<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/NCT03297294</url>
  </required_header>
  <id_info>
    <org_study_id>CEMA401A2202</org_study_id>
    <secondary_id>2016-000281-39</secondary_id>
    <nct_id>NCT03297294</nct_id>
  </id_info>
  <brief_title>Safety and Efficacy of EMA401 in Patients With Painful Diabetic Neuropathy (PDN)</brief_title>
  <acronym>EMPADINE</acronym>
  <official_title>A Double-blind, Placebo-controlled, Randomized Trial to Determine the Safety and Efficacy of EMA401 in Reducing 24-hour Average Pain Intensity Score in Patients With Painful Diabetic Neuropathy (EMPADINE)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Novartis</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>
      The purpose of this study is to evaluate safety and efficacy of EMA401 compared to placebo in&#xD;
      patients with painful diabetic neuropathy (PDN).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This was an interventional, randomized, parallel, placebo-controlled, double-blind treatment&#xD;
      study consisting of 3 periods i.e. Screening, Treatment, and Treatment withdrawal. Patients&#xD;
      were planned to be randomized in a 1:1 ratio to Placebo b.i.d. or EMA401 100 mg b.i.d..&#xD;
      Concomitant use of pregabalin or duloxetine at stable doses was allowed. Based on historical&#xD;
      data, it was planned that the study would enroll approximately 50% of patients who were on&#xD;
      stable doses of concomitant pregabalin or duloxetine in the study. At the end of treatment&#xD;
      period the 100mg b.i.d. arm was re-randomized (1:1) to the same treatment or placebo. Placebo&#xD;
      arm stayed on placebo. The planned duration of treatment period was 12 weeks and 1 week of&#xD;
      treatment withdrawal at the end of treatment period.&#xD;
&#xD;
      The study was terminated early due to pre-clinical toxicity data that became available after&#xD;
      start of trial. Novartis implemented a Urgent Safety Measure (USM) which instructed sites to&#xD;
      discontinue study treatment immediately and to have all patients return for additional&#xD;
      laboratory assessments (full hematology including coagulation and clinical chemistry panel).&#xD;
      Safety data from the USM was presented as a separate outcome measure table and not included&#xD;
      in the Adverse Event section&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Study was terminated due to animal toxicity data&#xD;
  </why_stopped>
  <start_date type="Actual">March 14, 2018</start_date>
  <completion_date type="Actual">March 25, 2019</completion_date>
  <primary_completion_date type="Actual">March 25, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Weekly Mean 24-hour Average Pain Score Using the 11 Point Numerical Rating Scale (NRS) From Baseline to Week 12</measure>
    <time_frame>Baseline up to Week 12</time_frame>
    <description>The NRS is an 11-point scale ranging from zero (&quot;no pain&quot;) to ten (&quot;pain as bad as you can imagine&quot;) for self-reporting of pain by patients. The following parameters were evaluated using the 11-point NRS: 24-hour Average Pain Score and 24-hour Worst Pain Score Patients evaluated their &quot;average pain&quot; and &quot;worst pain&quot; during the past 24 hours in the evening prior to sleep by touching the appropriate corresponding number between zero and ten on a eDiary device.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Neuropathic Pain Symptom Inventory (NPSI) From Baseline to Week 12</measure>
    <time_frame>Baseline up to Week 12</time_frame>
    <description>The Neuropathic Pain Symptom Inventory (NPSI) is a 12 item patient reported outcome measure that contains 10 descriptors representing 5 dimensions of pain (burning pain, deep/pressing pain, paroxysmal pain, evoked pain and paraesthesia/dysesthesia) and 2 temporal items designed to assess pain duration and the number of pain paroxysms. The sum of the responses to the 10 questions (all except temporal questions) was regarded as the total score and was divided by 10 (10 questions). The range of the total score and of the 5 dimensional scores is 0 to 10. Lower values represent better outcomes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Brief Pain Inventory-Short Form Interference (BPI-SF) Mean Total Score From Baseline to Week 12</measure>
    <time_frame>Baseline up to Week 12</time_frame>
    <description>The BPI-SF is a validated, self-administered (at clinic) questionnaire that assesses pain severity and its mpact on daily functions. Patients were asked to complete the 7-item pain interference scale that assessed the degree to which pain interfered with walking and other physical activity, work, mood, relations with others and sleep using a zero to ten scale with zero being &quot;does not interfere&quot; and ten being &quot;completely interferes&quot;. The BPI total score is the sum of the 7 items. Each item ranges from 0 to 10, thus the total score ranges from 0 to 70. Lower values indicate a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Weekly Mean of the 24-hour Worst Pain Score, Using an 11-point NRS, From Baseline to Week 12</measure>
    <time_frame>Baseline up to Week 12</time_frame>
    <description>The NRS is an 11-point scale ranging from zero (&quot;no pain&quot;) to ten (&quot;pain as bad as you can imagine&quot;) for self-reporting of pain by patients. The following parameters were evaluated using the 11-point NRS: 24-hour Average Pain Score and 24-hour Worst Pain Score Patients evaluated their &quot;average pain&quot; and &quot;worst pain&quot; during the past 24 hours in the evening prior to sleep by touching the appropriate corresponding number between zero and ten on a eDiary device.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants Per Patient Global Impression of Change Category at Week 12</measure>
    <time_frame>Baseline up to Week 12</time_frame>
    <description>The Patient Global Impression of Change (PGIC) is a patient-reported instrument that measures change in overall status on a scale ranging from one (&quot;very much improved&quot;) to seven (&quot;very much worse&quot;). The PGIC is based on the validated Clinical Global Impression of Change scale. The PGIC was to be completed by patients using the electronic tablet at the site</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Patients Achieving at Least 30% Pain Reduction at Week 12 on NRS 11 Point Scale</measure>
    <time_frame>Baseline up to Week 12</time_frame>
    <description>The NRS is an 11-point scale ranging from zero (&quot;no pain&quot;) to ten (&quot;pain as bad as you can imagine&quot;) for self-reporting of pain by patients. The number of patients with observed response, i.e. a decrease of 30% units in weekly mean of the 24-hour average pain score NRS. Logistic regression model with region, treatment, sex, use of PHN medications (yes/no) as factors and age and baseline NRS as covariates. An odds ratio &gt;1 = higher chance of a clinically important improvement.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Patients Achieving at Least 50% Pain Reduction at Week 12 on NRS 11 Point Scale</measure>
    <time_frame>Baseline up to Week 12</time_frame>
    <description>The NRS is an 11-point scale ranging from zero (&quot;no pain&quot;) to ten (&quot;pain as bad as you can imagine&quot;) for self-reporting of pain by patients. The number of patients with observed response, i.e. a decrease of 50% units in weekly mean of the 24-hour average pain score NRS. Logistic regression model with region, treatment, sex, use of PHN medications (yes/no) as factors and age and baseline NRS as covariates. An odds ratio &gt;1 = higher chance of a clinically important improvement.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean Change in Insomnia Severity Index (ISI) From Baseline to Week 12</measure>
    <time_frame>Baseline up to Week 12</time_frame>
    <description>Patients were asked to complete the ISI using five-point Likert-style scale as a measure of perceived sleep difficulties. The questionnaire assessed the severity of insomnia, satisfaction with current sleep pattern, sleep interference, &quot;noticeability&quot; of sleeping problem to others and concern about sleeping problems. The scale consists of 7 items. The sum of seven items represents the total score. Each of the 7 items is scored using a range from 0 to 4, thus the total score values ranges from zero to 28. Lower values represent better outcomes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Pharmacokinetics (PK) Concentrations at Week 8 and 12</measure>
    <time_frame>Week 8 (Prior dose, 1-3 hours, 4-6 hours), Week 12 (Prior dose, 1-3 hours, 4-6 hours)</time_frame>
    <description>Due to the premature termination of the study, the number of patients and observations providing PK data was much smaller than planned, and no PK model was developed. As a consequence, no PK parameters (Cmax, Tmax, AUC) were derived for this study. Only, summary statistics of the plasma concentrations were calculated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Patients Who Required Rescue Medication in Double-blind Treatment Period</measure>
    <time_frame>Baseline and weekly up to 12 weeks, once during double-blind period</time_frame>
