<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/NCT03287960</url>
  </required_header>
  <id_info>
    <org_study_id>RM-493-015</org_study_id>
    <secondary_id>2017-002005-36</secondary_id>
    <nct_id>NCT03287960</nct_id>
  </id_info>
  <brief_title>Setmelanotide for the Treatment of Leptin Receptor (LEPR) Deficiency Obesity</brief_title>
  <official_title>An Open Label, 1-Year Trial, Including a Double-Blind Placebo-Controlled Withdrawal Period, of Setmelanotide (RM-493), a Melanocortin 4 Receptor (MC4R) Agonist, in Leptin Receptor (LEPR) Deficiency Obesity Due to Bi-Allelic Loss-of-Function LEPR Genetic Mutation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rhythm Pharmaceuticals, Inc.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Rhythm Pharmaceuticals, Inc.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To demonstrate statistically significant and clinically meaningful effects of setmelanotide&#xD;
      on percent body weight change in participants with LEPR deficiency obesity due to rare&#xD;
      bi-allelic or loss-of function mutations at the end of 1 year of treatment.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 30, 2018</start_date>
  <completion_date type="Actual">September 25, 2020</completion_date>
  <primary_completion_date type="Actual">September 25, 2020</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>
    <intervention_model_description>Open-label with an 8 week Double-Blind Placebo-Controlled Withdrawal Period</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>During the 8 week double-blind placebo-controlled withdrawal period, participants received 4 weeks of daily setmelanotide and 4 weeks of daily placebo. Participants, investigators, and sites remained blinded as to when placebo treatment was administered.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal Cohort)</measure>
    <time_frame>Week 52</time_frame>
    <description>The percentage of participants who met the ≥10% weight loss threshold (responders) after approximately Week 52 (~1 year) of treatment were analyzed.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal + Supplemental Cohort)</measure>
    <time_frame>Week 52</time_frame>
    <description>The percentage of participants who met the ≥10% weight loss threshold (responders) after approximately Week 52 (~1 year) of treatment were analyzed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Percent Change From Baseline in Body Weight</measure>
    <time_frame>Baseline and Week 52</time_frame>
    <description>The mean percent change from baseline in body weight at 52 weeks was analyzed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Percent Change From Baseline in Hunger Score ('Most Hunger')</measure>
    <time_frame>Baseline and Week 52</time_frame>
    <description>The mean percent change in hunger scores for participants ≥12 years of age with leptin receptor (LEPR) deficiency obesity in treatment with setmelanotide was evaluated. Hunger score ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants Achieving at Least 25% Improvement in Daily Hunger From Baseline</measure>
    <time_frame>Baseline and Week 52</time_frame>
    <description>The percentage of participants (≥12 years of age) achieving a ≥25% improvement from baseline in hunger score at Week 52 (i.e., after treatment with setmelanotide for 52 weeks at the therapeutic dose) was assessed. Hunger ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute Change From Baseline in Waist Circumference</measure>
    <time_frame>Baseline and Week 52</time_frame>
    <description>Waist circumference (cm) was measured according to the National Heart, Lung, and Blood Institute (NHLBI) criteria. Waist circumference was measured when participants were fasting at approximately the same time at each visit. The absolute change from baseline in waist circumference was assessed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute Change in Body Weight (Reversal of Weight Loss) During Double-Blind Placebo-Controlled Withdrawal Period</measure>
    <time_frame>Baseline and Week 8 of withdrawal period</time_frame>
    <description>A comparison of weight change was evaluated during the 8 week placebo-controlled withdrawal period for each participant, during which each participant received 4 weeks of placebo and 4 weeks active therapy in a blinded fashion.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Absolute Daily Hunger Reduction Score During the Double-Blind Placebo-Controlled Withdrawal Period</measure>
    <time_frame>Week 8 of withdrawal period</time_frame>
    <description>The absolute score in daily hunger reduction during the double-blind placebo-controlled withdrawal period (≥12 Years of Age) was assessed. Hunger ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis. The weekly average hunger score of the daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. Lower scores represent lower hunger, higher scores represent greater hunger.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Percent Change From Baseline in Body Mass Index</measure>
    <time_frame>Baseline and Week 52</time_frame>
    <description>The mean percent change from baseline in body mass index (BMI) was assessed.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Glucose Parameters</measure>
    <time_frame>Baseline and Week 52</time_frame>
    <description>Glucose parameters included glucose, glycated hemoglobin (HbA1c) and Oral glucose tolerance test (OGTT). Data is planned to be reported only for change from baseline in glucose levels.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Leptin Receptor Deficiency Obesity</condition>
  <arm_group>
    <arm_group_label>Setmelanotide</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants received titrated doses of setmelanotide once daily, by SC injection during titration period for 2 - 12 weeks. Thereafter, participants continued setmelanotide at their specific therapeutic dose for an additional 10 weeks during the open label treatment period. Participants who achieved at least a 5 kg weight loss (or at least 5% weight loss if baseline body weight was &lt;100 kg) at the end of the open label treatment period, continued into the 8-week double-blind withdrawal period and received 4 weeks setmelanotide and 4 weeks placebo. Following the withdrawal period, participants entered open label treatment period and received setmelanotide to complete approximately 52 weeks (~1 year) of treatment at a therapeutic dose.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Setmelanotide</intervention_name>
    <description>Once daily subcutaneous injection</description>
    <arm_group_label>Setmelanotide</arm_group_label>
    <other_name>RM-493</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Once daily subcutaneous injection</description>
    <arm_group_label>Setmelanotide</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Bi-allelic, homozygous or compound heterozygous (a different gene mutation on each&#xD;
             allele) genetic status for the LEPR gene, with the loss-of-function (LOF) variant for&#xD;
             each allele conferring a severe obesity phenotype.&#xD;
