<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/NCT03749642</url>
  </required_header>
  <id_info>
    <org_study_id>039(1)PO16357</org_study_id>
    <secondary_id>2018-000133-12</secondary_id>
    <nct_id>NCT03749642</nct_id>
  </id_info>
  <brief_title>Trazodone/Gabapentin Fixed Dose Combination Products in Painful Diabetic Neuropathy</brief_title>
  <official_title>Efficacy and Safety of Fixed-Dose Combination (FDC) Products Containing Trazodone and Gabapentin in Patients Affected by Painful Diabetic Neuropathy: Randomized, Controlled, Dose Finding Study.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Aziende Chimiche Riunite Angelini Francesco S.p.A</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Chiltern International Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Aziende Chimiche Riunite Angelini Francesco S.p.A</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective of the study is to collect preliminary information on the effect of&#xD;
      three doses of trazodone/gabapentin FDC products on pain intensity in patients with painful&#xD;
      diabetic neuropathy after 8-week treatment period.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The present phase II study is designed to collect preliminary data on the efficacy and safety&#xD;
      of trazodone/gabapentin Fixed-Dose Combination (FDC)products for treatment of patients&#xD;
      affected by painful diabetic neuropathy in a randomized controlled clinical trial. Diabetic&#xD;
      peripheral neuropathic pain represents an important therapeutic challenge as its&#xD;
      pathophysiology is not yet fully understood and pain relief is still unsatisfactory. The&#xD;
      pharmacological treatments, with exception to those targeted to the glycemic control, are&#xD;
      symptomatic and their use is limited by not universal efficacy, side effects or by the&#xD;
      development of tolerance. A wide variety of drugs, used both alone and in combination, has&#xD;
      shown to significantly reduce neuropathic pain when compared with placebo in randomized&#xD;
      controlled trials, even though pain relief remains inadequate for most of the patients.&#xD;
&#xD;
      In this contest, Angelini S.p.A is developing a fixed-dose combination medicinal product for&#xD;
      the treatment of neuropathic pain containing low doses of active ingredients: trazodone, a&#xD;
      widely used antidepressant drug, and gabapentin which is indicated for the treatment of&#xD;
      neuropathic pain.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 22, 2018</start_date>
  <completion_date type="Actual">June 6, 2020</completion_date>
  <primary_completion_date type="Actual">June 6, 2020</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>
    <intervention_model_description>Randomized, double-blind, placebo and reference controlled, placebo unbalanced, double-dummy, dose finding, parallel group, multicentre, international, prospective study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>The present study will be performed in double blind conditions. During the study neither the Investigator nor the patient will be aware of the treatment assigned.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change of the average daily pain score based on the 11-point Numeric Rating Scale (NRS).</measure>
    <time_frame>Baseline - Day 56</time_frame>
    <description>The NRS is based on a 11-point from 0 for [no pain] to 10 [worst possible pain].</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change of the average daily pain score based on the 11-point Numeric Rating Scale (NRS).</measure>
    <time_frame>Baseline - Days 7, 14, 21, 28, 42</time_frame>
    <description>The NRS is based on a 11-point from 0 for [no pain] to 10 [worst possible pain].</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of responder patients</measure>
    <time_frame>Baseline - Day 56</time_frame>
    <description>Responder patients are defined as ≥30% and ≥50% reduction from baseline of the average daily pain score based on the 11-point NRS.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of the average daily pain score based on the 11-point NRS between gabapentin and placebo as assay sensitivity.</measure>
    <time_frame>Baseline - Day 56</time_frame>
    <description>The NRS is based on a 11-point from 0 for [no pain] to 10 [worst possible pain].</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of Brief Pain Inventory Short Form (BPI-SF) items 3, 4, 5, 6, 8 and 9 score.</measure>
    <time_frame>Baseline - Days 28, 56</time_frame>
    <description>The BPI-SF is a numeric rating scale that assesses the severity of pain, its impact on daily functioning and other aspects of pain (e.g. location of pain, relief from medications). Items use a 0-10 numeric rating scale anchored at zero for &quot;no pain&quot; and 10 for &quot;pain as bad as you can imagine&quot; for Severity, and &quot;does not interfere&quot; to &quot;completely interferes&quot; for Interference.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of Neuropathic Pain Symptom Inventory (NPSI) total score.</measure>
    <time_frame>Baseline - Days 28, 56</time_frame>
    <description>The NPSI is a self-questionnaire specifically designed to evaluate the different symptoms of neuropathic pain: It includes 10 descriptors plus two temporal items that allow discrimination and quantification of five distinct clinically relevant dimensions of neuropathic pain syndromes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of Beck Depression Inventory - Second Edition (BDI-II)</measure>
    <time_frame>Baseline - Days 28, 56</time_frame>
    <description>The BDI-II consists of 21 items to assess the intensity of depression in clinical and normal patients. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression and scored from 0 to 3.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of Hospital Anxiety and Depression Scale (HADS).</measure>
    <time_frame>Baseline - Days 28, 56</time_frame>