    <description>Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Percentages of patients presented are those who required rescue meds within 7 days prior to visit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Patients Who Required Rescue Medication in Treatment Withdrawal Period</measure>
    <time_frame>Week 12 to Week 13 (planned duration subject to varibility in visit scheduling)</time_frame>
    <description>Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Percentages of patients presented are those who required rescue meds within 7 days prior to visit.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to First Rescue Medication Intake</measure>
    <time_frame>Baseline up to day 92</time_frame>
    <description>Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Patients who did not take any rescue medication were censored at the last date of double-blind treatment period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment Emergent Adverse Events During Urgent Safety Measure (USM) Follow-Up</measure>
    <time_frame>Approximately from 3 weeks after end of study up to 16 weeks</time_frame>
    <description>Participants were instructed to stop taking drug immediately upon termination of study and asked to come in for two unscheduled visits for follow up safety assessments</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">142</enrollment>
  <condition>Painful Diabetic Neuropathy</condition>
  <arm_group>
    <arm_group_label>EMA401</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>During the treatment epoch, patients will receive EMA401 for 12 weeks. During the treatment withdrawal epoch, patients will receive EMA401 or matching placebo for 1 week.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Participants will receive matching placebo to EMA401 during both the treatment and treatment withdrawal epochs for a total of 13 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>EMA401</intervention_name>
    <description>capsules, oral</description>
    <arm_group_label>EMA401</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo to EMA401 capsules, oral</description>
    <arm_group_label>EMA401</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  At the time of Screening, must have had documented diagnosis of Type I OR Type II&#xD;
             diabetes mellitus (DM) with painful distal symmetrical sensorimotor neuropathy (ICD-10&#xD;
             code G63.2) of more than 6 months duration with any one or more of the following:&#xD;
&#xD;
               -  Neuropathic symptoms (e.g. numbness, non-painful paresthesias or tingling,&#xD;
                  non-painful sensory distortions or misinterpretations, etc.)&#xD;
&#xD;
               -  Decreased distal sensation (e.g. decreased vibration, pinprick sensation, light&#xD;
                  touch, etc.)&#xD;
&#xD;
          -  Been assessed as suffering from moderate to severe neuropathic pain across the&#xD;
             Screening epoch (NRS ≥ 4).&#xD;
&#xD;
          -  A score of ≥4 on the Douleur Neuropathique en 4 Questions (DN4) questionnaire at&#xD;
             Screening.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Women of child-bearing potential, defined as all women physiologically capable of&#xD;
             becoming pregnant, unless they were using highly effective methods of contraception&#xD;
             during dosing and for 3 days after stopping of study medication. Highly effective&#xD;
             contraception methods included:&#xD;
&#xD;
               -  Total abstinence (when this was is in line with the preferred and usual lifestyle&#xD;
                  of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal,&#xD;
                  post-ovulation methods) and withdrawal were not acceptable methods of&#xD;
                  contraception.&#xD;
&#xD;
               -  Female sterilization (have had surgical bilateral oophorectomy with or without&#xD;
                  hysterectomy), total hysterectomy or tubal ligation at least six weeks before&#xD;
                  taking investigational drug. In case of oophorectomy alone, only when the&#xD;
                  reproductive status of the woman had been confirmed by follow up hormone level&#xD;
                  assessment.&#xD;
&#xD;
               -  Male sterilization (at least 6 months prior to screening). For female subjects on&#xD;
                  the study, the vasectomized male partner should have been the sole partner for&#xD;
                  that subject.&#xD;
&#xD;
               -  Placement of an intrauterine device (IUD) or intrauterine system (IUS).&#xD;
&#xD;
          -  History or current diagnosis of electrocardiogram (ECG) abnormalities indicating&#xD;
             significant risk of safety for patients participating in the study.&#xD;
&#xD;
          -  Major depressive episode within 6 months prior to Screening and/or a history of&#xD;
             diagnosed recurrent major depressive disorder according to Diagnostic and Statistical&#xD;
             Manual of Mental Disorders, 5th Edition (DSM-V) diagnostic criteria.&#xD;
&#xD;
          -  Had evidence of significant renal insufficiency or pre-existing liver condition.&#xD;
&#xD;
          -  Had platelets ≤ 100 x 10^9/L, or neutrophil count &lt; 1.2 x 10^9/L (or equivalent),&#xD;
             hemoglobin ≤ 100 g/L for women or hemoglobin ≤ 110 g/L for men.&#xD;
&#xD;
          -  Participants whose glycemic control had been unstable within 3 months immediately&#xD;
             prior to screening (e.g., ketoacidosis requiring hospitalization, any recent episode&#xD;
             of hypoglycemia requiring assistance through medical intervention, uncontrolled&#xD;
             hyperglycemia)&#xD;
&#xD;
          -  Patients who had any differential diagnosis of PDN including but not limited to other&#xD;
             neuropathies (e.g. Vitamin B12 deficiency, Chronic Inflammatory Demyelinating&#xD;
             Polyneuropathy), polyradiculopathies, central disorders (e.g. demyelinating disease),&#xD;
             or rheumatological disease (e.g., foot arthritis, plantar fasciitis).&#xD;
&#xD;
          -  Patient was unwilling or unable to complete daily eDiary.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Novartis Pharmaceuticals</last_name>
    <role>Study Director</role>
    <affiliation>Novartis Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Broadmeadow</city>
        <state>New South Wales</state>
        <zip>2292</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Orange</city>
        <state>New South Wales</state>
        <zip>2800</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Adelaide</city>
        <state>South Australia</state>
        <zip>5000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Heidelberg Heights</city>
        <state>Victoria</state>
        <zip>3081</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Graz</city>
        <zip>A-8036</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Klagenfurt</city>
        <zip>9020</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Wien</city>
        <zip>A-1090</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Edegem</city>
        <zip>2650</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Liege</city>
        <zip>4000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Pellenberg</city>
        <zip>3212</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sofia</city>
        <state>Sofia-Grad</state>
        <zip>1336</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sofia</city>
        <zip>1000</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sofia</city>
        <zip>1407</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sofia</city>
        <zip>1431</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Ontario</city>
        <state>CAN</state>
        <zip>L4J 1W3</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Thornhill</city>
        <state>Ontario</state>
        <zip>L4J 8L7</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M4G 3E8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Laval</city>
        <state>Quebec</state>
        <zip>H7T 2P5</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Aarhus</city>
        <zip>8000</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Gentofte</city>
        <zip>DK 2820</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Odense C</city>
        <zip>DK 5000</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Tampere</city>
        <zip>FIN-33520</zip>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Boulogne Billancourt</city>
        <zip>92104</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bielefeld</city>
        <zip>D 33647</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Duesseldorf</city>
        <zip>40225</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Essen</city>
        <zip>45147</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Halle (Saale)</city>
        <zip>06120</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Kassel</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Kiel</city>
        <zip>24119</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Leipzig</city>
        <zip>04109</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Wiesbaden</city>
        <zip>65191</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Debrecen</city>
        <state>HUN</state>
        <zip>4032</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Esztergom</city>
        <state>HUN</state>