&#xD;
          2. Age 6 years and above. 6+: Germany, Netherlands, UK. 12+: France&#xD;
&#xD;
          3. If adult age ≥18 years, obesity with body mass index (BMI) ≥ 30 kilograms per meters&#xD;
             squared (kg/m^2); if child or adolescent (&lt; 18 years of age), obesity with weight &gt;&#xD;
             97th percentile for age on growth chart assessment.&#xD;
&#xD;
          4. Study participant and/or parent or guardian is able to communicate well with the&#xD;
             investigator, to understand and comply with the requirements of the study, and is able&#xD;
             to understand and sign the written informed consent/assent, after being informed about&#xD;
             the study.&#xD;
&#xD;
          5. Female participants of child-bearing potential must agree to use contraception as&#xD;
             outlined in the protocol. Female participants of non-childbearing potential, defined&#xD;
             as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral&#xD;
             tubal ligation) post-menopausal for at least 12 months (and confirmed with a screening&#xD;
             FSH level in the post-menopausal lab range), or failure to have progressed to Tanner&#xD;
             Stage V and/or failure to have achieved menarche, do not require contraception during&#xD;
             the study.&#xD;
&#xD;
          6. Male participants with female partners of childbearing potential must agree to a&#xD;
             double barrier method if they become sexually active during the study. Male&#xD;
             participants must not donate sperm during and for 90 days following their&#xD;
             participation in the study.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Recent intensive (within 2 months) diet and/or exercise regimen with or without the&#xD;
             use of weight loss agents including herbal medications, that has resulted in weight&#xD;
             loss or weight stabilization.&#xD;
&#xD;
          2. Prior gastric bypass surgery resulting in &gt;10% weight loss durably maintained from the&#xD;
             baseline pre-operative weight with no evidence of weight regain.&#xD;
&#xD;
          3. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other Diagnostic&#xD;
             and Statistical Manual of Mental Disorders (DSM-III) disorders that the investigator&#xD;
             believes will interfere significantly with study compliance.&#xD;
&#xD;
          4. A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15.&#xD;
&#xD;
          5. Any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale&#xD;
             (C-SSRS). Any lifetime history of a suicide attempt, or any suicidal behavior in the&#xD;
             last month.&#xD;
&#xD;
          6. Current, severe stable restrictive or obstructive lung disease arising because of&#xD;
             extreme obesity, evidence of significant heart failure (New York Heart Association&#xD;
             [NYHA] Class 3 or greater), or oncologic disease, if these were severe enough to&#xD;
             interfere with the study and/or would confound the results.&#xD;
&#xD;
          7. History of significant liver disease or liver injury, or current liver assessment for&#xD;
             a cause of abnormal liver tests [as indicated by abnormal liver function tests,&#xD;
             alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, or&#xD;
             serum bilirubin (&gt; 2.0 x upper limit of normal (ULN) for any of these tests)] for an&#xD;
             etiology other than non-alcoholic fatty liver disease (NAFLD).&#xD;
&#xD;
          8. History or presence of impaired renal function as indicated by clinically significant&#xD;
             abnormal creatinine, blood urea nitrogen (BUN), or urinary constituents (e.g.,&#xD;
             albuminuria) or moderate to severe renal dysfunction as defined by the Cockcroft Gault&#xD;
             equation &lt; 30 milliliter/minute (mL/min).&#xD;
&#xD;
          9. History or close family history (parents or siblings) of skin cancer or melanoma, or&#xD;
             participant history of ocular-cutaneous albinism.&#xD;
&#xD;
         10. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions,&#xD;
             determined as part of a screening comprehensive skin evaluation performed by a&#xD;
             qualified dermatologist.&#xD;
&#xD;
         11. Volunteer is, in the opinion of the study investigator, not suitable to participate in&#xD;
             the study.&#xD;
&#xD;
         12. Participation in any clinical study with an investigational drug/device within 3&#xD;
             months prior to the first day of dosing.&#xD;
&#xD;
         13. Significant hypersensitivity to study drug.&#xD;
&#xD;
         14. Inability to comply with every day (QD) injection regimen.&#xD;
&#xD;
         15. Participants who have been placed in an institution through an official or court&#xD;
             order, as well as those who are dependent on the sponsor, Investigator or study site.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David Meeker, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Rhythm Pharmaceuticals, Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Markham Stouffville Hospital</name>
      <address>
        <city>Markham</city>
        <state>Ontario</state>
        <zip>L3P 7P3</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institute of Cardiometabolism and Nutrition / Pitié-Salpêtrière Hospital</name>
      <address>
        <city>Paris</city>
        <zip>75013</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Ulm</name>
      <address>
        <city>Ulm</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Erasmus Medical Center</name>
      <address>
        <city>Rotterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Félix GUYON</name>
      <address>
        <city>Saint Denis</city>
        <zip>97405</zip>
        <country>Réunion</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Cambridge Metabolic Research Laboratories</name>
      <address>
        <city>Cambridge</city>
        <zip>CB2 0QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>France</country>
    <country>Germany</country>
    <country>Netherlands</country>
    <country>Réunion</country>
    <country>United Kingdom</country>
  </location_countries>
  <removed_countries>
    <country>United States</country>
  </removed_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>September 14, 2017</study_first_submitted>
  <study_first_submitted_qc>September 15, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 19, 2017</study_first_posted>
  <results_first_submitted>April 11, 2023</results_first_submitted>
  <results_first_submitted_qc>May 18, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">May 23, 2023</results_first_posted>
  <last_update_submitted>May 18, 2023</last_update_submitted>
  <last_update_submitted_qc>May 18, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 23, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>LEPR deficiency obesity</keyword>
  <keyword>setmelanotide</keyword>
  <keyword>RM-493</keyword>
  <keyword>Leptin receptor</keyword>
