<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/NCT01733316</url>
  </required_header>
  <id_info>
    <org_study_id>RP103-07</org_study_id>
    <secondary_id>2012-002773-64</secondary_id>
    <nct_id>NCT01733316</nct_id>
  </id_info>
  <brief_title>Open-Label, Safety and Superior Effectiveness Study of Cysteamine Bitartrate Delayed-Release Capsules (RP103) in Cystinosis</brief_title>
  <official_title>A Long-Term, Open-Label, Safety, Tolerability and Superior Effectiveness Study of Cysteamine Bitartrate Delayed-release Capsules (RP103) in Patients With Cystinosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Horizon Pharma USA, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Horizon Pharma USA, Inc.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to gather information about the effectiveness (how well it works&#xD;
      to treat cystinosis) and safety of a new form of cysteamine bitartrate called RP103, compared&#xD;
      to the already-approved drug cystinosis patients are taking called Cystagon®.&#xD;
&#xD;
      In cystinosis, the body builds up cystine. When taken regularly, the active ingredient of&#xD;
      Cystagon® (cysteamine bitartrate) reduces cystine in the body. RP103 has the same active&#xD;
      ingredient as Cystagon® and is designed to reduce cystine in a similar way that Cystagon®&#xD;
      does. To decide if RP103 is better than Cystagon®, the study will look at two types of blood&#xD;
      tests. One test is pharmacodynamics (PD), which measures the amount of white blood cell (WBC)&#xD;
      cystine after taking study drug. WBC cystine is a laboratory test used to find out if&#xD;
      cysteamine bitartrate is reducing cystine levels in the body. The second test is&#xD;
      pharmacokinetics (PK), which measures the amount of cysteamine in the blood after taking the&#xD;
      drug.&#xD;
&#xD;
      RP103 is different from Cystagon®: Instead of the cysteamine bitartrate being absorbed from&#xD;
      the stomach, RP103 is designed to be absorbed from the small intestine. This may make the&#xD;
      effects of the drug last longer, so that it can be taken twice a day instead of four times a&#xD;
      day like Cystagon®.&#xD;
&#xD;
      Some cystinosis patients have bad breath (halitosis) when they take Cystagon®. Study&#xD;
      participants who experience bad breath with Cystagon® will be asked if they would like to&#xD;
      participate in an optional &quot;halitosis substudy&quot; to investigate this issue by collecting some&#xD;
      extra PK blood samples.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 31, 2013</start_date>
  <completion_date type="Actual">July 10, 2017</completion_date>
  <primary_completion_date type="Actual">February 2015</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Average Difference Between Morning and Non-Morning Log White Blood Cell (WBC) Cystine Values</measure>
    <time_frame>While taking Cystagon® (Months 1, 2, 3): within 15 minutes pre-morning (AM) and pre-non AM dose. During 3 months of RP103 (Months 5, 6, 7): 30 minutes post-AM and post-evening (PM) dose.</time_frame>
    <description>The primary analysis of WBC cystine was performed using the natural log transformed WBC cystine level; the log transformation is a normalizing transformation. For each participant, the difference between the morning and corresponding non-morning log WBC cystine value (non-morning minus morning) at each monthly visit during the Cystagon® phase (Months 1, 2, and 3) was computed and these differences were averaged. The average difference between morning and non-morning log WBC cystine value was similarly computed for each participant during the RP103 phase (Months 5, 6, and 7). The primary analysis compared within-subject pairs (Cystagon® phase paired with RP103 phase) of non-morning minus morning average differences of log WBC cystine level.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs</measure>
    <time_frame>From first dose of study drug to 7 days after last dose. Median duration of exposure was 91 days (range 82-108) for Cystagon® phase, 119 days (range 98-137) for the RP103 phase, and 861 days (range 30 - 1350) during the long-term RP-103 phase.</time_frame>
    <description>AE: any untoward medical occurrence that does not necessarily have a causal relationship with study drug. SAE: any untoward medical occurrence that at any dose: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; or is medically significant, and though not included in the above list, is an important medical event, according to the Investigator. Treatment-emergent adverse events (TEAEs) occurred after first dose of study drug. Clinically significant abnormalities in laboratory values (hematology, blood chemistry, urinalysis), electrocardiograms (ECGs), vital signs, and physical examinations were to be reported as adverse events and so are included in this summary of TEAEs</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Halitosis Substudy: Maximum Plasma Concentration (Cmax) for Plasma Cysteamine</measure>
    <time_frame>While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose, 30 minutes post-dose, 1, 2, 4 and 6 hours post-dose. While taking RP103 (Month 5, 6, or 7): 30 minutes after morning dose and 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose</time_frame>
    <description>Participants who reported halitosis (&quot;bad breath&quot;) as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of dimethylsulfide (DMS) in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state pharmacokinetic (PK) samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Halitosis Substudy: Time to Cmax (Tmax) for Plasma Cysteamine</measure>
    <time_frame>While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose, 30 minutes post-dose, 1, 2, 4 and 6 hours post-dose. While taking RP103 (Month 5, 6, or 7): 30 minutes after morning dose and 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose</time_frame>
    <description>Participants who reported halitosis (&quot;bad breath&quot;) as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area Under the Plasma Concentration Time Curve From Time Point 0 Through the Last Measurable Point (AUC0-t) for Plasma Cysteamine</measure>