        <zip>2500</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Szeged</city>
        <state>HUN</state>
        <zip>6720</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Balatonfured</city>
        <zip>8230</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Budapest</city>
        <zip>1085</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Budapest</city>
        <zip>1089</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Kistarcsa</city>
        <zip>2143</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Pecs</city>
        <zip>7632</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Szeged</city>
        <zip>6725</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Oslo</city>
        <zip>0450</zip>
        <country>Norway</country>
      </address>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Krakow</city>
        <state>POL</state>
        <zip>31 505</zip>
        <country>Poland</country>
      </address>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bialystok</city>
        <zip>15-351</zip>
        <country>Poland</country>
      </address>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Warszawa</city>
        <zip>00 144</zip>
        <country>Poland</country>
      </address>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Caldas da Rainha</city>
        <zip>2500 176</zip>
        <country>Portugal</country>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Lisboa</city>
        <zip>1250 203</zip>
        <country>Portugal</country>
      </address>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Matosinhos</city>
        <zip>4454 509</zip>
        <country>Portugal</country>
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    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Porto</city>
        <zip>4200 319</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Viana do Castelo</city>
        <zip>4901858</zip>
        <country>Portugal</country>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Vila Nova de Gaia</city>
        <zip>4434 502</zip>
        <country>Portugal</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Lucenec</city>
        <state>Slovak Republic</state>
        <zip>98401</zip>
        <country>Slovakia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bratislava</city>
        <zip>83305</zip>
        <country>Slovakia</country>
      </address>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bratislava</city>
        <zip>85101</zip>
        <country>Slovakia</country>
      </address>
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  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Presov</city>
        <zip>080 01</zip>
        <country>Slovakia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Presov</city>
        <zip>08001</zip>
        <country>Slovakia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sevilla</city>
        <state>Andalucia</state>
        <zip>41014</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Madrid</city>
        <zip>28222</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bradford</city>
        <state>West Yorkshire</state>
        <zip>BD9 6RJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bath</city>
        <zip>BA1 3NG</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Bournemouth</city>
        <zip>BH7 7DW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Edinburgh</city>
        <zip>EH4 2XU</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>London</city>
        <zip>SE1 7EH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Middlesborough</city>
        <zip>TS4 3BW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Oldham</city>
        <zip>OL1 2JH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Austria</country>
    <country>Belgium</country>
    <country>Bulgaria</country>
    <country>Canada</country>
    <country>Denmark</country>
    <country>Finland</country>
    <country>France</country>
    <country>Germany</country>
    <country>Hungary</country>
    <country>Norway</country>
    <country>Poland</country>
    <country>Portugal</country>
    <country>Slovakia</country>
    <country>Spain</country>
    <country>United Kingdom</country>
  </location_countries>
  <link>
    <url>https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=619</url>
    <description>A Plain Language Trial Summary is available on novartisclinicaltrials.com</description>
  </link>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>September 26, 2017</study_first_submitted>
  <study_first_submitted_qc>September 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 29, 2017</study_first_posted>
  <results_first_submitted>March 20, 2020</results_first_submitted>
  <results_first_submitted_qc>May 20, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">June 4, 2020</results_first_posted>
  <last_update_submitted>October 7, 2021</last_update_submitted>
  <last_update_submitted_qc>October 7, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 8, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Painful diabetic neuropathy</keyword>
  <keyword>Neuropathic pain</keyword>
  <keyword>Angiotensin II type 2 receptor antagonist</keyword>
  <keyword>adult</keyword>
  <keyword>EMA401</keyword>
  <keyword>diabetic neuropathy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Peripheral Nervous System Diseases</mesh_term>
    <mesh_term>Diabetic Neuropathies</mesh_term>
    <mesh_term>Pain</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.&#xD;
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.</ipd_description>
  </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>September 15, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/94/NCT03297294/Prot_001.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>June 18, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/94/NCT03297294/SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>Three hundred six patients were screened and 137 randomized</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>EMA401 100mg BID DB</title>
          <description>Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period</description>
        </group>
        <group group_id="P2">
          <title>Placebo BID DB</title>
          <description>Matching placebo capsules administered orally twice a day during double blind (DB) treatment period</description>
        </group>
        <group group_id="P3">
          <title>EMA401 100mg BID -&gt; EMA401 100mg BID TW</title>
          <description>Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)</description>
        </group>
        <group group_id="P4">
          <title>EMA401 100mg BID -&gt; Placebo BID TW</title>
          <description>Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)</description>
        </group>
        <group group_id="P5">
          <title>Placebo BID -&gt; Placebo BID TW</title>
          <description>Participants on placebo remained on placebo at end of DB treatment period (week 12)</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Double-Blind Treatment Period (DB)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="70"/>
                <participants group_id="P2" count="67"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="32"/>
                <participants group_id="P2" count="30"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="38"/>
                <participants group_id="P2" count="37"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Study terminated by sponsor</title>
              <participants_list>
                <participants group_id="P1" count="30"/>
                <participants group_id="P2" count="31"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Treatment Withdrawal Period (TW)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="14"/>
                <participants group_id="P4" count="12"/>
                <participants group_id="P5" count="27"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="14"/>
                <participants group_id="P4" count="11"/>
                <participants group_id="P5" count="27"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Study terminated by sponsor</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
                <participants group_id="P5" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>EMA401 100mg BID DB</title>
          <description>Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period</description>
        </group>
        <group group_id="B2">
          <title>Placebo BID DB</title>
          <description>Matching placebo capsules administered orally twice a day during double blind (DB) treatment period</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="70"/>
            <count group_id="B2" value="67"/>
            <count group_id="B3" value="137"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>18 - 64 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="34"/>
                    <measurement group_id="B2" value="33"/>
                    <measurement group_id="B3" value="67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>65 - 84 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="36"/>
                    <measurement group_id="B2" value="33"/>
                    <measurement group_id="B3" value="69"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>≥ 85 years</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </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="20"/>