  <keyword>Obesity</keyword>
  <keyword>Melanocortin 4 receptor</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Obesity</mesh_term>
    <mesh_term>Obesity, Morbid</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>December 10, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/60/NCT03287960/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 16, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/60/NCT03287960/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants were enrolled into the pivotal cohort (11 participants) or supplemental cohort (4 participants).&#xD;
Pivotal cohort: Set of participants under study constituted a collection of detailed clinical case reports with a comprehensive baseline and past medical history assessment and complete clinical efficacy, safety and laboratory evaluations conducted for each participant.&#xD;
Supplemental cohort: Any additional participants enrolled were included in supplemental cohort.</recruitment_details>
      <pre_assignment_details>At screening, a blood sample was obtained for genotyping for mechanisms considered to be possibly related to the safety or efficacy response to the study medication (e.g., other obesity related genes). Complete physical, relevant bloodwork and other standard assessments were performed.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Setmelanotide</title>
          <description>Participants received titrated doses of setmelanotide once daily, by subcutaneous (SC) injection during titration period for 2 - 12 weeks. Thereafter, participants continued setmelanotide at their specific therapeutic dose for an additional 10 weeks during the open label treatment period. Participants who achieved at least a 5 kg weight loss (or at least 5% weight loss if baseline body weight was &lt;100 kg) at the end of the open label treatment period, continued into the 8-week double-blind withdrawal period and received 4 weeks setmelanotide and 4 weeks placebo. Following the withdrawal period, participants entered open label treatment period and received setmelanotide to complete approximately 52 weeks (~1 year) of treatment at a therapeutic dose.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Titration Period (2 to 12 Weeks)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Open-Label Period (10 Weeks)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
              </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>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Double-Blind Withdrawal Period (8 Weeks)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Open-Label Period (32 Weeks)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
              </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>Serious Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Setmelanotide</title>
          <description>Participants received titrated doses of setmelanotide once daily, by SC injection during titration period for 2 - 12 weeks. Thereafter, participants continued setmelanotide at their specific therapeutic dose for an additional 10 weeks during the open label treatment period. Participants who achieved at least a 5 kg weight loss (or at least 5% weight loss if baseline body weight was &lt;100 kg) at the end of the open label treatment period, continued into the 8-week double-blind withdrawal period and received 4 weeks setmelanotide and 4 weeks placebo. Following the withdrawal period, participants entered open label treatment period and received setmelanotide to complete approximately 52 weeks (~1 year) of treatment at a therapeutic dose.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="15"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <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="21.67" spread="8.52"/>
                  </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="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Netherlands</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>United Kingdom</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>France</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Germany</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Canada</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal Cohort)</title>
        <description>The percentage of participants who met the ≥10% weight loss threshold (responders) after approximately Week 52 (~1 year) of treatment were analyzed.</description>
        <time_frame>Week 52</time_frame>
        <population>The full analysis set (FAS) consisted of participants who received any of the study drug injections and at least one baseline assessment (included those who did and did not demonstrate ≥5 kg weight loss or 5% of body weight if weight is &lt;100 kg at baseline over the initial12-week open label treatment period and proceeded into the double blind, placebo-controlled withdrawal period). Participants in pivotal cohort were included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Setmelanotide (Entire Study)</title>
            <description>Participants received setmelanotide once daily by SC injection for approximately 52 weeks (~ 1 year).</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal Cohort)</title>
          <description>The percentage of participants who met the ≥10% weight loss threshold (responders) after approximately Week 52 (~1 year) of treatment were analyzed.</description>
          <population>The full analysis set (FAS) consisted of participants who received any of the study drug injections and at least one baseline assessment (included those who did and did not demonstrate ≥5 kg weight loss or 5% of body weight if weight is &lt;100 kg at baseline over the initial12-week open label treatment period and proceeded into the double blind, placebo-controlled withdrawal period). Participants in pivotal cohort were included in the analysis.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="45.5" lower_limit="19.96" upper_limit="72.88"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two-sided confidence interval obtained using Clopper-Pearson method and one-sided p-value obtained from exact binomial test, testing that at least 5% of participants in the population of interest will achieve 10% weight loss.</non_inferiority_desc>
            <p_value>0.0001</p_value>
            <method>Clopper-Pearson method</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal + Supplemental Cohort)</title>
        <description>The percentage of participants who met the ≥10% weight loss threshold (responders) after approximately Week 52 (~1 year) of treatment were analyzed.</description>
        <time_frame>Week 52</time_frame>
        <population>FAS Population. Participants in pivotal and supplemental cohort were included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Setmelanotide (Entire Study)</title>
            <description>Participants received setmelanotide once daily by SC injection for approximately 52 weeks (~ 1 year).</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal + Supplemental Cohort)</title>
          <description>The percentage of participants who met the ≥10% weight loss threshold (responders) after approximately Week 52 (~1 year) of treatment were analyzed.</description>