    <time_frame>While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose, 30 minutes post-dose, 1, 2, 4 and 6 hours post-dose. While taking RP103 (Month 5, 6, or 7): 30 minutes after morning dose and 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose</time_frame>
    <description>Participants who reported halitosis (&quot;bad breath&quot;) as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Halitosis Substudy: Expired Air DMS Concentrations</measure>
    <time_frame>While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose 30 min post-dose, 2, 3, 4 and 6 hours post-dose. While taking RP103 (Month 4, 5, or 7): Within 15 min. prior to morning dose. 1, 2, 3, 4, 5, 6, 8, 10, 12 hours post dose</time_frame>
    <description>Participants who reported halitosis (&quot;bad breath&quot;) as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">41</enrollment>
  <condition>Cystinosis</condition>
  <arm_group>
    <arm_group_label>All Participants</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cystagon® Phase: From Screening and during Months 1, 2, 3 participants receive their usual dose of Cystagon® every 6 hours (Q6H).&#xD;
RP103 Phase: During Months 3.5, 4, 5, 6, 7 participants receive RP103 every 12 hours (Q12H).&#xD;
Long Term Phase: On or after Month 7, for the remainder of study participants receive RP103 Q12H.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>RP103</intervention_name>
    <arm_group_label>All Participants</arm_group_label>
    <other_name>cysteamine bitartrate delayed-release capsules</other_name>
    <other_name>PROCYSBI®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cystagon®</intervention_name>
    <arm_group_label>All Participants</arm_group_label>
    <other_name>cysteamine bitartrate</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        INCLUSION CRITERIA:&#xD;
&#xD;
          -  Male or female with a documented diagnosis of cystinosis&#xD;
&#xD;
          -  On a stable dose of Cystagon® at least 21 days prior to Screening&#xD;
&#xD;
          -  WBC cystine level &gt; 1 nmol 1/2 cystine/mg of protein, on average over at least 2&#xD;
             measurements collected during the 2 years prior to Screening&#xD;
&#xD;
          -  No clinically significant change in liver function tests, i.e. 1.5 times upper limit&#xD;
             of normal (ULN) for alanine aminotransferase and aspartate aminotransferase, and/or&#xD;
             1.5 times ULN for total bilirubin, within 6 months prior to Screening&#xD;
&#xD;
          -  No clinically significant change in renal function, i.e. estimated glomerular&#xD;
             filtration rate (GFR) within 6 months prior to Screening&#xD;
&#xD;
          -  Must have an estimated GFR &gt; 20 mL/minute/1.73m^2 (using the equation from Schwartz&#xD;
             2009 J Am Soc Nephrol 20:629-647)&#xD;
&#xD;
          -  Female subjects who are sexually active and of childbearing potential, i.e. not&#xD;
             surgically sterile (tubal ligation, bilateral oophorectomy, or hysterectomy) or at&#xD;
             least 2 years naturally postmenopausal must agree to use an acceptable form of&#xD;
             contraception from Screening through completion of the study. Acceptable forms of&#xD;
             contraception for this study include hormonal contraceptives (oral, implant,&#xD;
             transdermal patch, or injection) at a stable dose for at least 3 months prior to&#xD;
             Screening, barrier (spermicidal condom or diaphragm with spermicide), intrauterine&#xD;
             device, or a partner who has been vasectomized for at least 6 months.&#xD;
&#xD;
          -  Subject or their parent or guardian must provide written informed consent, assent&#xD;
             (where applicable), prior to participation in the study&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Younger than 12 years of age&#xD;
&#xD;
          -  Current history of the following conditions or any other health issues that make it,&#xD;
             in the opinion of the investigator, unsafe for study participation:&#xD;
&#xD;
               -  Inflammatory bowel disease, if currently active, or prior resection of the small&#xD;
                  intestine;&#xD;
&#xD;
               -  Heart disease (e.g., myocardial infarction, heart failure, unstable arrhythmias,&#xD;
                  or poorly controlled hypertension) within 90 days prior to Screening;&#xD;
&#xD;
               -  Active bleeding disorder within 90 days prior to Screening;&#xD;
&#xD;
               -  History of malignant disease within 2 years prior to Screening&#xD;
&#xD;
          -  Hemoglobin level of &lt; 9 g/dL at Screening or, in the opinion of the investigator, a&#xD;
             hemoglobin level that would make it unsafe for study participation&#xD;
&#xD;
          -  Known hypersensitivity to cysteamine and penicillamine&#xD;
&#xD;
          -  Female subjects who are nursing, planning a pregnancy, or are known or suspected to be&#xD;
             pregnant&#xD;
&#xD;
          -  Subjects who, in the opinion of the investigator, are not able or willing to comply&#xD;
             with study requirements.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Evelyn Olson, BS</last_name>
    <role>Study Director</role>
    <affiliation>Horizon Pharma USA, Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>California Pacific Medical Center (CPMC) Research Institute</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stanford University Medical School</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Emory Children's Center</name>
      <address>
        <city>Atlanta</city>
        <state>Georgia</state>
        <zip>30322</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ann &amp; Robert H. Lurie Children's Hospital of Chicago</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60614</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baylor College of Medicine / Texas Childrens Hospital</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital of Leuven</name>