                    <measurement group_id="B2" value="24"/>
                    <measurement group_id="B3" value="44"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="50"/>
                    <measurement group_id="B2" value="43"/>
                    <measurement group_id="B3" value="93"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Caucasian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="70"/>
                    <measurement group_id="B2" value="63"/>
                    <measurement group_id="B3" value="133"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Other</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body mass index</title>
          <units>kg/m^2</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="30.8" lower_limit="22.7" upper_limit="43.2"/>
                    <measurement group_id="B2" value="30.2" lower_limit="19.5" upper_limit="48.2"/>
                    <measurement group_id="B3" value="30.6" lower_limit="19.5" upper_limit="48.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Weekly Mean 24-hour Average Pain Score Using the 11 Point Numerical Rating Scale (NRS) From Baseline to Week 12</title>
        <description>The NRS is an 11-point scale ranging from zero (&quot;no pain&quot;) to ten (&quot;pain as bad as you can imagine&quot;) for self-reporting of pain by patients. The following parameters were evaluated using the 11-point NRS: 24-hour Average Pain Score and 24-hour Worst Pain Score Patients evaluated their &quot;average pain&quot; and &quot;worst pain&quot; during the past 24 hours in the evening prior to sleep by touching the appropriate corresponding number between zero and ten on a eDiary device.</description>
        <time_frame>Baseline up to Week 12</time_frame>
        <population>Full analysis set</population>
        <group_list>
          <group group_id="O1">
            <title>EMA401 100mg BID DB</title>
            <description>Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period</description>
          </group>
          <group group_id="O2">
            <title>Placebo BID DB</title>
            <description>Matching placebo capsules administered orally twice a day during double blind (DB) treatment period</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Weekly Mean 24-hour Average Pain Score Using the 11 Point Numerical Rating Scale (NRS) From Baseline to Week 12</title>
          <description>The NRS is an 11-point scale ranging from zero (&quot;no pain&quot;) to ten (&quot;pain as bad as you can imagine&quot;) for self-reporting of pain by patients. The following parameters were evaluated using the 11-point NRS: 24-hour Average Pain Score and 24-hour Worst Pain Score Patients evaluated their &quot;average pain&quot; and &quot;worst pain&quot; during the past 24 hours in the evening prior to sleep by touching the appropriate corresponding number between zero and ten on a eDiary device.</description>
          <population>Full analysis set</population>
          <units>scores on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="70"/>
                <count group_id="O2" value="67"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.0" spread="0.21"/>
                    <measurement group_id="O2" value="-0.8" spread="0.18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.7" spread="0.29"/>
                    <measurement group_id="O2" value="-1.1" spread="0.26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.9" spread="0.31"/>
                    <measurement group_id="O2" value="-1.3" spread="0.27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>at week 12</non_inferiority_desc>
            <p_value>0.101</p_value>
            <method>ANCOVA</method>
            <param_type>least squares mean</param_type>
            <param_value>-0.6</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.39</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.4</ci_lower_limit>
            <ci_upper_limit>0.1</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Neuropathic Pain Symptom Inventory (NPSI) From Baseline to Week 12</title>
        <description>The Neuropathic Pain Symptom Inventory (NPSI) is a 12 item patient reported outcome measure that contains 10 descriptors representing 5 dimensions of pain (burning pain, deep/pressing pain, paroxysmal pain, evoked pain and paraesthesia/dysesthesia) and 2 temporal items designed to assess pain duration and the number of pain paroxysms. The sum of the responses to the 10 questions (all except temporal questions) was regarded as the total score and was divided by 10 (10 questions). The range of the total score and of the 5 dimensional scores is 0 to 10. Lower values represent better outcomes.</description>
        <time_frame>Baseline up to Week 12</time_frame>
        <group_list>
          <group group_id="O1">
            <title>EMA401 100mg BID DB</title>
            <description>Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period</description>
          </group>
          <group group_id="O2">
            <title>Placebo BID DB</title>
            <description>Matching placebo capsules administered orally twice a day during double blind (DB) treatment period</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Neuropathic Pain Symptom Inventory (NPSI) From Baseline to Week 12</title>
          <description>The Neuropathic Pain Symptom Inventory (NPSI) is a 12 item patient reported outcome measure that contains 10 descriptors representing 5 dimensions of pain (burning pain, deep/pressing pain, paroxysmal pain, evoked pain and paraesthesia/dysesthesia) and 2 temporal items designed to assess pain duration and the number of pain paroxysms. The sum of the responses to the 10 questions (all except temporal questions) was regarded as the total score and was divided by 10 (10 questions). The range of the total score and of the 5 dimensional scores is 0 to 10. Lower values represent better outcomes.</description>
          <units>scores on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="70"/>
                <count group_id="O2" value="67"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.2" spread="0.19"/>
                    <measurement group_id="O2" value="-1.0" spread="0.18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.3" spread="0.25"/>
                    <measurement group_id="O2" value="-0.9" spread="0.22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.6" spread="0.32"/>
                    <measurement group_id="O2" value="-1.1" spread="0.26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>At week 12</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.168</p_value>
            <method>ANCOVA</method>
            <param_type>LS mean difference</param_type>
            <param_value>-0.5</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.38</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-1.3</ci_lower_limit>
            <ci_upper_limit>0.2</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Brief Pain Inventory-Short Form Interference (BPI-SF) Mean Total Score From Baseline to Week 12</title>
        <description>The BPI-SF is a validated, self-administered (at clinic) questionnaire that assesses pain severity and its mpact on daily functions. Patients were asked to complete the 7-item pain interference scale that assessed the degree to which pain interfered with walking and other physical activity, work, mood, relations with others and sleep using a zero to ten scale with zero being &quot;does not interfere&quot; and ten being &quot;completely interferes&quot;. The BPI total score is the sum of the 7 items. Each item ranges from 0 to 10, thus the total score ranges from 0 to 70. Lower values indicate a better outcome.</description>
        <time_frame>Baseline up to Week 12</time_frame>
        <group_list>
          <group group_id="O1">
            <title>EMA401 100mg BID DB</title>
            <description>Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period</description>
          </group>
          <group group_id="O2">
            <title>Placebo BID DB</title>
            <description>Matching placebo capsules administered orally twice a day during double blind (DB) treatment period</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Brief Pain Inventory-Short Form Interference (BPI-SF) Mean Total Score From Baseline to Week 12</title>
          <description>The BPI-SF is a validated, self-administered (at clinic) questionnaire that assesses pain severity and its mpact on daily functions. Patients were asked to complete the 7-item pain interference scale that assessed the degree to which pain interfered with walking and other physical activity, work, mood, relations with others and sleep using a zero to ten scale with zero being &quot;does not interfere&quot; and ten being &quot;completely interferes&quot;. The BPI total score is the sum of the 7 items. Each item ranges from 0 to 10, thus the total score ranges from 0 to 70. Lower values indicate a better outcome.</description>
          <units>scores 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="70"/>
                <count group_id="O2" value="67"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-12.03" spread="13.336"/>
                    <measurement group_id="O2" value="-10.83" spread="14.602"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Weekly Mean of the 24-hour Worst Pain Score, Using an 11-point NRS, From Baseline to Week 12</title>
