence or history of any hypersensitivity to rhGUS or its excipients that, in the&#xD;
             judgment of the Investigator, places the subject at increased risk for adverse&#xD;
             effects.&#xD;
&#xD;
          -  Pregnant or breastfeeding at Screening or planning to become pregnant (self or&#xD;
             partner) at any time during the study.&#xD;
&#xD;
          -  Use of any investigational product (drug or device or combination) within 30 days&#xD;
             prior to Screening, or requirement for any investigational agent prior to completion&#xD;
             of all scheduled study assessments.&#xD;
&#xD;
          -  Presence of a condition of such severity and acuity that, in the opinion of the&#xD;
             Investigator, warrants immediate surgical intervention or other treatment or may not&#xD;
             allow safe participation in the study.&#xD;
&#xD;
          -  Concurrent disease or condition, or laboratory abnormality that, in the view of the&#xD;
             Investigator, places the subject at high risk of poor treatment compliance or of not&#xD;
             completing the study, or would interfere with study participation or introduce&#xD;
             additional safety concerns.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>5 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paul Harmatz, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UCSF Benioff Children's Hospital Oakland</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Raymond Wang, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children's Hospital of Orange County</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Mislen Bauer, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Nicklaus Children's Hospital f/k/a Miami Children's Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Chester Whitley, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Minnesota</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Children's Hospital Oakland</name>
      <address>
        <city>Oakland</city>
        <state>California</state>
        <zip>94609</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital of Orange County</name>
      <address>
        <city>Orange</city>
        <state>California</state>
        <zip>92868</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Miami Children's Hospital</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33155</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Minnesota</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55455</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Wang RY, da Silva Franco JF, Lopez-Valdez J, Martins E, Sutton VR, Whitley CB, Zhang L, Cimms T, Marsden D, Jurecka A, Harmatz P. The long-term safety and efficacy of vestronidase alfa, rhGUS enzyme replacement therapy, in subjects with mucopolysaccharidosis VII. Mol Genet Metab. 2020 Mar;129(3):219-227. doi: 10.1016/j.ymgme.2020.01.003. Epub 2020 Jan 11. Erratum In: Mol Genet Metab. 2020 Sep - Oct;131(1-2):285.</citation>
    <PMID>32063397</PMID>
  </results_reference>
  <results_reference>
    <citation>Harmatz P, Whitley CB, Wang RY, Bauer M, Song W, Haller C, Kakkis E. A novel Blind Start study design to investigate vestronidase alfa for mucopolysaccharidosis VII, an ultra-rare genetic disease. Mol Genet Metab. 2018 Apr;123(4):488-494. doi: 10.1016/j.ymgme.2018.02.006. Epub 2018 Feb 12.</citation>
    <PMID>29478819</PMID>
  </results_reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>August 22, 2014</study_first_submitted>
  <study_first_submitted_qc>August 28, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 3, 2014</study_first_posted>
  <results_first_submitted>November 29, 2017</results_first_submitted>
  <results_first_submitted_qc>January 22, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">February 19, 2018</results_first_posted>
  <disposition_first_submitted>May 8, 2017</disposition_first_submitted>
  <disposition_first_submitted_qc>May 8, 2017</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">May 10, 2017</disposition_first_posted>
  <last_update_submitted>July 16, 2020</last_update_submitted>
  <last_update_submitted_qc>July 16, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 30, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>MPS 7</keyword>
  <keyword>Sly Syndrome</keyword>
  <keyword>Mucopolysaccharidosis</keyword>
  <keyword>MPS VII</keyword>
  <keyword>Enzyme Replacement Therapy</keyword>
  <keyword>Mucopolysaccharidosis type 7</keyword>
  <keyword>rare disease</keyword>
  <keyword>lysosomal storage disease</keyword>
  <keyword>metabolic disorder</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mucopolysaccharidoses</mesh_term>
    <mesh_term>Mucopolysaccharidosis VII</mesh_term>
  </condition_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Group A: 4 mg/kg UX003</title>
          <description>4 mg/kg UX003 every other week (QOW) through Week 46</description>
        </group>
        <group group_id="P2">
          <title>Group B: 8 Weeks Placebo Then 4 mg/kg UX003</title>
          <description>Placebo QOW for the first 8 weeks followed by 4 mg/kg UX003 QOW through Week 46</description>
        </group>
        <group group_id="P3">
          <title>Group C: 16 Weeks Placebo Then 4 mg/kg UX003</title>
          <description>Placebo QOW for the first 16 weeks followed by 4 mg/kg UX003 QOW through Week 46</description>
        </group>
        <group group_id="P4">
          <title>Group D: 24 Weeks Placebo Then 4 mg/kg UX003</title>
          <description>Placebo QOW for the first 24 weeks followed by 4 mg/kg UX003 QOW through Week 46</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
                <participants group_id="P3" count="3"/>
                <participants group_id="P4" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Group A: 4 mg/kg UX003</title>
          <description>4 mg/kg UX003 QOW through Week 46</description>
        </group>
        <group group_id="B2">
          <title>Group B: 8 Weeks Placebo Then 4 mg/kg UX003</title>
          <description>Placebo QOW for the first 8 weeks followed by 4 mg/kg UX003 QOW through Week 46</description>
        </group>
        <group group_id="B3">
          <title>Group C: 16 Weeks Placebo Then 4 mg/kg UX003</title>
          <description>Placebo QOW for the first 16 weeks followed by 4 mg/kg UX003 QOW through Week 46</description>
        </group>
        <group group_id="B4">
          <title>Group D: 24 Weeks Placebo Then 4 mg/kg UX003</title>
          <description>Placebo QOW for the first 24 weeks followed by 4 mg/kg UX003 QOW through Week 46</description>
        </group>
        <group group_id="B5">
          <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="3"/>
            <count group_id="B2" value="3"/>
            <count group_id="B3" value="3"/>
            <count group_id="B4" value="3"/>
            <count group_id="B5" value="12"/>
          </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="13.13" spread="1.656"/>