      <address>
        <city>Leuven</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospices Civils de Lyon</name>
      <address>
        <city>Lyon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Necker-Enfants Malades</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Robert Debré</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ospedale Pediatrico Bambino Gesù</name>
      <address>
        <city>Rome</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Radboud University Nijmegen Medical Center</name>
      <address>
        <city>Nijmegen</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Queen Elizabeth Hospital Birmingham</name>
      <address>
        <city>Birmingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Great Ormond Street</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Guy's Hospital</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>France</country>
    <country>Italy</country>
    <country>Netherlands</country>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://procysbi.com/</url>
    <description>RP103 (marketed as PROCYSBI) is now approved by the US FDA for management of nephropathic cystinosis in patients 6 years and older.</description>
  </link>
  <reference>
    <citation>Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009 Mar;20(3):629-37. doi: 10.1681/ASN.2008030287. Epub 2009 Jan 21.</citation>
    <PMID>19158356</PMID>
  </reference>
  <verification_date>July 2018</verification_date>
  <study_first_submitted>November 16, 2012</study_first_submitted>
  <study_first_submitted_qc>November 20, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 27, 2012</study_first_posted>
  <results_first_submitted>April 10, 2017</results_first_submitted>
  <results_first_submitted_qc>May 19, 2017</results_first_submitted_qc>
  <results_first_posted type="Actual">May 24, 2017</results_first_posted>
  <last_update_submitted>July 10, 2018</last_update_submitted>
  <last_update_submitted_qc>July 10, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">August 13, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Nephropathic Cystinosis</keyword>
  <keyword>Cysteamine</keyword>
  <keyword>Delayed-Release Cysteamine</keyword>
  <keyword>Orphan Disease</keyword>
  <keyword>CTNS Protein, Human</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cystinosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cysteamine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>All Participants</title>
          <description>Cystagon® Phase: From Screening and during Months 1, 2, 3 participants received their usual dose of Cystagon® every 6 hours (Q6H).&#xD;
RP103 Phase: During Months 3.5, 4, 5, 6, 7 participants received RP103 every 12 hours (Q12H).&#xD;
Long Term Phase: On or after Month 7, for the remainder of study participants received RP103 Q12H.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Cystagon® Phase</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="41"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="41"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>RP103 Phase</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="41"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="40"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Non-compliance</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Long Term Extension Phase</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="38">Two participants did not enter the long term follow up period.</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="33"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Consent Withdrawn by Subject</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Sponsor Decision</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>All Participants</title>
          <description>Cystagon® Phase: From Screening and during Months 1, 2, 3 participants received their usual dose of Cystagon® Q6H.&#xD;
RP103 Phase: During Months 3.5, 4, 5, 6, 7 participants received RP103 Q12H.&#xD;
Long Term Phase: On or after Month 7, for the remainder of study participants received RP103 Q12H.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="41"/>
          </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="24.5" spread="11.56"/>
                  </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="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Average Difference Between Morning and Non-Morning Log White Blood Cell (WBC) Cystine Values</title>
        <description>The primary analysis of WBC cystine was performed using the natural log transformed WBC cystine level; the log transformation is a normalizing transformation. For each participant, the difference between the morning and corresponding non-morning log WBC cystine value (non-morning minus morning) at each monthly visit during the Cystagon® phase (Months 1, 2, and 3) was computed and these differences were averaged. The average difference between morning and non-morning log WBC cystine value was similarly computed for each participant during the RP103 phase (Months 5, 6, and 7). The primary analysis compared within-subject pairs (Cystagon® phase paired with RP103 phase) of non-morning minus morning average differences of log WBC cystine level.</description>
        <time_frame>While taking Cystagon® (Months 1, 2, 3): within 15 minutes pre-morning (AM) and pre-non AM dose. During 3 months of RP103 (Months 5, 6, 7): 30 minutes post-AM and post-evening (PM) dose.</time_frame>
        <population>Pharmacodynamic (PD) Analysis Set: All participants who received at least one treatment of Cystagon® and RP103 and who had at least one WBC cystine level recorded after each of Cystagon® treatment and RP103 treatment. Only participants with an average difference during both the Cystagon® and RP103 phases were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Cystagon® Phase</title>
            <description>From Screening and during Months 1, 2, 3: participants received their usual dose of Cystagon® Q6H.</description>
          </group>
          <group group_id="O2">
            <title>RP103 Phase</title>