        <description>The NRS is an 11-point scale ranging from zero (&quot;no pain&quot;) to ten (&quot;pain as bad as you can imagine&quot;) for self-reporting of pain by patients. The following parameters were evaluated using the 11-point NRS: 24-hour Average Pain Score and 24-hour Worst Pain Score Patients evaluated their &quot;average pain&quot; and &quot;worst pain&quot; during the past 24 hours in the evening prior to sleep by touching the appropriate corresponding number between zero and ten on a eDiary device.</description>
        <time_frame>Baseline up to Week 12</time_frame>
        <group_list>
          <group group_id="O1">
            <title>EMA401 100mg BID DB</title>
            <description>Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period</description>
          </group>
          <group group_id="O2">
            <title>Placebo BID DB</title>
            <description>Matching placebo capsules administered orally twice a day during double blind (DB) treatment period</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Weekly Mean of the 24-hour Worst Pain Score, Using an 11-point NRS, From Baseline to Week 12</title>
          <description>The NRS is an 11-point scale ranging from zero (&quot;no pain&quot;) to ten (&quot;pain as bad as you can imagine&quot;) for self-reporting of pain by patients. The following parameters were evaluated using the 11-point NRS: 24-hour Average Pain Score and 24-hour Worst Pain Score Patients evaluated their &quot;average pain&quot; and &quot;worst pain&quot; during the past 24 hours in the evening prior to sleep by touching the appropriate corresponding number between zero and ten on a eDiary device.</description>
          <units>scores on numeric rating 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="70"/>
                <count group_id="O2" value="67"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.63" spread="1.837"/>
                    <measurement group_id="O2" value="-1.28" spread="1.577"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants Per Patient Global Impression of Change Category at Week 12</title>
        <description>The Patient Global Impression of Change (PGIC) is a patient-reported instrument that measures change in overall status on a scale ranging from one (&quot;very much improved&quot;) to seven (&quot;very much worse&quot;). The PGIC is based on the validated Clinical Global Impression of Change scale. The PGIC was to be completed by patients using the electronic tablet at the site</description>
        <time_frame>Baseline up to Week 12</time_frame>
        <group_list>
          <group group_id="O1">
            <title>EMA401 100mg BID DB</title>
            <description>Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period</description>
          </group>
          <group group_id="O2">
            <title>Placebo BID DB</title>
            <description>Matching placebo capsules administered orally twice a day during double blind (DB) treatment period</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Per Patient Global Impression of Change Category at Week 12</title>
          <description>The Patient Global Impression of Change (PGIC) is a patient-reported instrument that measures change in overall status on a scale ranging from one (&quot;very much improved&quot;) to seven (&quot;very much worse&quot;). The PGIC is based on the validated Clinical Global Impression of Change scale. The PGIC was to be completed by patients using the electronic tablet at the site</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="70"/>
                <count group_id="O2" value="67"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Very much improved</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Much improved</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Minimally improved</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17"/>
                    <measurement group_id="O2" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>No change</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18"/>
                    <measurement group_id="O2" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Minimally worse</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Much worse</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Very much worse</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Missing</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21"/>
                    <measurement group_id="O2" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Patients Achieving at Least 30% Pain Reduction at Week 12 on NRS 11 Point Scale</title>
        <description>The NRS is an 11-point scale ranging from zero (&quot;no pain&quot;) to ten (&quot;pain as bad as you can imagine&quot;) for self-reporting of pain by patients. The number of patients with observed response, i.e. a decrease of 30% units in weekly mean of the 24-hour average pain score NRS. Logistic regression model with region, treatment, sex, use of PHN medications (yes/no) as factors and age and baseline NRS as covariates. An odds ratio &gt;1 = higher chance of a clinically important improvement.</description>
        <time_frame>Baseline up to Week 12</time_frame>
        <population>Full analysis set</population>
        <group_list>
          <group group_id="O1">
            <title>EMA401 100mg BID DB</title>
            <description>Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period</description>
          </group>
          <group group_id="O2">
            <title>Placebo BID DB</title>
            <description>Matching placebo capsules administered orally twice a day during double blind (DB) treatment period</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Patients Achieving at Least 30% Pain Reduction at Week 12 on NRS 11 Point Scale</title>
          <description>The NRS is an 11-point scale ranging from zero (&quot;no pain&quot;) to ten (&quot;pain as bad as you can imagine&quot;) for self-reporting of pain by patients. The number of patients with observed response, i.e. a decrease of 30% units in weekly mean of the 24-hour average pain score NRS. Logistic regression model with region, treatment, sex, use of PHN medications (yes/no) as factors and age and baseline NRS as covariates. An odds ratio &gt;1 = higher chance of a clinically important improvement.</description>
          <population>Full analysis set</population>
          <units>% of participants - model adjusted rate</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="70"/>
                <count group_id="O2" value="67"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 4 - at least 30% pain reduction</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="18"/>
                    <count group_id="O2" value="14"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="34.0"/>
                    <measurement group_id="O2" value="24.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12 - at least 30% pain reduction</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="14"/>
                    <count group_id="O2" value="12"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="52.7"/>
                    <measurement group_id="O2" value="40.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Week 12</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.255</p_value>
            <method>Regression, Logistic</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>1.6</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.7</ci_lower_limit>
            <ci_upper_limit>3.9</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Patients Achieving at Least 50% Pain Reduction at Week 12 on NRS 11 Point Scale</title>
        <description>The NRS is an 11-point scale ranging from zero (&quot;no pain&quot;) to ten (&quot;pain as bad as you can imagine&quot;) for self-reporting of pain by patients. The number of patients with observed response, i.e. a decrease of 50% units in weekly mean of the 24-hour average pain score NRS. Logistic regression model with region, treatment, sex, use of PHN medications (yes/no) as factors and age and baseline NRS as covariates. An odds ratio &gt;1 = higher chance of a clinically important improvement.</description>
        <time_frame>Baseline up to Week 12</time_frame>
        <population>Full analysis set</population>
        <group_list>
          <group group_id="O1">
            <title>EMA401 100mg BID DB</title>
            <description>Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period</description>
          </group>
          <group group_id="O2">
            <title>Placebo BID DB</title>
            <description>Matching placebo capsules administered orally twice a day during double blind (DB) treatment period</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Patients Achieving at Least 50% Pain Reduction at Week 12 on NRS 11 Point Scale</title>
          <description>The NRS is an 11-point scale ranging from zero (&quot;no pain&quot;) to ten (&quot;pain as bad as you can imagine&quot;) for self-reporting of pain by patients. The number of patients with observed response, i.e. a decrease of 50% units in weekly mean of the 24-hour average pain score NRS. Logistic regression model with region, treatment, sex, use of PHN medications (yes/no) as factors and age and baseline NRS as covariates. An odds ratio &gt;1 = higher chance of a clinically important improvement.</description>