          <population>FAS Population. Participants in pivotal and supplemental cohort were included in the analysis.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="53.3" lower_limit="30.00" upper_limit="75.63"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two-sided confidence interval (CI) obtained using Clopper-Pearson method and one-sided p-value obtained from exact binomial test, testing that at least 5% of patients in the population of interest would achieve 10% weight loss.</non_inferiority_desc>
            <p_value>&lt;0.0001</p_value>
            <method>Clopper-Pearson method</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Percent Change From Baseline in Body Weight</title>
        <description>The mean percent change from baseline in body weight at 52 weeks was analyzed.</description>
        <time_frame>Baseline and Week 52</time_frame>
        <population>The Designated Use Set (DUS) consisted of participants who received any of the study drug injections, demonstrated ≥5 kg weight loss [or 5% of body weight if weight was &lt;100 kg at baseline] during the initial 12-week open label treatment period, and proceeded into the double-blind, placebo-controlled withdrawal period. Participants in pivotal and supplemental cohort were included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Setmelanotide (Entire Study)</title>
            <description>Participants received setmelanotide once daily by SC injection for approximately 52 weeks (~ 1 year).</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Percent Change From Baseline in Body Weight</title>
          <description>The mean percent change from baseline in body weight at 52 weeks was analyzed.</description>
          <population>The Designated Use Set (DUS) consisted of participants who received any of the study drug injections, demonstrated ≥5 kg weight loss [or 5% of body weight if weight was &lt;100 kg at baseline] during the initial 12-week open label treatment period, and proceeded into the double-blind, placebo-controlled withdrawal period. Participants in pivotal and supplemental cohort were included in the analysis.</population>
          <units>Percent change</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-12.34" spread="7.534"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Model based summary statistics from longitudinal mixed analysis of variance (ANOVA) model with fixed effect for visit, baseline body weight and random effect for participant, one sided p-value from model.</non_inferiority_desc>
            <p_value>&lt;.0001</p_value>
            <method>ANOVA</method>
            <method_desc>Longitudinal mixed ANOVA</method_desc>
            <param_type>Least Squares Mean</param_type>
            <param_value>-12.37</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-15.08</ci_lower_limit>
            <ci_upper_limit>-9.66</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Percent Change From Baseline in Hunger Score ('Most Hunger')</title>
        <description>The mean percent change in hunger scores for participants ≥12 years of age with leptin receptor (LEPR) deficiency obesity in treatment with setmelanotide was evaluated. Hunger score ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis.</description>
        <time_frame>Baseline and Week 52</time_frame>
        <population>DUS Population. Participants in pivotal and supplemental cohort were included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Setmelanotide (Entire Study)</title>
            <description>Participants received setmelanotide once daily by SC injection for approximately 52 weeks (~ 1 year).</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Percent Change From Baseline in Hunger Score ('Most Hunger')</title>
          <description>The mean percent change in hunger scores for participants ≥12 years of age with leptin receptor (LEPR) deficiency obesity in treatment with setmelanotide was evaluated. Hunger score ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis.</description>
          <population>DUS Population. Participants in pivotal and supplemental cohort were included in the analysis.</population>
          <units>Percent Change</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-42.7" spread="27.49"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Model based summary statistics from longitudinal mixed analysis of variance model with fixed effect for week, baseline daily hunger score and random effect for participant, one sided p-value from model.</non_inferiority_desc>
            <p_value>&lt;.0001</p_value>
            <method>ANOVA</method>
            <method_desc>Longitudinal mixed analysis of variance (ANOVA) model</method_desc>
            <param_type>Least Squares Mean</param_type>
            <param_value>-42.69</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-56.35</ci_lower_limit>
            <ci_upper_limit>-29.02</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants Achieving at Least 25% Improvement in Daily Hunger From Baseline</title>
        <description>The percentage of participants (≥12 years of age) achieving a ≥25% improvement from baseline in hunger score at Week 52 (i.e., after treatment with setmelanotide for 52 weeks at the therapeutic dose) was assessed. Hunger ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis.</description>
        <time_frame>Baseline and Week 52</time_frame>
        <population>FAS population with available data at specified time point. Participants in pivotal and supplemental cohort were included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Setmelanotide (Entire Study)</title>
            <description>Participants received setmelanotide once daily by SC injection for approximately 52 weeks (~ 1 year).</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants Achieving at Least 25% Improvement in Daily Hunger From Baseline</title>
          <description>The percentage of participants (≥12 years of age) achieving a ≥25% improvement from baseline in hunger score at Week 52 (i.e., after treatment with setmelanotide for 52 weeks at the therapeutic dose) was assessed. Hunger ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis.</description>
          <population>FAS population with available data at specified time point. Participants in pivotal and supplemental cohort were included in the analysis.</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="71.4" lower_limit="46.00" upper_limit="89.60"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Two-sided CI obtained using Clopper-Pearson method and one-sided p-value obtained from exact binomial test, testing that ≥5 % of participants in the population of interest would achieve ≥25 % improvement in daily hunger score.</non_inferiority_desc>
            <p_value>&lt;.0001</p_value>
            <method>Clopper-Pearson method</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Absolute Change From Baseline in Waist Circumference</title>
