<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/NCT02982161</url>
  </required_header>
  <id_info>
    <org_study_id>MR308-3501</org_study_id>
    <nct_id>NCT02982161</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety in a Randomised Acute Pain Study of MR308 (Tramadol/Celecoxib).</brief_title>
  <acronym>STARDOM1</acronym>
  <official_title>A Randomized, Double-Blind, Multicenter, Placebo- and Active Comparator-Controlled Study to Evaluate Efficacy and Safety of MR308 in the Treatment of Acute Pain After Third Molar Tooth Extraction (STARDOM1).</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mundipharma Research GmbH &amp; Co KG</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Mundipharma Research GmbH &amp; Co KG</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The MR308-3501 study is a multicenter, randomised, double-blind, parallel-group study in male&#xD;
      and female adult subjects to demonstrate the efficacy of MR308 in the treatment of acute&#xD;
      moderate to severe pain after the extraction of at least two third molars requiring bone&#xD;
      removal.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a multicenter double-blind, randomised, phase III study in male and female subjects&#xD;
      with acute pain after third molar tooth extraction. The dental procedure must have involved&#xD;
      extraction of at least two impacted third molars requiring bone removal. If only two impacted&#xD;
      third molars are extracted, they must be ipsilateral and both require bone removal under&#xD;
      local anaesthesia.&#xD;
&#xD;
      The Screening Visit (Visit 1) can take place up to 28 days before the planned third molar&#xD;
      extractions. The randomisation visit (Visit 2) consists of three different sections, a part&#xD;
      before the surgery, the part with the surgery and before randomisation, and a part with the&#xD;
      randomisation and post-randomisation assessments. The visits 3 and 4, one respectively two&#xD;
      days after the randomisation can be performed by telephone if the subject does not&#xD;
      participate in the pharmacokinetic sampling.&#xD;
&#xD;
      The last dose of IMP should be taken by the subject about 72h after the initial dose and&#xD;
      before the Completion/Discontinuation Visit (Visit 5) is performed.&#xD;
&#xD;
      The Adverse Event (AE) Follow-up Visit (Visit 6) is the last study visit and should not be&#xD;
      done earlier than seven days after the subject's last dose of IMP. It can be performed by&#xD;
      telephone.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 28, 2016</start_date>
  <completion_date type="Actual">January 4, 2018</completion_date>
  <primary_completion_date type="Actual">January 4, 2018</primary_completion_date>
  <phase>Phase 3</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>Efficacy of MR308 doses in the treatment of moderate to severe acute pain, based on the Sum of Pain Intensity Differences (SPID).</measure>
    <time_frame>0-4 hours</time_frame>
    <description>The primary efficacy endpoint is the Sum of Pain Intensity Differences over 0-4 hours (SPID4). SPID4 is derived as the weighted Sum of Pain Intensity Differences (baseline pain - current pain), measured at different time points via the PI-VAS. Time between two consecutive measurements will be used for weighting. Larger values indicate larger pain relief.</description>
  </primary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">818</enrollment>
  <condition>Acute Pain</condition>
  <arm_group>
    <arm_group_label>MR308 100 mg bid</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Tramadol/Celecoxib 100 mg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>MR308 150 mg bid</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Tramadol/Celecoxib 150 mg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>MR308 200 mg bid</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Tramadol/Celecoxib 200 mg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Tramadol 100 mg qid</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Tramadol IR 100 mg</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo to match MR308 and Tramadol IR</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>MR308</intervention_name>
    <description>Over-encapsulated tablet, Dosing frequency: two times daily, Mode of administration: oral</description>
    <arm_group_label>MR308 100 mg bid</arm_group_label>
    <arm_group_label>MR308 150 mg bid</arm_group_label>
    <arm_group_label>MR308 200 mg bid</arm_group_label>
    <other_name>Tramadol/Celecoxib</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tramadol</intervention_name>
    <description>Over-encapsulated capsule, Dosing frequency: four times daily, Mode of administration: oral</description>
    <arm_group_label>Tramadol 100 mg qid</arm_group_label>