          <population>Full analysis set</population>
          <units>% of participants - model adjusted rate</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="70"/>
                <count group_id="O2" value="67"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31.4"/>
                    <measurement group_id="O2" value="14.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.100</p_value>
            <method>Regression, Logistic</method>
            <param_type>Odds Ratio (OR)</param_type>
            <param_value>2.8</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.8</ci_lower_limit>
            <ci_upper_limit>9.6</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Mean Change in Insomnia Severity Index (ISI) From Baseline to Week 12</title>
        <description>Patients were asked to complete the ISI using five-point Likert-style scale as a measure of perceived sleep difficulties. The questionnaire assessed the severity of insomnia, satisfaction with current sleep pattern, sleep interference, &quot;noticeability&quot; of sleeping problem to others and concern about sleeping problems. The scale consists of 7 items. The sum of seven items represents the total score. Each of the 7 items is scored using a range from 0 to 4, thus the total score values ranges from zero to 28. Lower values represent better outcomes.</description>
        <time_frame>Baseline up to Week 12</time_frame>
        <population>Full analysis set</population>
        <group_list>
          <group group_id="O1">
            <title>EMA401 100mg BID DB</title>
            <description>Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period</description>
          </group>
          <group group_id="O2">
            <title>Placebo BID DB</title>
            <description>Matching placebo capsules administered orally twice a day during double blind (DB) treatment period</description>
          </group>
        </group_list>
        <measure>
          <title>Mean Change in Insomnia Severity Index (ISI) From Baseline to Week 12</title>
          <description>Patients were asked to complete the ISI using five-point Likert-style scale as a measure of perceived sleep difficulties. The questionnaire assessed the severity of insomnia, satisfaction with current sleep pattern, sleep interference, &quot;noticeability&quot; of sleeping problem to others and concern about sleeping problems. The scale consists of 7 items. The sum of seven items represents the total score. Each of the 7 items is scored using a range from 0 to 4, thus the total score values ranges from zero to 28. Lower values represent better outcomes.</description>
          <population>Full analysis set</population>
          <units>scores 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="70"/>
                <count group_id="O2" value="67"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-4.00" spread="4.854"/>
                    <measurement group_id="O2" value="-1.03" spread="6.312"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Plasma Pharmacokinetics (PK) Concentrations at Week 8 and 12</title>
        <description>Due to the premature termination of the study, the number of patients and observations providing PK data was much smaller than planned, and no PK model was developed. As a consequence, no PK parameters (Cmax, Tmax, AUC) were derived for this study. Only, summary statistics of the plasma concentrations were calculated</description>
        <time_frame>Week 8 (Prior dose, 1-3 hours, 4-6 hours), Week 12 (Prior dose, 1-3 hours, 4-6 hours)</time_frame>
        <population>PK analysis set</population>
        <group_list>
          <group group_id="O1">
            <title>EMA401 100mg BID DB</title>
            <description>Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period</description>
          </group>
        </group_list>
        <measure>
          <title>Plasma Pharmacokinetics (PK) Concentrations at Week 8 and 12</title>
          <description>Due to the premature termination of the study, the number of patients and observations providing PK data was much smaller than planned, and no PK model was developed. As a consequence, no PK parameters (Cmax, Tmax, AUC) were derived for this study. Only, summary statistics of the plasma concentrations were calculated</description>
          <population>PK analysis set</population>
          <units>ng/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 8 Prior dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="32"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="30.5" spread="126.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8 1-3 hours</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="32"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="205.1" spread="212.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8 4-6 hours</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="32"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="72.8" spread="115.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12 Prior dose</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="25"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="29.5" spread="209.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12 1-3 hours</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="26"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="118.4" spread="278.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12 4-6 hours</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="26"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="89.8" spread="117.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Patients Who Required Rescue Medication in Double-blind Treatment Period</title>
        <description>Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Percentages of patients presented are those who required rescue meds within 7 days prior to visit.</description>
        <time_frame>Baseline and weekly up to 12 weeks, once during double-blind period</time_frame>
        <population>Full analysis set</population>
        <group_list>
          <group group_id="O1">
            <title>EMA401 100mg BID DB</title>
            <description>Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period</description>
          </group>
          <group group_id="O2">
            <title>Placebo BID DB</title>
            <description>Matching placebo capsules administered orally twice a day during double blind (DB) treatment period</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Patients Who Required Rescue Medication in Double-blind Treatment Period</title>
          <description>Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Percentages of patients presented are those who required rescue meds within 7 days prior to visit.</description>
          <population>Full analysis set</population>
          <units>Percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="70"/>
                <count group_id="O2" value="67"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Week 1</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.0"/>
                    <measurement group_id="O2" value="10.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 2</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.7"/>
                    <measurement group_id="O2" value="9.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 4</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.6"/>
                    <measurement group_id="O2" value="7.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 6</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.8"/>
                    <measurement group_id="O2" value="7.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 8</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.3"/>
                    <measurement group_id="O2" value="9.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 10</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.3"/>
                    <measurement group_id="O2" value="13.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 12</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.9"/>
                    <measurement group_id="O2" value="8.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>At least once during double-blind period</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20.0"/>
                    <measurement group_id="O2" value="19.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Patients Who Required Rescue Medication in Treatment Withdrawal Period</title>
        <description>Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Percentages of patients presented are those who required rescue meds within 7 days prior to visit.</description>
        <time_frame>Week 12 to Week 13 (planned duration subject to varibility in visit scheduling)</time_frame>
        <population>Full analysis set</population>
        <group_list>
          <group group_id="O1">
            <title>EMA401 100mg BID -&gt; EMA401 100mg BID TW</title>
            <description>Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)</description>
          </group>
          <group group_id="O2">
            <title>EMA401 100mg BID -&gt; Placebo BID TW</title>
            <description>Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)</description>