            <description>During Months 3.5, 4, 5, 6, 7: participants received RP103 Q12H.</description>
          </group>
        </group_list>
        <measure>
          <title>Average Difference Between Morning and Non-Morning Log White Blood Cell (WBC) Cystine Values</title>
          <description>The primary analysis of WBC cystine was performed using the natural log transformed WBC cystine level; the log transformation is a normalizing transformation. For each participant, the difference between the morning and corresponding non-morning log WBC cystine value (non-morning minus morning) at each monthly visit during the Cystagon® phase (Months 1, 2, and 3) was computed and these differences were averaged. The average difference between morning and non-morning log WBC cystine value was similarly computed for each participant during the RP103 phase (Months 5, 6, and 7). The primary analysis compared within-subject pairs (Cystagon® phase paired with RP103 phase) of non-morning minus morning average differences of log WBC cystine level.</description>
          <population>Pharmacodynamic (PD) Analysis Set: All participants who received at least one treatment of Cystagon® and RP103 and who had at least one WBC cystine level recorded after each of Cystagon® treatment and RP103 treatment. Only participants with an average difference during both the Cystagon® and RP103 phases were included.</population>
          <units>log [nmol ½ cystine/mg protein]</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
                <count group_id="O2" value="40"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.229" spread="0.5027"/>
                    <measurement group_id="O2" value="0.080" spread="0.3939"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.0048</p_value>
            <p_value_desc>Paired t-test testing the null hypothesis that the population average difference during the Cystagon® phase is equal to the population average difference during the RP103 phase.</p_value_desc>
            <method>Paired t-test, two-sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs</title>
        <description>AE: any untoward medical occurrence that does not necessarily have a causal relationship with study drug. SAE: any untoward medical occurrence that at any dose: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; or is medically significant, and though not included in the above list, is an important medical event, according to the Investigator. Treatment-emergent adverse events (TEAEs) occurred after first dose of study drug. Clinically significant abnormalities in laboratory values (hematology, blood chemistry, urinalysis), electrocardiograms (ECGs), vital signs, and physical examinations were to be reported as adverse events and so are included in this summary of TEAEs</description>
        <time_frame>From first dose of study drug to 7 days after last dose. Median duration of exposure was 91 days (range 82-108) for Cystagon® phase, 119 days (range 98-137) for the RP103 phase, and 861 days (range 30 - 1350) during the long-term RP-103 phase.</time_frame>
        <population>Safety Analysis Set: all participants who received at least 1 dose of study drug (RP103). The row &quot;At least 1 TEAE&quot; includes both serious and non-serious AEs.</population>
        <group_list>
          <group group_id="O1">
            <title>Cystagon® Phase</title>
            <description>From Screening and during Months 1, 2, 3: participants received their usual dose of Cystagon® Q6H.&#xD;
Observations from Day 1 Cystagon® dosing up to the first dose of RP103 were attributed to the Cystagon® Phase.</description>
          </group>
          <group group_id="O2">
            <title>RP103 Phase</title>
            <description>During Months 3.5, 4, 5, 6, 7: participants received RP103 Q12H.&#xD;
Observations on or after the first dose of RP103 up to Month 7 or study termination visit (whichever occurred first) were attributed to the RP103 Phase.</description>
          </group>
          <group group_id="O3">
            <title>Long-Term Phase</title>
            <description>From Month 7 and for the remainder of study: participants received RP103 Q12H.&#xD;
Observations on or after the Month 7 visit through study termination were attributed to the Long-Term RP103 Phase.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs</title>
          <description>AE: any untoward medical occurrence that does not necessarily have a causal relationship with study drug. SAE: any untoward medical occurrence that at any dose: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; or is medically significant, and though not included in the above list, is an important medical event, according to the Investigator. Treatment-emergent adverse events (TEAEs) occurred after first dose of study drug. Clinically significant abnormalities in laboratory values (hematology, blood chemistry, urinalysis), electrocardiograms (ECGs), vital signs, and physical examinations were to be reported as adverse events and so are included in this summary of TEAEs</description>
          <population>Safety Analysis Set: all participants who received at least 1 dose of study drug (RP103). The row &quot;At least 1 TEAE&quot; includes both serious and non-serious AEs.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="41"/>
                <count group_id="O2" value="41"/>
                <count group_id="O3" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>At least 1 TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31"/>
                    <measurement group_id="O2" value="38"/>
                    <measurement group_id="O3" value="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>At least 1 TEAE-related to study drug</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="20"/>
                    <measurement group_id="O3" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>At least 1 grade ≥ 3 TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="4"/>
                    <measurement group_id="O3" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>At least 1 serious TEAE</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="6"/>