        <description>Waist circumference (cm) was measured according to the National Heart, Lung, and Blood Institute (NHLBI) criteria. Waist circumference was measured when participants were fasting at approximately the same time at each visit. The absolute change from baseline in waist circumference was assessed.</description>
        <time_frame>Baseline and Week 52</time_frame>
        <population>DUS population with available data at specified time point. Participants in pivotal and supplemental cohort were included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Setmelanotide (Entire Study)</title>
            <description>Participants received setmelanotide once daily by SC injection for approximately 52 weeks (~ 1 year).</description>
          </group>
        </group_list>
        <measure>
          <title>Absolute Change From Baseline in Waist Circumference</title>
          <description>Waist circumference (cm) was measured according to the National Heart, Lung, and Blood Institute (NHLBI) criteria. Waist circumference was measured when participants were fasting at approximately the same time at each visit. The absolute change from baseline in waist circumference was assessed.</description>
          <population>DUS population with available data at specified time point. Participants in pivotal and supplemental cohort were included in the analysis.</population>
          <units>Centimeter</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="131.58" spread="24.047"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at Week 52</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-9.80" spread="6.095"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Model based summary statistics from longitudinal mixed analysis of variance model with fixed effect for visit, baseline waist circumference and random effect for participant, one sided p-value from model.</non_inferiority_desc>
            <p_value>0.0031</p_value>
            <method>ANOVA</method>
            <method_desc>Longitudinal mixed ANOVA</method_desc>
            <param_type>Least Squares Mean</param_type>
            <param_value>-8.9</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-14.10</ci_lower_limit>
            <ci_upper_limit>-3.61</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Absolute Change in Body Weight (Reversal of Weight Loss) During Double-Blind Placebo-Controlled Withdrawal Period</title>
        <description>A comparison of weight change was evaluated during the 8 week placebo-controlled withdrawal period for each participant, during which each participant received 4 weeks of placebo and 4 weeks active therapy in a blinded fashion.</description>
        <time_frame>Baseline and Week 8 of withdrawal period</time_frame>
        <population>DUS population with available data at specified time point. Participants in pivotal and supplemental cohort were included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Setmelanotide (Double-Blind)</title>
            <description>Participants received setmelanotide once daily by SC injection for 4 weeks and placebo matched to setmelanotide for 4 weeks during the double-blind placebo controlled withdrawal period.</description>
          </group>
        </group_list>
        <measure>
          <title>Absolute Change in Body Weight (Reversal of Weight Loss) During Double-Blind Placebo-Controlled Withdrawal Period</title>
          <description>A comparison of weight change was evaluated during the 8 week placebo-controlled withdrawal period for each participant, during which each participant received 4 weeks of placebo and 4 weeks active therapy in a blinded fashion.</description>
          <population>DUS population with available data at specified time point. Participants in pivotal and supplemental cohort were included in the analysis.</population>
          <units>Kilogram</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Change at Week 4: Setmelanotide</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.2" spread="3.04"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at Week 4: Placebo</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.9" spread="2.82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Absolute Daily Hunger Reduction Score During the Double-Blind Placebo-Controlled Withdrawal Period</title>
        <description>The absolute score in daily hunger reduction during the double-blind placebo-controlled withdrawal period (≥12 Years of Age) was assessed. Hunger ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis. The weekly average hunger score of the daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. Lower scores represent lower hunger, higher scores represent greater hunger.</description>
        <time_frame>Week 8 of withdrawal period</time_frame>
        <population>DUS population with available data at specified time point. Participants in pivotal and supplemental cohort were included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Setmelanotide (Double-Blind)</title>
            <description>Participants received setmelanotide once daily by SC injection for 4 weeks and placebo matched to setmelanotide for 4 weeks during the double-blind placebo controlled withdrawal period.</description>
          </group>
        </group_list>
        <measure>
          <title>Absolute Daily Hunger Reduction Score During the Double-Blind Placebo-Controlled Withdrawal Period</title>
          <description>The absolute score in daily hunger reduction during the double-blind placebo-controlled withdrawal period (≥12 Years of Age) was assessed. Hunger ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis. The weekly average hunger score of the daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. Lower scores represent lower hunger, higher scores represent greater hunger.</description>
          <population>DUS population with available data at specified time point. Participants in pivotal and supplemental cohort were included in the analysis.</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Setmelanotide</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.4" spread="1.63"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Placebo</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="8"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.3" spread="2.13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Percent Change From Baseline in Body Mass Index</title>
        <description>The mean percent change from baseline in body mass index (BMI) was assessed.</description>
        <time_frame>Baseline and Week 52</time_frame>
        <population>DUS population with available data at specified time point. Participants in pivotal and supplemental cohort were included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Setmelanotide (Entire Study)</title>
            <description>Participants received setmelanotide once daily by SC injection for approximately 52 weeks (~ 1 year).</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Percent Change From Baseline in Body Mass Index</title>
          <description>The mean percent change from baseline in body mass index (BMI) was assessed.</description>