                    <measurement group_id="B2" value="12.50" spread="4.004"/>
                    <measurement group_id="B3" value="20.77" spread="3.004"/>
                    <measurement group_id="B4" value="15.23" spread="8.633"/>
                    <measurement group_id="B5" value="15.41" spread="5.492"/>
                  </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="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>European Union (EU) and Rest of World: Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate (DS) at UX003 Treatment Week 24</title>
        <description>Baseline was defined as the average of all assessments prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect was subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Percent change from baseline in uGAG DS was analyzed by generalized estimating equation (GEE) modeling based on observed data. The GEE model included included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable.&#xD;
In the United States (US), this was considered a secondary outcome measure. Per guidance from the Food and Drug Administration (FDA), no primary efficacy variable was declared in the US. Efficacy was to be based on the totality of the clinical data on a per participant basis.</description>
        <time_frame>Baseline (defined as the average of all assessments prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
        <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
        <group_list>
          <group group_id="O1">
            <title>UX003 4 mg/kg</title>
            <description>Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.</description>
          </group>
        </group_list>
        <measure>
          <title>European Union (EU) and Rest of World: Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate (DS) at UX003 Treatment Week 24</title>
          <description>Baseline was defined as the average of all assessments prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect was subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Percent change from baseline in uGAG DS was analyzed by generalized estimating equation (GEE) modeling based on observed data. The GEE model included included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable.&#xD;
In the United States (US), this was considered a secondary outcome measure. Per guidance from the Food and Drug Administration (FDA), no primary efficacy variable was declared in the US. Efficacy was to be based on the totality of the clinical data on a per participant basis.</description>
          <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
          <units>percentage change</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-64.82" spread="2.468"/>
                  </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>Superiority</non_inferiority_type>
            <p_value>&lt; 0.0001</p_value>
            <p_value_desc>P-values are from GEE model including baseline value, and the post UX003 Treatment Week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</p_value_desc>
            <method>GEE</method>
            <param_type>LS Mean</param_type>
            <param_value>-64.82</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-69.66</ci_lower_limit>
            <ci_upper_limit>-59.98</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Multi-Domain Responder Index (MDRI) Score at UX003 Treatment Week 24</title>
        <description>MDRI score, calculated as the total response score at UX003 Treatment Week 24 across 6 domains: 6-Minute Walk Test, forced vital capacity predicted value, shoulder flexion, visual acuity, and Bruininks-Oseretsky Test of Motor Proficiency fine motor and gross motor capacity. For each domain, a minimally important difference (MID) was pre-specified. Changes from before treatment (baseline) to 24 weeks after treatment in each domain variable were scored against pre-specified MIDs. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) An improvement or decline ≥ MID was scored either as a +1 or -1, respectively, and a change &lt;MID was scored as 0. The integration of benefit occurred by summing the responses (-1, +1, 0) across all 6 domain variables to derive the MDRI score, with a range of -6 (greatest possible decline) to +6 (greatest possible improvement).</description>
        <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
        <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
        <group_list>
          <group group_id="O1">
            <title>UX003 4 mg/kg</title>
            <description>Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.</description>
          </group>
        </group_list>
        <measure>
          <title>Multi-Domain Responder Index (MDRI) Score at UX003 Treatment Week 24</title>
          <description>MDRI score, calculated as the total response score at UX003 Treatment Week 24 across 6 domains: 6-Minute Walk Test, forced vital capacity predicted value, shoulder flexion, visual acuity, and Bruininks-Oseretsky Test of Motor Proficiency fine motor and gross motor capacity. For each domain, a minimally important difference (MID) was pre-specified. Changes from before treatment (baseline) to 24 weeks after treatment in each domain variable were scored against pre-specified MIDs. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) An improvement or decline ≥ MID was scored either as a +1 or -1, respectively, and a change &lt;MID was scored as 0. The integration of benefit occurred by summing the responses (-1, +1, 0) across all 6 domain variables to derive the MDRI score, with a range of -6 (greatest possible decline) to +6 (greatest possible improvement).</description>
          <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.5" spread="0.8"/>
                  </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>Superiority</non_inferiority_type>
            <p_value>0.0527</p_value>
            <method>t-test</method>
            <method_desc>P value from t-test of &quot;no change&quot; (0 change) from baseline</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in 6-Minute Walk Test (6MWT) at UX003 Treatment Week 24</title>
        <description>The total distance walked (in meters) in a 6-minute period was measured. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) A positive change from Baseline indicates improvement. Change from baseline in 6MWT was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</description>
        <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
        <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
        <group_list>
          <group group_id="O1">
            <title>UX003 4 mg/kg</title>
            <description>Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in 6-Minute Walk Test (6MWT) at UX003 Treatment Week 24</title>
          <description>The total distance walked (in meters) in a 6-minute period was measured. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) A positive change from Baseline indicates improvement. Change from baseline in 6MWT was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</description>