          </group>
          <group group_id="O3">
            <title>Placebo BID -&gt; Placebo BID TW</title>
            <description>Participants on placebo remained on placebo at end of DB treatment period (week 12)</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Patients Who Required Rescue Medication in Treatment Withdrawal Period</title>
          <description>Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Percentages of patients presented are those who required rescue meds within 7 days prior to visit.</description>
          <population>Full analysis set</population>
          <units>Percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="35"/>
                <count group_id="O2" value="35"/>
                <count group_id="O3" value="67"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14.3"/>
                    <measurement group_id="O2" value="8.3"/>
                    <measurement group_id="O3" value="7.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to First Rescue Medication Intake</title>
        <description>Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Patients who did not take any rescue medication were censored at the last date of double-blind treatment period.</description>
        <time_frame>Baseline up to day 92</time_frame>
        <population>Full analysis set</population>
        <group_list>
          <group group_id="O1">
            <title>EMA401 100mg BID DB</title>
            <description>Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period</description>
          </group>
          <group group_id="O2">
            <title>Placebo BID DB</title>
            <description>Matching placebo capsules administered orally twice a day during double blind (DB) treatment period</description>
          </group>
        </group_list>
        <measure>
          <title>Time to First Rescue Medication Intake</title>
          <description>Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Patients who did not take any rescue medication were censored at the last date of double-blind treatment period.</description>
          <population>Full analysis set</population>
          <units>days</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="70"/>
                <count group_id="O2" value="67"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="44.0" lower_limit="2" upper_limit="90"/>
                    <measurement group_id="O2" value="56.5" lower_limit="2" upper_limit="92"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Treatment Emergent Adverse Events During Urgent Safety Measure (USM) Follow-Up</title>
        <description>Participants were instructed to stop taking drug immediately upon termination of study and asked to come in for two unscheduled visits for follow up safety assessments</description>
        <time_frame>Approximately from 3 weeks after end of study up to 16 weeks</time_frame>
        <population>The Overall Number of Participants Analyzed reflects the Safety population, regardless of whether they completed the study</population>
        <group_list>
          <group group_id="O1">
            <title>EMA401 100mg BID -&gt; EMA401 100mg BID TW</title>
            <description>Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)</description>
          </group>
          <group group_id="O2">
            <title>EMA401 100mg BID -&gt; Placebo BID TW</title>
            <description>Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)</description>
          </group>
          <group group_id="O3">
            <title>Placebo BID -&gt; Placebo BID TW</title>
            <description>Participants on placebo remained on placebo at end of DB treatment period (week 12)</description>
          </group>
        </group_list>
        <measure>
          <title>Treatment Emergent Adverse Events During Urgent Safety Measure (USM) Follow-Up</title>
          <description>Participants were instructed to stop taking drug immediately upon termination of study and asked to come in for two unscheduled visits for follow up safety assessments</description>
          <population>The Overall Number of Participants Analyzed reflects the Safety population, regardless of whether they completed the study</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="35"/>
                <count group_id="O3" value="66"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Peritoneal adhesions</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cholelithiasis</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Liver abscess</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Blood creatinine increased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were collected from first dose of study treatment until end of study treatment plus 21 days post treatment, up to maximum duration of 111 days</time_frame>
      <desc>Any sign or symptom that occurs during the study treatment plus the 21 days post treatment are reported in adverse event (AE) section. Upon termination of study, participants were instructed to attend two unscheduled visits for follow-up safety assessments for Urgent Safety Measure (USM) follow-up. Adverse events collected during USM are not included in this AE section but reported in secondary outcome measure 13 entitled Treatment Emergent Adverse Events During Urgent Safety Measure Follow-up</desc>
      <group_list>
        <group group_id="E1">
          <title>EMA401 100mg BID DB</title>
          <description>Ema401 100 mg was administered orally twice a day during double blind (DB) treatment period</description>
        </group>
        <group group_id="E2">
          <title>Placebo BID DB</title>
          <description>Matching placebo capsules administered orally twice a day during double blind (DB) treatment period</description>
        </group>
        <group group_id="E3">
          <title>EMA401 100mg BID -&gt; EMA401 100mg BID TW</title>
          <description>Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)</description>
        </group>
        <group group_id="E4">
          <title>EMA401 100mg BID -&gt; Placebo BID TW</title>
          <description>Participants on EMA401 100mg were randomized 1:1 to EMA401 100mg or placebo at end of DB treatment period (week 12)</description>
        </group>
        <group group_id="E5">
          <title>Placebo BID -&gt; Placebo BID TW</title>
          <description>Participants on placebo remained on placebo at end of DB treatment period (week 12)</description>
        </group>
      </group_list>
      <serious_events>
        <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, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Acute coronary syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Product intolerance</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Cholecystitis acute</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
              <event>
                <sub_title>Cholelithiasis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Erysipelas</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
              <event>
                <sub_title>Localised infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Chronic obstructive pulmonary disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </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="23" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Nasopharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Gamma-glutamyltransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="69"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="66"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="26"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Study Director</name_or_title>
      <organization>Novartis Pharmaceuticals</organization>
      <phone>862-778-8300</phone>
      <email>Novartis.email@novartis.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/NCT03297294
org study id: CEMA401A2202
secondary id: 2016-000281-39
nct id: NCT03297294
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to evaluate safety and efficacy of EMA401 compared to placebo in
      patients with painful diabetic neuropathy (PDN).
This was an interventional, randomized, parallel, placebo-controlled, double-blind treatment
      study consisting of 3 periods i.e. Screening, Treatment, and Treatment withdrawal. Patients
      were planned to be randomized in a 1:1 ratio to Placebo b.i.d. or EMA401 100 mg b.i.d..
      Concomitant use of pregabalin or duloxetine at stable doses was allowed. Based on historical
      data, it was planned that the study would enroll approximately 50% of patients who were on
      stable doses of concomitant pregabalin or duloxetine in the study. At the end of treatment
      period the 100mg b.i.d. arm was re-randomized (1:1) to the same treatment or placebo. Placebo
      arm stayed on placebo. The planned duration of treatment period was 12 weeks and 1 week of
      treatment withdrawal at the end of treatment period.

      The study was terminated early due to pre-clinical toxicity data that became available after
      start of trial. Novartis implemented a Urgent Safety Measure (USM) which instructed sites to
      discontinue study treatment immediately and to have all patients return for additional
      laboratory assessments (full hematology including coagulation and clinical chemistry panel).