          <population>DUS population with available data at specified time point. Participants in pivotal and supplemental cohort were included in the analysis.</population>
          <units>Percent change</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-14.24" spread="9.096"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Model based summary statistics from longitudinal mixed analysis of variance model with fixed effect for week, baseline BMI and random effect for participant, one sided p-value from model.</non_inferiority_desc>
            <p_value>&lt;.0001</p_value>
            <method>ANOVA</method>
            <method_desc>Longitudinal mixed ANOVA model</method_desc>
            <param_type>Least Squares Mean</param_type>
            <param_value>-14.0</param_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-16.80</ci_lower_limit>
            <ci_upper_limit>-11.20</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Glucose Parameters</title>
        <description>Glucose parameters included glucose, glycated hemoglobin (HbA1c) and Oral glucose tolerance test (OGTT). Data is planned to be reported only for change from baseline in glucose levels.</description>
        <time_frame>Baseline and Week 52</time_frame>
        <population>The Safety Analysis Set (SAS) was defined as all participants who received any study drug injections at least one post-dose safety assessment. Participants with available data were analyzed. Participants in pivotal and supplemental cohort were included in the analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Setmelanotide (Entire Study)</title>
            <description>Participants received setmelanotide once daily by SC injection for approximately 52 weeks (~ 1 year).</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Glucose Parameters</title>
          <description>Glucose parameters included glucose, glycated hemoglobin (HbA1c) and Oral glucose tolerance test (OGTT). Data is planned to be reported only for change from baseline in glucose levels.</description>
          <population>The Safety Analysis Set (SAS) was defined as all participants who received any study drug injections at least one post-dose safety assessment. Participants with available data were analyzed. Participants in pivotal and supplemental cohort were included in the analysis.</population>
          <units>millimole per liter</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="15"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.586" spread="2.3740"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Change at Week 52</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="6"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.465" spread="1.4350"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From first dose up to ~30 days after last dose of study drug (Up to ~ 1 year)</time_frame>
      <desc>SAS population. Participants in pivotal and supplemental cohort were included. Adverse events were analyzed for participants in placebo &amp; setmelanotide groups combined as one group per planned analysis.</desc>
      <group_list>
        <group group_id="E1">
          <title>Setmelanotide</title>
          <description>Participants received titrated doses of setmelanotide once daily, by SC injection during titration period for 2 - 12 weeks. Thereafter, participants continued setmelanotide at their specific therapeutic dose for an additional 10 weeks during the open label treatment period. Participants who achieved at least a 5 kg weight loss (or at least 5% weight loss if baseline body weight was &lt;100 kg) at the end of the open label treatment period, continued into the 8-week double-blind withdrawal period and received 4 weeks setmelanotide and 4 weeks placebo. Following the withdrawal period, participants entered open label treatment period and received setmelanotide to complete approximately 52 weeks (~1 year) of treatment at a therapeutic dose.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA</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="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholecystitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Road Traffic Accident</sub_title>
                <description>Leading to event</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title vocab="MedDRA 22.0">Suicidal Ideation</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title vocab="MedDRA 22.0">Gastric Banding Reversal</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 22.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Eosinophilia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Iron deficiency anemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cardiac flutter</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Ear pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Tinnitus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Hypogonadism</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="16" subjects_affected="8" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" events="13" subjects_affected="4" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="13" subjects_affected="7" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Gingival discolouration</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Abdominal discomfort</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Gastrooesophageal reflux disease</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Haemorrhoids</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Injection site erythema</sub_title>
                <counts group_id="E1" events="32" subjects_affected="11" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Injection site induration</sub_title>
                <counts group_id="E1" events="16" subjects_affected="7" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Injection site pain</sub_title>
                <counts group_id="E1" events="14" subjects_affected="7" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Injection site oedema</sub_title>
                <counts group_id="E1" events="13" subjects_affected="6" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Injection site pruritus</sub_title>
                <counts group_id="E1" events="13" subjects_affected="8" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="9" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Injection site bruising</sub_title>
                <counts group_id="E1" events="8" subjects_affected="5" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="4" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Injection site haematoma</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Injection site hypersensitivity</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Injection site atrophy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Injection site reaction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Injection site urticaria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Medical device pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Medical device site erythema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Oedema</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Xerosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Suicidal ideation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Affect lability</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Vaginal haemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholestasis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Hepatocellular injury</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Lower respiratory tract infection</sub_title>