                    <measurement group_id="O3" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>At least 1 TEAE leading to discontinuation</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Halitosis Substudy: Maximum Plasma Concentration (Cmax) for Plasma Cysteamine</title>
        <description>Participants who reported halitosis (&quot;bad breath&quot;) as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of dimethylsulfide (DMS) in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state pharmacokinetic (PK) samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.</description>
        <time_frame>While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose, 30 minutes post-dose, 1, 2, 4 and 6 hours post-dose. While taking RP103 (Month 5, 6, or 7): 30 minutes after morning dose and 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose</time_frame>
        <population>PK Analysis Set: All participants who received at least one dose of RP103 and had available PK data at given timepoint.</population>
        <group_list>
          <group group_id="O1">
            <title>Halitosis Substudy Participants</title>
            <description>Cystagon® Phase: From Screening and during Months 1, 2, 3 participants received their usual dose of Cystagon® Q6H.&#xD;
RP103 Phase: During Months 3.5, 4, 5, 6, 7 participants received RP103 Q12H.</description>
          </group>
        </group_list>
        <measure>
          <title>Halitosis Substudy: Maximum Plasma Concentration (Cmax) for Plasma Cysteamine</title>
          <description>Participants who reported halitosis (&quot;bad breath&quot;) as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of dimethylsulfide (DMS) in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state pharmacokinetic (PK) samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.</description>
          <population>PK Analysis Set: All participants who received at least one dose of RP103 and had available PK data at given timepoint.</population>
          <units>mg/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cystagon® dosing period</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.5" spread="1.87"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RP103 dosing period</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.9" spread="1.65"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Halitosis Substudy: Time to Cmax (Tmax) for Plasma Cysteamine</title>
        <description>Participants who reported halitosis (&quot;bad breath&quot;) as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.</description>
        <time_frame>While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose, 30 minutes post-dose, 1, 2, 4 and 6 hours post-dose. While taking RP103 (Month 5, 6, or 7): 30 minutes after morning dose and 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose</time_frame>
        <population>PK Analysis Set: All participants who received at least one dose of RP103 and had available PK data at given timepoint.</population>
        <group_list>
          <group group_id="O1">
            <title>Halitosis Substudy Participants</title>
            <description>Cystagon® Phase: From Screening and during Months 1, 2, 3 participants received their usual dose of Cystagon® Q6H.&#xD;
RP103 Phase: During Months 3.5, 4, 5, 6, 7 participants received RP103 Q12H.</description>
          </group>
        </group_list>
        <measure>
          <title>Halitosis Substudy: Time to Cmax (Tmax) for Plasma Cysteamine</title>
          <description>Participants who reported halitosis (&quot;bad breath&quot;) as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.</description>
          <population>PK Analysis Set: All participants who received at least one dose of RP103 and had available PK data at given timepoint.</population>
          <units>hour</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cystagon® dosing period</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.2" spread="0.87"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RP103 dosing period</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.2" spread="1.30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Area Under the Plasma Concentration Time Curve From Time Point 0 Through the Last Measurable Point (AUC0-t) for Plasma Cysteamine</title>
        <description>Participants who reported halitosis (&quot;bad breath&quot;) as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.</description>
        <time_frame>While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose, 30 minutes post-dose, 1, 2, 4 and 6 hours post-dose. While taking RP103 (Month 5, 6, or 7): 30 minutes after morning dose and 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose</time_frame>
        <population>PK Analysis Set: All participants who received at least one dose of RP103 and had available PK data at given timepoint.</population>
        <group_list>
          <group group_id="O1">
            <title>Halitosis Substudy Participants</title>
            <description>Cystagon® Phase: From Screening and during Months 1, 2, 3 participants received their usual dose of Cystagon® Q6H.&#xD;
RP103 Phase: During Months 3.5, 4, 5, 6, 7 participants received RP103 Q12H.</description>
          </group>
        </group_list>
        <measure>
          <title>Area Under the Plasma Concentration Time Curve From Time Point 0 Through the Last Measurable Point (AUC0-t) for Plasma Cysteamine</title>
          <description>Participants who reported halitosis (&quot;bad breath&quot;) as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.</description>
          <population>PK Analysis Set: All participants who received at least one dose of RP103 and had available PK data at given timepoint.</population>
          <units>hr*mg/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cystagon® dosing period</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="19"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.8" spread="5.18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RP103 dosing period</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.4" spread="4.86"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Halitosis Substudy: Expired Air DMS Concentrations</title>