      Safety data from the USM was presented as a separate outcome measure table and not included
      in the Adverse Event section
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Change in Weekly Mean 24-hour Average Pain Score Using the 11 Point Numerical Rating Scale (NRS) From Baseline to Week 12
time frame: Baseline up to Week 12
description: The NRS is an 11-point scale ranging from zero ("no pain") to ten ("pain as bad as you can imagine") for self-reporting of pain by patients. The following parameters were evaluated using the 11-point NRS: 24-hour Average Pain Score and 24-hour Worst Pain Score Patients evaluated their "average pain" and "worst pain" during the past 24 hours in the evening prior to sleep by touching the appropriate corresponding number between zero and ten on a eDiary device.
measure: Change in Neuropathic Pain Symptom Inventory (NPSI) From Baseline to Week 12
time frame: Baseline up to Week 12
description: The Neuropathic Pain Symptom Inventory (NPSI) is a 12 item patient reported outcome measure that contains 10 descriptors representing 5 dimensions of pain (burning pain, deep/pressing pain, paroxysmal pain, evoked pain and paraesthesia/dysesthesia) and 2 temporal items designed to assess pain duration and the number of pain paroxysms. The sum of the responses to the 10 questions (all except temporal questions) was regarded as the total score and was divided by 10 (10 questions). The range of the total score and of the 5 dimensional scores is 0 to 10. Lower values represent better outcomes.
measure: Change in Brief Pain Inventory-Short Form Interference (BPI-SF) Mean Total Score From Baseline to Week 12
time frame: Baseline up to Week 12
description: The BPI-SF is a validated, self-administered (at clinic) questionnaire that assesses pain severity and its mpact on daily functions. Patients were asked to complete the 7-item pain interference scale that assessed the degree to which pain interfered with walking and other physical activity, work, mood, relations with others and sleep using a zero to ten scale with zero being "does not interfere" and ten being "completely interferes". The BPI total score is the sum of the 7 items. Each item ranges from 0 to 10, thus the total score ranges from 0 to 70. Lower values indicate a better outcome.
measure: Change in Weekly Mean of the 24-hour Worst Pain Score, Using an 11-point NRS, From Baseline to Week 12
time frame: Baseline up to Week 12
description: The NRS is an 11-point scale ranging from zero ("no pain") to ten ("pain as bad as you can imagine") for self-reporting of pain by patients. The following parameters were evaluated using the 11-point NRS: 24-hour Average Pain Score and 24-hour Worst Pain Score Patients evaluated their "average pain" and "worst pain" during the past 24 hours in the evening prior to sleep by touching the appropriate corresponding number between zero and ten on a eDiary device.
measure: Number of Participants Per Patient Global Impression of Change Category at Week 12
time frame: Baseline up to Week 12
description: The Patient Global Impression of Change (PGIC) is a patient-reported instrument that measures change in overall status on a scale ranging from one ("very much improved") to seven ("very much worse"). The PGIC is based on the validated Clinical Global Impression of Change scale. The PGIC was to be completed by patients using the electronic tablet at the site
measure: Percentage of Patients Achieving at Least 30% Pain Reduction at Week 12 on NRS 11 Point Scale
time frame: Baseline up to Week 12
description: The NRS is an 11-point scale ranging from zero ("no pain") to ten ("pain as bad as you can imagine") for self-reporting of pain by patients. The number of patients with observed response, i.e. a decrease of 30% units in weekly mean of the 24-hour average pain score NRS. Logistic regression model with region, treatment, sex, use of PHN medications (yes/no) as factors and age and baseline NRS as covariates. An odds ratio >1 = higher chance of a clinically important improvement.
measure: Percentage of Patients Achieving at Least 50% Pain Reduction at Week 12 on NRS 11 Point Scale
time frame: Baseline up to Week 12
description: The NRS is an 11-point scale ranging from zero ("no pain") to ten ("pain as bad as you can imagine") for self-reporting of pain by patients. The number of patients with observed response, i.e. a decrease of 50% units in weekly mean of the 24-hour average pain score NRS. Logistic regression model with region, treatment, sex, use of PHN medications (yes/no) as factors and age and baseline NRS as covariates. An odds ratio >1 = higher chance of a clinically important improvement.
measure: Mean Change in Insomnia Severity Index (ISI) From Baseline to Week 12
time frame: Baseline up to Week 12
description: Patients were asked to complete the ISI using five-point Likert-style scale as a measure of perceived sleep difficulties. The questionnaire assessed the severity of insomnia, satisfaction with current sleep pattern, sleep interference, "noticeability" of sleeping problem to others and concern about sleeping problems. The scale consists of 7 items. The sum of seven items represents the total score. Each of the 7 items is scored using a range from 0 to 4, thus the total score values ranges from zero to 28. Lower values represent better outcomes.
measure: Plasma Pharmacokinetics (PK) Concentrations at Week 8 and 12
time frame: Week 8 (Prior dose, 1-3 hours, 4-6 hours), Week 12 (Prior dose, 1-3 hours, 4-6 hours)
description: Due to the premature termination of the study, the number of patients and observations providing PK data was much smaller than planned, and no PK model was developed. As a consequence, no PK parameters (Cmax, Tmax, AUC) were derived for this study. Only, summary statistics of the plasma concentrations were calculated
measure: Percentage of Patients Who Required Rescue Medication in Double-blind Treatment Period
time frame: Baseline and weekly up to 12 weeks, once during double-blind period
description: Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Percentages of patients presented are those who required rescue meds within 7 days prior to visit.
measure: Percentage of Patients Who Required Rescue Medication in Treatment Withdrawal Period
time frame: Week 12 to Week 13 (planned duration subject to varibility in visit scheduling)
description: Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Percentages of patients presented are those who required rescue meds within 7 days prior to visit.
measure: Time to First Rescue Medication Intake
time frame: Baseline up to day 92
description: Patients were allowed to take acetaminophen/paracetamol up to a maximum of 3 g daily (divided into 4 times/day) for unacceptable pain due to any reason during the study. This medication use was to be recorded in eDiary prior to use. Patients who did not take any rescue medication were censored at the last date of double-blind treatment period.
measure: Treatment Emergent Adverse Events During Urgent Safety Measure (USM) Follow-Up
time frame: Approximately from 3 weeks after end of study up to 16 weeks
description: Participants were instructed to stop taking drug immediately upon termination of study and asked to come in for two unscheduled visits for follow up safety assessments
arm group label: EMA401
arm group type: Experimental
description: During the treatment epoch, patients will receive EMA401 for 12 weeks. During the treatment withdrawal epoch, patients will receive EMA401 or matching placebo for 1 week.
arm group label: Placebo
arm group type: Placebo Comparator
description: Participants will receive matching placebo to EMA401 during both the treatment and treatment withdrawal epochs for a total of 13 weeks.
intervention type: Drug
intervention name: EMA401
description: capsules, oral
arm group label: EMA401
intervention type: Drug
intervention name: Placebo
description: Placebo to EMA401 capsules, oral
arm group label: EMA401
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Novartis Pharmaceuticals
role: Study Director
affiliation: Novartis Pharmaceuticals
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country: Australia
country: Austria
country: Belgium
country: Bulgaria
country: Canada
country: Denmark
country: Finland
country: France
country: Germany
country: Hungary
country: Norway
country: Poland
country: Portugal
country: Slovakia
country: Spain
country: United Kingdom
url: https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=619
description: A Plain Language Trial Summary is available on novartisclinicaltrials.com
responsible party type: Sponsor
mesh term: Peripheral Nervous System Diseases
mesh term: Diabetic Neuropathies
mesh term: Pain
sharing ipd: Undecided
ipd description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 