                <counts group_id="E1" events="6" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" events="6" subjects_affected="4" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Gastrointestinal infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Influenza</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Rhinitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Arthritis viral</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Fungal infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Gastroenteritis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Injection site abscess</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Otitis externa</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Arthropod bite</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Foot fracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Joint Injury</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Ligament sprain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Blood creatine phosphokinase abnormal</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Blood follicle stimulating hormone increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Blood lactate dehydrogenase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Blood luteinising hormone increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Blood urea decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Blood uric acid increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Heart rate increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Insulin tolerance test abnormal</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Neutrophil count increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Weight increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Dyslipidaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Folate deficiency</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Glucose tolerance impaired</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Gout</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Vitamin A deficiency</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="7" subjects_affected="4" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Musculoskeletal chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Torticollis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Melanocytic naevus</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Eye naevus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="18" subjects_affected="5" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Sleep paralysis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Sciatica</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Migraine</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Tic</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="4" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Depressed mood</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Drug abuse</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Fear of injection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Illusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Haematuria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Renal colic</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Renal failure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Dysmenorrhoea</sub_title>
                <counts group_id="E1" events="5" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Spontaneous penile erection</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Ejaculation disorder</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Metrorrhagia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Amenorrhoea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Ovarian cyst</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Asthma</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin hyperpigmentation</sub_title>
                <counts group_id="E1" events="20" subjects_affected="11" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Erythema</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Skin striae</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Urticaria</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Hair growth rate abnormal</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Hyperkeratosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Lentigo</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Lipodystrophy acquired</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Melanocytic naevus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pain of skin</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pigmentation disorder</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="15"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>All information regarding setmelanotide supplied by Rhythm to the investigator is privileged and confidential information. The investigator agrees to use this information to accomplish the study and will not use it for other purposes without consent from Rhythm. The information obtained from the clinical study will be used towards the development of setmelanotide and may be disclosed to regulatory authority(ies), other investigators, corporate partners, or consultants as required.</restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Based on meetings with the Federal Drug Administration (FDA), the structure of the endpoints was slightly different in the statistical analysis plan (SAP) and the protocol.&#xD;
In addition, there was no planned comparison to a randomized placebo group given the rarity of monogenic LEPR deficiency obesity.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Rhythm Clinical Trials</name_or_title>
      <organization>Rhythm Pharmaceuticals, Inc.</organization>
      <phone>857-264-4280</phone>
      <email>clinicaltrials@rhythmtx.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/NCT03287960
org study id: RM-493-015
secondary id: 2017-002005-36
nct id: NCT03287960
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
To demonstrate statistically significant and clinically meaningful effects of setmelanotide
      on percent body weight change in participants with LEPR deficiency obesity due to rare
      bi-allelic or loss-of function mutations at the end of 1 year of treatment.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Open-label with an 8 week Double-Blind Placebo-Controlled Withdrawal Period
primary purpose: Treatment
masking: None (Open Label)
masking description: During the 8 week double-blind placebo-controlled withdrawal period, participants received 4 weeks of daily setmelanotide and 4 weeks of daily placebo. Participants, investigators, and sites remained blinded as to when placebo treatment was administered.