          <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
          <units>meters</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20.8" spread="16.75"/>
                  </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>Superiority</non_inferiority_type>
            <p_value>0.2137</p_value>
            <p_value_desc>P-values are from GEE model including baseline value, and the post UX003 Treatment Week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</p_value_desc>
            <method>GEE</method>
            <param_type>LS Mean</param_type>
            <param_value>20.8</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-12.0</ci_lower_limit>
            <ci_upper_limit>53.7</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Pulmonary Function Testing: Percentage of Predicted Forced Vital Capacity (FVC%Pred) at UX003 Treatment Week 24</title>
        <description>Spirometry was administered to participants who did not require invasive ventilatory support or have a tracheostomy and measured percentage of predicted FVC. The percent predicted values were calculated after testing using published normative data. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) No GEE analysis was performed for FVC due to the limitation of the sample size.</description>
        <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
        <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
        <group_list>
          <group group_id="O1">
            <title>UX003 4 mg/kg</title>
            <description>Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Pulmonary Function Testing: Percentage of Predicted Forced Vital Capacity (FVC%Pred) at UX003 Treatment Week 24</title>
          <description>Spirometry was administered to participants who did not require invasive ventilatory support or have a tracheostomy and measured percentage of predicted FVC. The percent predicted values were calculated after testing using published normative data. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) No GEE analysis was performed for FVC due to the limitation of the sample size.</description>
          <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
          <units>percentage predicted FVC</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" spread="NA">1 participant evaluated</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Pulmonary Function Testing: Maximum Ventilatory Ventilation (MVV) at UX003 Treatment Week 24</title>
        <description>Spirometry was administered to participants who did not require invasive ventilatory support or have a tracheostomy to measure MVV. The percent predicted values were calculated after testing using published normative data. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.)</description>
        <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
        <population>No change from baseline was calculated and no GEE analysis was performed due to lack of data at baseline and/or UX003 Treatment Week 24.</population>
        <group_list>
          <group group_id="O1">
            <title>UX003 4 mg/kg</title>
            <description>Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Pulmonary Function Testing: Maximum Ventilatory Ventilation (MVV) at UX003 Treatment Week 24</title>
          <description>Spirometry was administered to participants who did not require invasive ventilatory support or have a tracheostomy to measure MVV. The percent predicted values were calculated after testing using published normative data. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.)</description>
          <population>No change from baseline was calculated and no GEE analysis was performed due to lack of data at baseline and/or UX003 Treatment Week 24.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Shoulder Flexion and Extension Maximum Range of Motion at UX003 Treatment Week 24</title>
        <description>Goniometry was used to measure (in degrees) the maximum passive shoulder range of motion in both flexion and extension. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in shoulder flexion-left was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</description>
        <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
        <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
        <group_list>
          <group group_id="O1">
            <title>UX003 4 mg/kg</title>
            <description>Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Shoulder Flexion and Extension Maximum Range of Motion at UX003 Treatment Week 24</title>
          <description>Goniometry was used to measure (in degrees) the maximum passive shoulder range of motion in both flexion and extension. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in shoulder flexion-left was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</description>
          <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
          <units>degrees</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Shoulder flexion - left</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="12"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-6.5" spread="4.86"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Shoulder extension - left</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.5" spread="4.83"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Shoulder flexion - right</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="12"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.8" spread="3.54"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Shoulder extension - right</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-3.4" spread="3.48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Tighter shoulder flexion</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="12"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-9.4" spread="4.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Tighter shoulder extension</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-6.7" spread="3.53"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Shoulder Flexion - Left</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1778</p_value>
            <method>GEE</method>
            <param_type>LS Mean</param_type>
            <param_value>-6.5</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-16.1</ci_lower_limit>
            <ci_upper_limit>3.0</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Shoulder Extension - Left</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.7632</p_value>
            <method>GEE</method>
            <param_type>LS Mean</param_type>
            <param_value>-1.5</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-10.9</ci_lower_limit>
            <ci_upper_limit>8.0</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Shoulder Flexion - Right</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.6034</p_value>
            <method>GEE</method>