        <description>Participants who reported halitosis (&quot;bad breath&quot;) as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.</description>
        <time_frame>While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose 30 min post-dose, 2, 3, 4 and 6 hours post-dose. While taking RP103 (Month 4, 5, or 7): Within 15 min. prior to morning dose. 1, 2, 3, 4, 5, 6, 8, 10, 12 hours post dose</time_frame>
        <population>PK Analysis Set: All participants who received at least one dose of RP103 and had available PK data at given timepoint.</population>
        <group_list>
          <group group_id="O1">
            <title>Halitosis Substudy Participants</title>
            <description>Cystagon® Phase: From Screening and during Months 1, 2, 3 participants received their usual dose of Cystagon® Q6H.&#xD;
RP103 Phase: During Months 3.5, 4, 5, 6, 7 participants received RP103 Q12H.</description>
          </group>
        </group_list>
        <measure>
          <title>Halitosis Substudy: Expired Air DMS Concentrations</title>
          <description>Participants who reported halitosis (&quot;bad breath&quot;) as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.</description>
          <population>PK Analysis Set: All participants who received at least one dose of RP103 and had available PK data at given timepoint.</population>
          <units>nmol/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cystagon®, within 15 minutes prior to dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.7" spread="5.54"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cystagon®, 30 minutes post dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.7" spread="4.75"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cystagon®, 1 hour post morning dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.9" spread="6.75"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cystagon®, 2 hours post morning dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.9" spread="11.26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cystagon®, 3 hours post morning dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.2" spread="13.32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cystagon®, 4 hours post morning dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.8" spread="12.05"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cystagon®, 6 hours post morning dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.4" spread="3.77"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RP103, within 15 minutes prior to dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.6" spread="6.05"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RP103, 1 hour post morning dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.4" spread="7.71"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RP103, 2 hours post morning dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.1" spread="6.28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RP103, 3 hours post morning dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.7" spread="8.53"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RP103, 4 hours post morning dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.6" spread="11.22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RP103, 5 hours post morning dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.2" spread="15.86"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RP103, 6 hours post morning dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.5" spread="13.87"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RP103, 8 hours post morning dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.7" spread="10.76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RP103, 10 hours post morning dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.2" spread="8.13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>RP103, 12 hours post morning dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.3" spread="5.32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From first dose of study drug to 7 days after last dose. Median duration of exposure was 91 days (range 82-108) for Cystagon® phase, 119 days (range 98-137) for the RP103 phase, and 861 days (range 30-1350) during the long term RP-103 phase.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Cystagon® Phase</title>
          <description>From Screening and during Months 1, 2, 3: participants received their usual dose of Cystagon® Q6H.</description>
        </group>
        <group group_id="E2">
          <title>RP103 Phase</title>
          <description>During Months 3.5, 4, 5, 6, 7: participants received RP103 Q12H.</description>
        </group>
        <group group_id="E3">
          <title>Long-Term Phase</title>
          <description>From Month 7 and for the remainder of study: participants received RP103 Q12H.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 15.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="13" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Death</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bacteraemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Diverticulitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Septic shock</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Gastroenteritis norovirus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Gastroenteritis viral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Graft infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Onychomycosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Tonsillitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Arteriovenous fistula thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Procedural hypotension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Arteriovenous fistula aneurysm</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Arteriovenous fistula site