    <other_name>Tramadol immediate release</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Capsule, Dosing frequency: four times daily, Mode of administration: oral</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male/female subjects ≥ 18 years on the day of consent.&#xD;
&#xD;
          2. Willing and able to provide written informed consent for this study.&#xD;
&#xD;
          3. Subjects must have a planned elective dental procedure i.e. extraction of at least two&#xD;
             impacted third molars (one of them must be mandibular) requiring bone removal, within&#xD;
             28 days after the Screening Visit. If only two impacted third molars are extracted,&#xD;
             they must be ipsilateral and require bone removal.&#xD;
&#xD;
          4. If a female is of child-bearing potential, she must be using highly effective methods&#xD;
             of contraception throughout the study, not breastfeeding, and have negative pregnancy&#xD;
             tests prior to receiving IMP. A highly effective method of birth control is defined as&#xD;
             one which results in a low failure rate (i.e. less than 1% per year) when used&#xD;
             consistently and correctly such as sterilisation, implants, injectables, combined oral&#xD;
             contraceptives, some IUDs (Intrauterine Device, hormonal), sexual abstinence or&#xD;
             vasectomised partner).&#xD;
&#xD;
          5. Good general health as judged by Investigators on the basis of medical history and&#xD;
             physical examination.&#xD;
&#xD;
          6. Willingness to comply with the study procedures and requirements.&#xD;
&#xD;
        Additional Inclusion Criteria after Surgery:&#xD;
&#xD;
          1. Third molar extractions completed without any immediate complication.&#xD;
&#xD;
          2. Tolerating oral fluids, no uncontrolled nausea/vomiting and ready to take oral&#xD;
             analgesia.&#xD;
&#xD;
          3. The subject is alert and calm, spontaneously pays attention to caregiver, e.g. RASS =&#xD;
             0 (Sessler et al., 2002 &amp; Ely et al., 2003).&#xD;
&#xD;
          4. Subjects with moderate or severe pain (qualifying PI-VAS score ≥ 45mm and &lt; 70mm or ≥&#xD;
             70mm) as a result of an oral surgical procedure under local anaesthesia and/or&#xD;
             sedation*. This must be measured within a maximum of 6 hours after the end of the&#xD;
             surgical procedure.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any abnormal laboratory value that is clinically significant in the opinion of&#xD;
             Investigator that would compromise the safety of the subject in the study.&#xD;
&#xD;
          2. Any recent history of frequent nausea or vomiting, dizziness within the last 3 months&#xD;
             regardless of etiology.&#xD;
&#xD;
          3. Subjects having any medical condition or treatment that is either a warning or&#xD;
             contraindication as per the SmPC of tramadol (e.g. selective serotonin reuptake&#xD;
             inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic&#xD;
             antidepressants, MAO inhibitors (within 14 days before taking IMP), antipsychotics,&#xD;
             anticonvulsant and other seizure threshold-lowering medicinal products), celecoxib&#xD;
             (e.g. increased risk of post-operative bleeding, active peptic ulceration, GI bleeding&#xD;
             or inflammatory bowel disease) or paracetamol.&#xD;
&#xD;
          4. Known sensitivity and/or contraindication to tramadol, celecoxib, paracetamol,&#xD;
             sulfonamides, opioids, NSAIDS, COX-2 inhibitors, or related compounds or formulation&#xD;
             excipients as well as severe hypersensitivity reactions (e.g. anaphylactic shock,&#xD;
             bronchospasm, angioedema) to any drugs.&#xD;
&#xD;
          5. Subjects who are known to have had inadequate pain relief from paracetamol, tramadol&#xD;
             or celecoxib.&#xD;
&#xD;
          6. Subjects requiring any medication which is prohibited as per section prohibited&#xD;
             medication.&#xD;
&#xD;
          7. Subjects who are in the Investigators opinion considered at increased risk of&#xD;
             post-operative complications e.g. major dental infection/abscess.&#xD;
&#xD;
          8. Any history of drug or alcohol abuse, misuse, physical or psychological dependence,&#xD;
             mood changes, sleep disturbance and functional capacity which have an impact on pain&#xD;
             perception.&#xD;
&#xD;
          9. Significant neurological or psychiatric disorders including mental instability&#xD;
             (unrelated to the pain) that could interfere with pain assessment; other pain that&#xD;
             might impair the assessment of the nociceptive pain.&#xD;
&#xD;
         10. Any medical history of significant and/or inadequately controlled cardiovascular&#xD;
             (uncontrolled high blood pressure, high risk of cardiovascular events, severe heart&#xD;
             failure), pulmonary, hematologic, (including coagulopathy/bleeding disorders),&#xD;