            <param_type>LS Mean</param_type>
            <param_value>-1.8</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-8.8</ci_lower_limit>
            <ci_upper_limit>5.1</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Shoulder Extension - Right</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.3332</p_value>
            <method>GEE</method>
            <param_type>LS Mean</param_type>
            <param_value>-3.4</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-10.2</ci_lower_limit>
            <ci_upper_limit>3.4</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Tighter Shoulder Flexion</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0415</p_value>
            <method>GEE</method>
            <param_type>LS Mean</param_type>
            <param_value>-9.4</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-18.4</ci_lower_limit>
            <ci_upper_limit>-0.4</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Tighter Shoulder Extension</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0563</p_value>
            <method>GEE</method>
            <param_type>LS Mean</param_type>
            <param_value>-6.7</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-13.6</ci_lower_limit>
            <ci_upper_limit>0.2</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Uncorrected Visual Acuity at UX003 Treatment Week 24</title>
        <description>Visual acuity was measured (corrected and uncorrected) using a standard eye chart and recorded for each eye independently. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. The change in the number of lines from pre-treatment baseline to 24 weeks of treatment was evaluated. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) A positive change from baseline indicates improvement. Change from baseline in uncorrected visual acuity was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</description>
        <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
        <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
        <group_list>
          <group group_id="O1">
            <title>UX003 4 mg/kg</title>
            <description>Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Uncorrected Visual Acuity at UX003 Treatment Week 24</title>
          <description>Visual acuity was measured (corrected and uncorrected) using a standard eye chart and recorded for each eye independently. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. The change in the number of lines from pre-treatment baseline to 24 weeks of treatment was evaluated. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) A positive change from baseline indicates improvement. Change from baseline in uncorrected visual acuity was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</description>
          <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
          <units>lines</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Left eye</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1" spread="0.63"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Right eye</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.9" spread="0.51"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>for the left eye</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1140</p_value>
            <method>GEE</method>
            <param_type>LS Mean</param_type>
            <param_value>1.0</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.2</ci_lower_limit>
            <ci_upper_limit>2.2</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>for the right eye</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0906</p_value>
            <method>GEE</method>
            <param_type>LS Mean</param_type>
            <param_value>0.9</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.1</ci_lower_limit>
            <ci_upper_limit>1.8</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) Scores at UX003 Treatment Week 24</title>
        <description>BOT-2 was administered to evaluate treatment-related changes in 4 domains assessing both fine and gross motor function: balance (score 0 to 37), fine motor precision (score 0 to 41), manual dexterity (score 0 to 45), and running speed/agility (score 0 to 52). Higher scores indicate more motor proficiency; a positive change from baseline indicates improvement. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in BOT-2 was analyzed by GEE modeling based on observed data. The GEE model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</description>
        <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
        <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
        <group_list>
          <group group_id="O1">
            <title>UX003 4 mg/kg</title>
            <description>Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) Scores at UX003 Treatment Week 24</title>
          <description>BOT-2 was administered to evaluate treatment-related changes in 4 domains assessing both fine and gross motor function: balance (score 0 to 37), fine motor precision (score 0 to 41), manual dexterity (score 0 to 45), and running speed/agility (score 0 to 52). Higher scores indicate more motor proficiency; a positive change from baseline indicates improvement. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in BOT-2 was analyzed by GEE modeling based on observed data. The GEE model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</description>
          <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
          <units>units on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Balance</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.8" spread="0.46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Fine motor precision</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.2" spread="0.23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Manual dexterity</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="11"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.2" spread="0.21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Running speed and agility</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.2" spread="0.12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Scale-BALANCE</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0883</p_value>
            <method>GEE</method>
            <param_type>LS Mean</param_type>
            <param_value>0.8</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.1</ci_lower_limit>
            <ci_upper_limit>1.7</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Scale: FINE MOTOR PRECISION</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.3528</p_value>
            <method>GEE</method>
            <param_type>LS Mean</param_type>
            <param_value>-0.2</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.7</ci_lower_limit>
            <ci_upper_limit>0.2</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Scale-MANUAL DEXTERITY</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.4094</p_value>
            <method>GEE</method>