complication</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Arteriovenous fistula site haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </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="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Hypocalcaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Scoliosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Squamous cell carcinoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Migraine with aura</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Cerebral haemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Loss of consciousness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Psychotic disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Renal failure acute</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Testicular pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Acute respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Arteriovenous fistula operation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Ossiculoplasty</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Renal transplant</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Peripheral artery thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 15.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="28" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="33" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="32" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Candidiasis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Ear infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="6" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Viral infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Viral upper respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Hepatic enzyme increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="38"/>
              </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="1" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Knee deformity</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Renal impairment</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Dysmenorrhoea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </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="41"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin lesion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="41"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="38"/>
              </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>Horizon requests that any investigator/institution that plans on presenting/publishing results provide written notification of their request 60 days prior to their presentation/publication. Horizon requests that no presentation/publication will be instituted until 12 months after a study is completed, or after the first presentation/publication whichever occurs first. A delay may be proposed of a presentation/publication if Horizon needs to secure patent or proprietary protection.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Evelyn Olson, Director</name_or_title>
      <organization>Horizon Pharma USA, Inc.</organization>
      <phone>224-383-3000</phone>
      <email>clinicaltrials@horizonpharma.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/NCT01733316
org study id: RP103-07
secondary id: 2012-002773-64
nct id: NCT01733316
lead sponsor: 
has dmc: No
The purpose of this study is to gather information about the effectiveness (how well it works
      to treat cystinosis) and safety of a new form of cysteamine bitartrate called RP103, compared
      to the already-approved drug cystinosis patients are taking called Cystagon®.

      In cystinosis, the body builds up cystine. When taken regularly, the active ingredient of
      Cystagon® (cysteamine bitartrate) reduces cystine in the body. RP103 has the same active
      ingredient as Cystagon® and is designed to reduce cystine in a similar way that Cystagon®
      does. To decide if RP103 is better than Cystagon®, the study will look at two types of blood
      tests. One test is pharmacodynamics (PD), which measures the amount of white blood cell (WBC)
      cystine after taking study drug. WBC cystine is a laboratory test used to find out if
      cysteamine bitartrate is reducing cystine levels in the body. The second test is
      pharmacokinetics (PK), which measures the amount of cysteamine in the blood after taking the
      drug.

      RP103 is different from Cystagon®: Instead of the cysteamine bitartrate being absorbed from
      the stomach, RP103 is designed to be absorbed from the small intestine. This may make the
      effects of the drug last longer, so that it can be taken twice a day instead of four times a
      day like Cystagon®.

      Some cystinosis patients have bad breath (halitosis) when they take Cystagon®. Study
      participants who experience bad breath with Cystagon® will be asked if they would like to
      participate in an optional "halitosis substudy" to investigate this issue by collecting some
      extra PK blood samples.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Average Difference Between Morning and Non-Morning Log White Blood Cell (WBC) Cystine Values
time frame: While taking Cystagon® (Months 1, 2, 3): within 15 minutes pre-morning (AM) and pre-non AM dose. During 3 months of RP103 (Months 5, 6, 7): 30 minutes post-AM and post-evening (PM) dose.
description: The primary analysis of WBC cystine was performed using the natural log transformed WBC cystine level; the log transformation is a normalizing transformation. For each participant, the difference between the morning and corresponding non-morning log WBC cystine value (non-morning minus morning) at each monthly visit during the Cystagon® phase (Months 1, 2, and 3) was computed and these differences were averaged. The average difference between morning and non-morning log WBC cystine value was similarly computed for each participant during the RP103 phase (Months 5, 6, and 7). The primary analysis compared within-subject pairs (Cystagon® phase paired with RP103 phase) of non-morning minus morning average differences of log WBC cystine level.