             neurological (e.g. subjects with epilepsy or those susceptible to seizures), liver&#xD;
             disease (e.g. severe hepatic impairment), kidney disease (e.g. serum creatinine level&#xD;
             greater than 1.5 times the upper limit of normal, impaired renal function in subjects&#xD;
             taking diuretics, ACE-inhibitors, or angiotensin II antagonists), endocrine,&#xD;
             immunologic, dermatologic painful conditions or any other conditions that may&#xD;
             compromise the ability of the subject to participate in the study or might interfere&#xD;
             with drug absorption, distribution, metabolism or excretion.&#xD;
&#xD;
         11. Previous randomisation in this study.&#xD;
&#xD;
         12. Subjects who participated in a clinical research study involving a new chemical entity&#xD;
             or an experimental drug within 30 days of study entry (defined as the start of the&#xD;
             Screening Period).&#xD;
&#xD;
         13. Subjects who were treated regularly with opioid analgesic or NSAIDs within 30 days&#xD;
             prior to screening or who have received a long-acting NSAID within three days prior to&#xD;
             the start of the surgery.&#xD;
&#xD;
         14. Subjects who have received any analgesic medication (e.g. NSAIDs, oral opioid&#xD;
             preparations etc.) other than short-acting preoperative or intraoperative local&#xD;
             anaesthetic agents within 12 hours before the start of the surgery or peri operatively&#xD;
             until randomisation.&#xD;
&#xD;
         15. Subjects who are incapable of complying with the protocol.&#xD;
&#xD;
        Additional Exclusion Criteria after Surgery:&#xD;
&#xD;
          1. Serious complication during surgery and up to randomisation, including:&#xD;
&#xD;
               -  Post-operative primary and secondary bleed that cannot be controlled.&#xD;
&#xD;
               -  Subjects who did not had the third molar extraction completed as planned.&#xD;
&#xD;
          2. Post-operative medications or treatments that can have an analgesic effect or cause&#xD;
             sedation or have amnesic effect are not permitted as these may interfere with the&#xD;
             study assessments. These include use of ice packs, corticosteroids, nitrous oxide,&#xD;
             benzodiazepines, alcohol, hypnotics, analgesics, opioids, other psychotropic medicinal&#xD;
             products and any other analgesia except the provided study treatments&#xD;
&#xD;
          3. If in the Investigators opinion there are any factors that may confound the analysis&#xD;
             of the study regarding efficacy and safety (e.g. a PI-VAS score greater than 90).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Medical Arts Health Research Group</name>
      <address>
        <city>Penticton</city>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mount Sinai Hospital</name>
      <address>
        <city>Toronto</city>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Greifswald</name>
      <address>
        <city>Greifswald</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Semmelweis Egyetem Fogorvostudomnyi Kar</name>
      <address>
        <city>Budapest</city>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Policlinico G.B. Rossi</name>
      <address>
        <city>Verona</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>POLIMEDICA Centrum Badań, Profilaktyki i Leczenia Sp. z o.o. Sp. k.</name>
      <address>
        <city>Zgierz</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Facultad de Odontología, Universitat de Barcelona</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>Germany</country>
    <country>Hungary</country>
    <country>Italy</country>
    <country>Poland</country>
    <country>Spain</country>
  </location_countries>
  <removed_countries>
    <country>France</country>
    <country>Japan</country>
  </removed_countries>
  <verification_date>May 2018</verification_date>
  <study_first_submitted>November 25, 2016</study_first_submitted>
  <study_first_submitted_qc>November 30, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 5, 2016</study_first_posted>
  <last_update_submitted>May 25, 2018</last_update_submitted>
  <last_update_submitted_qc>May 25, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">May 29, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Third Molar Tooth Extraction</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acute Pain</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Celecoxib</mesh_term>
    <mesh_term>Tramadol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT02982161
org study id: MR308-3501
nct id: NCT02982161
lead sponsor: 
has dmc: No
The MR308-3501 study is a multicenter, randomised, double-blind, parallel-group study in male
      and female adult subjects to demonstrate the efficacy of MR308 in the treatment of acute
      moderate to severe pain after the extraction of at least two third molars requiring bone
      removal.