            <param_type>LS Mean</param_type>
            <param_value>0.2</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.2</ci_lower_limit>
            <ci_upper_limit>0.6</ci_upper_limit>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>Scale-RUNNING SPEED AND AGILITY</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.1020</p_value>
            <method>GEE</method>
            <param_type>LS Mean</param_type>
            <param_value>0.2</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.0</ci_lower_limit>
            <ci_upper_limit>0.4</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale at UX003 Treatment Week 24</title>
        <description>The PedsQL 18-item scale is comprised of 3 dimensions: general fatigue (6 items), sleep/rest fatigue (6 items) and cognitive fatigue (6 items). Each item has a 5-point Likert response scale that is reverse scored and transformed to a 0 to 100 scale with higher scores indicating less fatigue. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in PedsQL total fatigue score was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and ≥1 post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</description>
        <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
        <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
        <group_list>
          <group group_id="O1">
            <title>UX003 4 mg/kg</title>
            <description>Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale at UX003 Treatment Week 24</title>
          <description>The PedsQL 18-item scale is comprised of 3 dimensions: general fatigue (6 items), sleep/rest fatigue (6 items) and cognitive fatigue (6 items). Each item has a 5-point Likert response scale that is reverse scored and transformed to a 0 to 100 scale with higher scores indicating less fatigue. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in PedsQL total fatigue score was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and ≥1 post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.</description>
          <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
          <units>units on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.4" spread="2.64"/>
                  </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>Superiority</non_inferiority_type>
            <p_value>0.1953</p_value>
            <method>GEE</method>
            <param_type>LS Mean</param_type>
            <param_value>3.4</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.8</ci_lower_limit>
            <ci_upper_limit>8.6</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Individual Clinical Response (ICR) Responders at UX003 Treatment Week 24</title>
        <description>Percentage of participants who were ICR responders based on MID criteria at Week 24. At the Randomization visit, the physician queried the participant or parent/caregiver about signs and symptoms of MPS VII that interfered most with the participant's daily life. Answers were mapped to an appropriate clinical outcome measure (e.g., difficulty walking could map to the 6MWT; breathing problems to FVC). The clinical outcome ranked with the highest impact on daily life that could be reliably completed by the participant and met a threshold level of impairment was selected as the ICR for that participant. ICR response was assessed based on a positive change (according to pre-specified MID criteria) of each participant's ICR. Agresti-Coull confidence interval with nominal coverage ≥ 95%.</description>
        <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
        <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
        <group_list>
          <group group_id="O1">
            <title>UX003 4 mg/kg</title>
            <description>Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Individual Clinical Response (ICR) Responders at UX003 Treatment Week 24</title>
          <description>Percentage of participants who were ICR responders based on MID criteria at Week 24. At the Randomization visit, the physician queried the participant or parent/caregiver about signs and symptoms of MPS VII that interfered most with the participant's daily life. Answers were mapped to an appropriate clinical outcome measure (e.g., difficulty walking could map to the 6MWT; breathing problems to FVC). The clinical outcome ranked with the highest impact on daily life that could be reliably completed by the participant and met a threshold level of impairment was selected as the ICR for that participant. ICR response was assessed based on a positive change (according to pre-specified MID criteria) of each participant's ICR. Agresti-Coull confidence interval with nominal coverage ≥ 95%.</description>
          <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</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="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="25" lower_limit="8.3" upper_limit="53.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Impactful Clinical Problem Total Score at UX003 Treatment Week 24</title>
        <description>The 3 most impactful clinical problems as reported by the subject/parent/caregiver during the Clinical Problem Evaluation were scored on a Likert scale from 1 (very little problem) to 7 (an extreme amount) at randomization and post-randomization visits. At post-randomization visits, each clinical problem was again scored for impact on daily activities. Total scores ranged from 3 to 21; lower scores reflect less impact on daily life. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) The change from baseline up to UX003 Treatment Week 24 were analyzed by GEE modeling, including baseline value, and the post-UX003 initiation treatment week as a categorical variable. The covariance structure within participants is assumed to be exchangeable.</description>
        <time_frame>Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment</time_frame>
        <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
        <group_list>
          <group group_id="O1">
            <title>UX003 4 mg/kg</title>
            <description>Participants were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Participants were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Impactful Clinical Problem Total Score at UX003 Treatment Week 24</title>
          <description>The 3 most impactful clinical problems as reported by the subject/parent/caregiver during the Clinical Problem Evaluation were scored on a Likert scale from 1 (very little problem) to 7 (an extreme amount) at randomization and post-randomization visits. At post-randomization visits, each clinical problem was again scored for impact on daily activities. Total scores ranged from 3 to 21; lower scores reflect less impact on daily life. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) The change from baseline up to UX003 Treatment Week 24 were analyzed by GEE modeling, including baseline value, and the post-UX003 initiation treatment week as a categorical variable. The covariance structure within participants is assumed to be exchangeable.</description>