measure: Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal Cohort)
time frame: Week 52
description: The percentage of participants who met the ≥10% weight loss threshold (responders) after approximately Week 52 (~1 year) of treatment were analyzed.
measure: Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal + Supplemental Cohort)
time frame: Week 52
description: The percentage of participants who met the ≥10% weight loss threshold (responders) after approximately Week 52 (~1 year) of treatment were analyzed.
measure: Mean Percent Change From Baseline in Body Weight
time frame: Baseline and Week 52
description: The mean percent change from baseline in body weight at 52 weeks was analyzed.
measure: Mean Percent Change From Baseline in Hunger Score ('Most Hunger')
time frame: Baseline and Week 52
description: The mean percent change in hunger scores for participants ≥12 years of age with leptin receptor (LEPR) deficiency obesity in treatment with setmelanotide was evaluated. Hunger score ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis.
measure: Percentage of Participants Achieving at Least 25% Improvement in Daily Hunger From Baseline
time frame: Baseline and Week 52
description: The percentage of participants (≥12 years of age) achieving a ≥25% improvement from baseline in hunger score at Week 52 (i.e., after treatment with setmelanotide for 52 weeks at the therapeutic dose) was assessed. Hunger ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis.
measure: Absolute Change From Baseline in Waist Circumference
time frame: Baseline and Week 52
description: Waist circumference (cm) was measured according to the National Heart, Lung, and Blood Institute (NHLBI) criteria. Waist circumference was measured when participants were fasting at approximately the same time at each visit. The absolute change from baseline in waist circumference was assessed.
measure: Absolute Change in Body Weight (Reversal of Weight Loss) During Double-Blind Placebo-Controlled Withdrawal Period
time frame: Baseline and Week 8 of withdrawal period
description: A comparison of weight change was evaluated during the 8 week placebo-controlled withdrawal period for each participant, during which each participant received 4 weeks of placebo and 4 weeks active therapy in a blinded fashion.
measure: Absolute Daily Hunger Reduction Score During the Double-Blind Placebo-Controlled Withdrawal Period
time frame: Week 8 of withdrawal period
description: The absolute score in daily hunger reduction during the double-blind placebo-controlled withdrawal period (≥12 Years of Age) was assessed. Hunger ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis. The weekly average hunger score of the daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. Lower scores represent lower hunger, higher scores represent greater hunger.
measure: Mean Percent Change From Baseline in Body Mass Index
time frame: Baseline and Week 52
description: The mean percent change from baseline in body mass index (BMI) was assessed.
measure: Change From Baseline in Glucose Parameters
time frame: Baseline and Week 52
description: Glucose parameters included glucose, glycated hemoglobin (HbA1c) and Oral glucose tolerance test (OGTT). Data is planned to be reported only for change from baseline in glucose levels.
arm group label: Setmelanotide
arm group type: Experimental
description: Participants received titrated doses of setmelanotide once daily, by SC injection during titration period for 2 - 12 weeks. Thereafter, participants continued setmelanotide at their specific therapeutic dose for an additional 10 weeks during the open label treatment period. Participants who achieved at least a 5 kg weight loss (or at least 5% weight loss if baseline body weight was <100 kg) at the end of the open label treatment period, continued into the 8-week double-blind withdrawal period and received 4 weeks setmelanotide and 4 weeks placebo. Following the withdrawal period, participants entered open label treatment period and received setmelanotide to complete approximately 52 weeks (~1 year) of treatment at a therapeutic dose.
intervention type: Drug
intervention name: Setmelanotide
description: Once daily subcutaneous injection
arm group label: Setmelanotide
other name: RM-493
intervention type: Drug
intervention name: Placebo
description: Once daily subcutaneous injection
arm group label: Setmelanotide
criteria: 
gender: All
minimum age: 6 Years
maximum age: N/A
healthy volunteers: No
last name: David Meeker, MD
role: Study Chair
affiliation: Rhythm Pharmaceuticals, Inc.
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Canada
country: France
country: Germany
country: Netherlands
country: Réunion
country: United Kingdom
country: United States
responsible party type: Sponsor
mesh term: Obesity
mesh term: Obesity, Morbid
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Based on meetings with the Federal Drug Administration (FDA), the structure of the endpoints was slightly different in the statistical analysis plan (SAP) and the protocol.
In addition, there was no planned comparison to a randomized placebo group given the rarity of monogenic LEPR deficiency obesity.
point of contact: 