This is a multicenter double-blind, randomised, phase III study in male and female subjects
      with acute pain after third molar tooth extraction. The dental procedure must have involved
      extraction of at least two impacted third molars requiring bone removal. If only two impacted
      third molars are extracted, they must be ipsilateral and both require bone removal under
      local anaesthesia.

      The Screening Visit (Visit 1) can take place up to 28 days before the planned third molar
      extractions. The randomisation visit (Visit 2) consists of three different sections, a part
      before the surgery, the part with the surgery and before randomisation, and a part with the
      randomisation and post-randomisation assessments. The visits 3 and 4, one respectively two
      days after the randomisation can be performed by telephone if the subject does not
      participate in the pharmacokinetic sampling.

      The last dose of IMP should be taken by the subject about 72h after the initial dose and
      before the Completion/Discontinuation Visit (Visit 5) is performed.

      The Adverse Event (AE) Follow-up Visit (Visit 6) is the last study visit and should not be
      done earlier than seven days after the subject's last dose of IMP. It can be performed by
      telephone.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: Efficacy of MR308 doses in the treatment of moderate to severe acute pain, based on the Sum of Pain Intensity Differences (SPID).
time frame: 0-4 hours
description: The primary efficacy endpoint is the Sum of Pain Intensity Differences over 0-4 hours (SPID4). SPID4 is derived as the weighted Sum of Pain Intensity Differences (baseline pain - current pain), measured at different time points via the PI-VAS. Time between two consecutive measurements will be used for weighting. Larger values indicate larger pain relief.
arm group label: MR308 100 mg bid
arm group type: Active Comparator
description: Tramadol/Celecoxib 100 mg
arm group label: MR308 150 mg bid
arm group type: Active Comparator
description: Tramadol/Celecoxib 150 mg
arm group label: MR308 200 mg bid
arm group type: Active Comparator
description: Tramadol/Celecoxib 200 mg
arm group label: Tramadol 100 mg qid
arm group type: Active Comparator
description: Tramadol IR 100 mg
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo to match MR308 and Tramadol IR
intervention type: Drug
intervention name: MR308
description: Over-encapsulated tablet, Dosing frequency: two times daily, Mode of administration: oral
arm group label: MR308 100 mg bid
arm group label: MR308 150 mg bid
arm group label: MR308 200 mg bid
other name: Tramadol/Celecoxib
intervention type: Drug
intervention name: Tramadol
description: Over-encapsulated capsule, Dosing frequency: four times daily, Mode of administration: oral
arm group label: Tramadol 100 mg qid
other name: Tramadol immediate release
intervention type: Drug
intervention name: Placebo
description: Capsule, Dosing frequency: four times daily, Mode of administration: oral
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Canada
country: Germany
country: Hungary
country: Italy
country: Poland
country: Spain
country: France
country: Japan
responsible party type: Sponsor
mesh term: Acute Pain
mesh term: Celecoxib
mesh term: Tramadol
sharing ipd: No