          <population>Participants who had non-missing baseline and ≥1 post-baseline value during 24 weeks of UX003 treatment. Given a randomized blind start and single crossover study design, all 4 groups received a minimum of 24 weeks of UX003 treatment, with a placebo treatment period ranging from 0-24 weeks, by group. Analysis of placebo data was not planned.</population>
          <units>units on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="12"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.2" spread="0.92"/>
                  </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>Superiority</non_inferiority_type>
            <p_value>0.2022</p_value>
            <method>GEE</method>
            <param_type>LS Mean</param_type>
            <param_value>-1.2</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-3.0</ci_lower_limit>
            <ci_upper_limit>0.6</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Safety information was collected for all participants who received any study drug from signing the informed consent form through 30 days after last dose of study drug. Mean treatment duration for UX003 was 36.0 weeks, and for placebo was 15.8 weeks.</time_frame>
      <desc>Treatment-emergent adverse events (TEAEs) are presented. Given that the study has only has 12 participants, and a by arm/group analysis would include no more than 3 participants per arm/group, the TEAE summary was planned to present data by treatment only.</desc>
      <group_list>
        <group group_id="E1">
          <title>Placebo</title>
          <description>Participants received placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study, based on the blind-start design.</description>
        </group>
        <group group_id="E2">
          <title>UX003 Active Treatment</title>
          <description>Participants received 4 mg/kg UX003 QOW per group assignment (based on the blind-start design) and were dosed through Week 46. All groups received a minimum of 24 weeks of treatment with UX003.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 19.0</default_vocab>
        <default_assessment>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="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaphylactoid reaction</sub_title>
                <description>CTCAE grade 3 treatment-related anaphylactoid reaction secondary to an infusion rate error occurring during the first hour of UX003 administration.</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Craniocerebral injury</sub_title>
                <description>CTCAE grade 2 non-related craniocerebral injury as a result of falling off the bed. Computed tomography scan of the head did not show intracranial bleeding nor acute intracranial injury.</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 19.0</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="9" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="12" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Ear pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eye pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Abdominal pain lower</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Abnormal faeces</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Rectal haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Cheilosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Infusion site extravasation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Oedema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Catheter site bruise</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Infusion site bruising</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Infusion site swelling</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Peripheral swelling</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Infusion site discomfort</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaphylactoid reaction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Seasonal allergy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Ear infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Gastrointestinal viral infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Oral herpes</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Rash pustular</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Otitis media acute</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Excoriation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Post-traumatic neck syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Tooth fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Craniocerebral injury</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Body temperature increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Arthritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Joint range of motion decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Musculoskeletal stiffness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Joint swelling</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Skin papilloma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Ataxia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Clonus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Dysstasia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Post-traumatic stress disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary incontinence</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Dyspnoea exertional</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Nasal obstruction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Rhinorrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Urticaria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Rash macular</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Rash papular</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
              <event>
                <sub_title>Skin ulcer</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="9"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="12"/>
              </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>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Kim Mooney, Associate Director, Patient Advocacy Medical Services</name_or_title>
      <organization>Ultragenyx Pharmaceutical Inc</organization>
      <phone>408-981-3526</phone>
      <email>kmooney@ultragenyx.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/NCT02230566
org study id: UX003-CL301
nct id: NCT02230566
lead sponsor: 
has dmc: Yes
The Phase 3 study will use a novel randomized, intra-subject placebo-controlled, single
      crossover design, referred to as Blind Start, to evaluate the safety and efficacy of UX003.
      The Blind Start is a novel design whereby participants will be randomized to 1 of 4 groups,
      each representing a different treatment sequence, and will cross over to UX003 at different
      pre-defined time points in a blinded manner. All groups will receive a minimum of 24 weeks
      treatment with 4 mg/kg UX003 every other week (QOW).