measure: Number of Participants With Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), and Discontinuations Due to AEs
time frame: From first dose of study drug to 7 days after last dose. Median duration of exposure was 91 days (range 82-108) for Cystagon® phase, 119 days (range 98-137) for the RP103 phase, and 861 days (range 30 - 1350) during the long-term RP-103 phase.
description: AE: any untoward medical occurrence that does not necessarily have a causal relationship with study drug. SAE: any untoward medical occurrence that at any dose: results in death; is life threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; or is medically significant, and though not included in the above list, is an important medical event, according to the Investigator. Treatment-emergent adverse events (TEAEs) occurred after first dose of study drug. Clinically significant abnormalities in laboratory values (hematology, blood chemistry, urinalysis), electrocardiograms (ECGs), vital signs, and physical examinations were to be reported as adverse events and so are included in this summary of TEAEs
measure: Halitosis Substudy: Maximum Plasma Concentration (Cmax) for Plasma Cysteamine
time frame: While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose, 30 minutes post-dose, 1, 2, 4 and 6 hours post-dose. While taking RP103 (Month 5, 6, or 7): 30 minutes after morning dose and 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose
description: Participants who reported halitosis ("bad breath") as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of dimethylsulfide (DMS) in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state pharmacokinetic (PK) samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.
measure: Halitosis Substudy: Time to Cmax (Tmax) for Plasma Cysteamine
time frame: While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose, 30 minutes post-dose, 1, 2, 4 and 6 hours post-dose. While taking RP103 (Month 5, 6, or 7): 30 minutes after morning dose and 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose
description: Participants who reported halitosis ("bad breath") as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.
measure: Area Under the Plasma Concentration Time Curve From Time Point 0 Through the Last Measurable Point (AUC0-t) for Plasma Cysteamine
time frame: While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose, 30 minutes post-dose, 1, 2, 4 and 6 hours post-dose. While taking RP103 (Month 5, 6, or 7): 30 minutes after morning dose and 1, 2, 3, 4, 6, 8, 10, 12 hours post-dose
description: Participants who reported halitosis ("bad breath") as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.
measure: Halitosis Substudy: Expired Air DMS Concentrations
time frame: While taking Cystagon® (Month 1, 2 or 3): Within 15 minutes prior to morning dose 30 min post-dose, 2, 3, 4 and 6 hours post-dose. While taking RP103 (Month 4, 5, or 7): Within 15 min. prior to morning dose. 1, 2, 3, 4, 5, 6, 8, 10, 12 hours post dose
description: Participants who reported halitosis ("bad breath") as a side effect while receiving Cystagon® were asked to participate in a substudy to investigate the concentration of DMS in expired air after the administration of study medication. To assess halitosis during study medication treatment, the steady state PK samples of cysteamine and DMS were collected over a 6 hour period when Cystagon® was administered and over a 12 hour period when RP103 was administered.
arm group label: All Participants
arm group type: Experimental
description: Cystagon® Phase: From Screening and during Months 1, 2, 3 participants receive their usual dose of Cystagon® every 6 hours (Q6H).
RP103 Phase: During Months 3.5, 4, 5, 6, 7 participants receive RP103 every 12 hours (Q12H).
Long Term Phase: On or after Month 7, for the remainder of study participants receive RP103 Q12H.
intervention type: Drug
intervention name: RP103
arm group label: All Participants
other name: cysteamine bitartrate delayed-release capsules
other name: PROCYSBI®
intervention type: Drug
intervention name: Cystagon®
arm group label: All Participants
other name: cysteamine bitartrate
criteria: 
gender: All
minimum age: 12 Years
maximum age: N/A
healthy volunteers: No
last name: Evelyn Olson, BS
role: Study Director
affiliation: Horizon Pharma USA, Inc.
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Belgium
country: France
country: Italy
country: Netherlands
country: United Kingdom
country: United States
url: http://procysbi.com/
description: RP103 (marketed as PROCYSBI) is now approved by the US FDA for management of nephropathic cystinosis in patients 6 years and older.
citation: Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009 Mar;20(3):629-37. doi: 10.1681/ASN.2008030287. Epub 2009 Jan 21.
PMID: 19158356
responsible party type: Sponsor
mesh term: Cystinosis
mesh term: Cysteamine
sharing ipd: Undecided
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 