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: European Union (EU) and Rest of World: Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate (DS) at UX003 Treatment Week 24
time frame: Baseline (defined as the average of all assessments prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
description: Baseline was defined as the average of all assessments prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect was subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Percent change from baseline in uGAG DS was analyzed by generalized estimating equation (GEE) modeling based on observed data. The GEE model included included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable.
In the United States (US), this was considered a secondary outcome measure. Per guidance from the Food and Drug Administration (FDA), no primary efficacy variable was declared in the US. Efficacy was to be based on the totality of the clinical data on a per participant basis.
measure: Multi-Domain Responder Index (MDRI) Score at UX003 Treatment Week 24
time frame: Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
description: MDRI score, calculated as the total response score at UX003 Treatment Week 24 across 6 domains: 6-Minute Walk Test, forced vital capacity predicted value, shoulder flexion, visual acuity, and Bruininks-Oseretsky Test of Motor Proficiency fine motor and gross motor capacity. For each domain, a minimally important difference (MID) was pre-specified. Changes from before treatment (baseline) to 24 weeks after treatment in each domain variable were scored against pre-specified MIDs. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) An improvement or decline ≥ MID was scored either as a +1 or -1, respectively, and a change <MID was scored as 0. The integration of benefit occurred by summing the responses (-1, +1, 0) across all 6 domain variables to derive the MDRI score, with a range of -6 (greatest possible decline) to +6 (greatest possible improvement).
measure: Change From Baseline in 6-Minute Walk Test (6MWT) at UX003 Treatment Week 24
time frame: Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
description: The total distance walked (in meters) in a 6-minute period was measured. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) A positive change from Baseline indicates improvement. Change from baseline in 6MWT was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.
measure: Change From Baseline in Pulmonary Function Testing: Percentage of Predicted Forced Vital Capacity (FVC%Pred) at UX003 Treatment Week 24
time frame: Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
description: Spirometry was administered to participants who did not require invasive ventilatory support or have a tracheostomy and measured percentage of predicted FVC. The percent predicted values were calculated after testing using published normative data. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) No GEE analysis was performed for FVC due to the limitation of the sample size.
measure: Change From Baseline in Pulmonary Function Testing: Maximum Ventilatory Ventilation (MVV) at UX003 Treatment Week 24
time frame: Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
description: Spirometry was administered to participants who did not require invasive ventilatory support or have a tracheostomy to measure MVV. The percent predicted values were calculated after testing using published normative data. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.)
measure: Change From Baseline in Shoulder Flexion and Extension Maximum Range of Motion at UX003 Treatment Week 24
time frame: Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
description: Goniometry was used to measure (in degrees) the maximum passive shoulder range of motion in both flexion and extension. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in shoulder flexion-left was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.
measure: Change From Baseline in Uncorrected Visual Acuity at UX003 Treatment Week 24
time frame: Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
description: Visual acuity was measured (corrected and uncorrected) using a standard eye chart and recorded for each eye independently. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. The change in the number of lines from pre-treatment baseline to 24 weeks of treatment was evaluated. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) A positive change from baseline indicates improvement. Change from baseline in uncorrected visual acuity was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.
measure: Change From Baseline in Bruininks-Oseretsky Test of Motor Proficiency (BOT-2) Scores at UX003 Treatment Week 24
time frame: Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
description: BOT-2 was administered to evaluate treatment-related changes in 4 domains assessing both fine and gross motor function: balance (score 0 to 37), fine motor precision (score 0 to 41), manual dexterity (score 0 to 45), and running speed/agility (score 0 to 52). Higher scores indicate more motor proficiency; a positive change from baseline indicates improvement. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in BOT-2 was analyzed by GEE modeling based on observed data. The GEE model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.
measure: Change From Baseline in Pediatric Quality of Life (PedsQL) Multidimensional Fatigue Scale at UX003 Treatment Week 24
time frame: Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
description: The PedsQL 18-item scale is comprised of 3 dimensions: general fatigue (6 items), sleep/rest fatigue (6 items) and cognitive fatigue (6 items). Each item has a 5-point Likert response scale that is reverse scored and transformed to a 0 to 100 scale with higher scores indicating less fatigue. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in PedsQL total fatigue score was analyzed by GEE modeling based on observed data. The GEE model included all participants who had non-missing baseline and ≥1 post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within participants was assumed to be exchangeable.
measure: Percentage of Individual Clinical Response (ICR) Responders at UX003 Treatment Week 24
time frame: Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
description: Percentage of participants who were ICR responders based on MID criteria at Week 24. At the Randomization visit, the physician queried the participant or parent/caregiver about signs and symptoms of MPS VII that interfered most with the participant's daily life. Answers were mapped to an appropriate clinical outcome measure (e.g., difficulty walking could map to the 6MWT; breathing problems to FVC). The clinical outcome ranked with the highest impact on daily life that could be reliably completed by the participant and met a threshold level of impairment was selected as the ICR for that participant. ICR response was assessed based on a positive change (according to pre-specified MID criteria) of each participant's ICR. Agresti-Coull confidence interval with nominal coverage ≥ 95%.
measure: Change From Baseline in Impactful Clinical Problem Total Score at UX003 Treatment Week 24
time frame: Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment
description: The 3 most impactful clinical problems as reported by the subject/parent/caregiver during the Clinical Problem Evaluation were scored on a Likert scale from 1 (very little problem) to 7 (an extreme amount) at randomization and post-randomization visits. At post-randomization visits, each clinical problem was again scored for impact on daily activities. Total scores ranged from 3 to 21; lower scores reflect less impact on daily life. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) The change from baseline up to UX003 Treatment Week 24 were analyzed by GEE modeling, including baseline value, and the post-UX003 initiation treatment week as a categorical variable. The covariance structure within participants is assumed to be exchangeable.
arm group label: Group A: 4 mg/kg UX003
arm group type: Experimental
description: 4 mg/kg UX003 QOW through Week 46
arm group label: Group B: 8 Weeks Placebo then 4 mg/kg UX003
arm group type: Experimental
description: Placebo QOW for the first 8 weeks followed by 4 mg/kg UX003 QOW through Week 46
arm group label: Group C: 16 Weeks Placebo then 4 mg/kg UX003
arm group type: Experimental
description: Placebo QOW for the first 16 weeks followed by 4 mg/kg UX003 QOW through Week 46
arm group label: Group D: 24 Weeks Placebo then 4 mg/kg UX003
arm group type: Experimental
description: Placebo QOW for the first 24 weeks followed by 4 mg/kg UX003 QOW through Week 46
intervention type: Drug
intervention name: UX003
description: UX003 is a sterile concentrate formulation of rhGUS for intravenous infusion
arm group label: Group A: 4 mg/kg UX003
arm group label: Group B: 8 Weeks Placebo then 4 mg/kg UX003
arm group label: Group C: 16 Weeks Placebo then 4 mg/kg UX003
arm group label: Group D: 24 Weeks Placebo then 4 mg/kg UX003
other name: recombinant human beta-glucuronidase
other name: rh-β-glucuronidase
other name: rhGUS
intervention type: Other
intervention name: Placebo
description: Placebo consisting of the UX003 formulation buffer (without rhGUS)
arm group label: Group B: 8 Weeks Placebo then 4 mg/kg UX003
arm group label: Group C: 16 Weeks Placebo then 4 mg/kg UX003
arm group label: Group D: 24 Weeks Placebo then 4 mg/kg UX003
other name: Reference therapy
criteria: 
gender: All
minimum age: 5 Years
maximum age: 35 Years
healthy volunteers: No
last name: Paul Harmatz, MD
role: Principal Investigator
affiliation: UCSF Benioff Children's Hospital Oakland
last name: Raymond Wang, MD
role: Principal Investigator
affiliation: Children's Hospital of Orange County
last name: Mislen Bauer, MD
role: Principal Investigator
affiliation: Nicklaus Children's Hospital f/k/a Miami Children's Hospital
last name: Chester Whitley, MD
role: Principal Investigator
affiliation: University of Minnesota
facility: 
facility: 
facility: 
facility: 
country: United States
citation: Wang RY, da Silva Franco JF, Lopez-Valdez J, Martins E, Sutton VR, Whitley CB, Zhang L, Cimms T, Marsden D, Jurecka A, Harmatz P. The long-term safety and efficacy of vestronidase alfa, rhGUS enzyme replacement therapy, in subjects with mucopolysaccharidosis VII. Mol Genet Metab. 2020 Mar;129(3):219-227. doi: 10.1016/j.ymgme.2020.01.003. Epub 2020 Jan 11. Erratum In: Mol Genet Metab. 2020 Sep - Oct;131(1-2):285.
PMID: 32063397
citation: Harmatz P, Whitley CB, Wang RY, Bauer M, Song W, Haller C, Kakkis E. A novel Blind Start study design to investigate vestronidase alfa for mucopolysaccharidosis VII, an ultra-rare genetic disease. Mol Genet Metab. 2018 Apr;123(4):488-494. doi: 10.1016/j.ymgme.2018.02.006. Epub 2018 Feb 12.
PMID: 29478819
responsible party type: Sponsor
mesh term: Mucopolysaccharidoses
mesh term: Mucopolysaccharidosis VII
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 