    <description>The HADS is used to assess the level of anxiety and depression that a patient is experiencing. This is 14-item scale: seven related to the anxiety and seven to depression. Each item is scored from 0 to 3.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of Insomnia Severity Index (ISI).</measure>
    <time_frame>Baseline - Days 28, 56</time_frame>
    <description>The ISI is a 7-item self-reported instrument measuring the patient's perception of his/her insomnia.Total score ranges from 0-28 and the following categorization is applicable: 0-7 = absence of insomnia; 8-14 = subthreshold insomnia; 15-21 = moderate insomnia; 22-28 = severe insomnia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of Euroqol-5D-5L (EQ-5D-5L)</measure>
    <time_frame>Baseline - Days 28, 56</time_frame>
    <description>The EQ-5D-5L consists of the EQ-5D descriptive system (five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression assessed as no problems, slight problems, moderate problems, severe problems and extreme problems) and the EQ visual analogue scale (where the patient self-rates his/her health on a vertical visual analogue scale from 'The best health you can imagine' to 'The worst health you can imagine').</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Global Improvement or Change (CGI-C).</measure>
    <time_frame>Baseline - Days 28, 56</time_frame>
    <description>CGI-C provides a global rating of patient's Improvement and scores range from &quot;0 - not assessed&quot; through to &quot;7 - very much worse&quot;.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of adverse events</measure>
    <time_frame>65 days</time_frame>
    <description>Monitoring of the treatment related adverse events.</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">240</enrollment>
  <condition>Painful Diabetic Neuropathy</condition>
  <arm_group>
    <arm_group_label>trazodone/gabapentin 2.5/25 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>One capsule, three times a day, for 8 weeks. The total daily doses administered will be trazodone 7,5 mg and gabapentin 75 mg.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>trazodone/gabapentin 5/50 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>One capsule, three times a day, for 8 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>trazodone/gabapentin 10/100 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>One capsule, three times a day, for 8 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Two capsules, three times a day, for 8 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Gabapentin</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>according to the following scheduling dosage regimen:&#xD;
100 mg (2 capsules) 3 times a day, from day 0 to day 6 (±1);&#xD;
300 mg (1 capsule) 3 times a day, from day 7 (±1) to day 13 (±1);&#xD;
400 mg (1 capsule) 3 times a day, from day 14 (±1) to day 20 (±1);&#xD;
300 mg (2 capsules) 3 times a day, from day 21 (±1) to day 55 (±2).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>trazodone/gabapentin 2.5/25 mg</intervention_name>
    <description>The total daily doses administered will be trazodone 7,5 mg and gabapentin 75 mg.</description>
    <arm_group_label>trazodone/gabapentin 2.5/25 mg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>trazodone/gabapentin 5/50 mg</intervention_name>
    <description>The total daily doses administered will be trazodone 15 mg and gabapentin 150 mg.</description>
    <arm_group_label>trazodone/gabapentin 5/50 mg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>trazodone/gabapentin 10/100</intervention_name>
    <description>The total daily doses administered will be trazodone 30 mg and gabapentin 300 mg.</description>
    <arm_group_label>trazodone/gabapentin 10/100 mg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gabapentin</intervention_name>
    <description>The total daily doses administered will be:&#xD;
600 mg from day 0 to day 6 (±1)&#xD;
900 mg from day 7 (±1) to day 13 (±1)&#xD;
1200 mg from day 14 (±1) to day 20 (±1)&#xD;
1800 mg from day 21 (±1) to day 56 (±2)</description>
    <arm_group_label>Gabapentin</arm_group_label>
    <other_name>Neurontin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo oral capsule</intervention_name>
    <description>Two capsules, three times a day, for 8 weeks.</description>
    <arm_group_label>placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male and female patient of any ethnic origin between 18 and 75 years of age (limits&#xD;
             included).&#xD;
&#xD;
          2. Neuropathic pain at feet/legs confirmed by Douleur Neuropatique 4 (DN4) score ≥ 4 at&#xD;
             Screening Visit.&#xD;
&#xD;
          3. Patient with bilateral distal symmetrical polyneuropathy confirmed by Toronto Clinical&#xD;
             Neuropathy Scoring System (TCNSS) score &gt; 5 at Screening visit.&#xD;
&#xD;
          4. Pain persisting or taking pain medication for neuropathic pain for at least 3 months.&#xD;
&#xD;
          5. Diabetic patient (type 1 or 2 diabetes mellitus) with value of glycated haemoglobin ≤&#xD;
             11% at Screening Visit and stable antidiabetic medication regimen for ≥30 days.&#xD;
&#xD;
          6. Patient who is currently not receiving treatment for diabetic neuropathic pain or&#xD;
             patient who is receiving treatment, with drug/s other than gabapentin, and has&#xD;
             completed the required washout.&#xD;
&#xD;
          7. Average daily pain score ≥ 4 based on the 11-point Numeric Rating Scale (NRS) at Visit&#xD;
             0, calculated from a minimum of four pain ratings in daily electronic device entries&#xD;
             during the baseline period.&#xD;
&#xD;
          8. Women of childbearing potential must have a negative pregnancy test at Screening Visit&#xD;
             and have to agree not to start a pregnancy from the signature of the informed consent&#xD;
             up to thirty days after the last administration of the investigational product, using&#xD;
             an appropriate birth control method, such as combined estrogen and progestogen&#xD;
             containing hormonal contraception (e.g. oral, intravaginal, transdermal),&#xD;
             progestogen-only hormonal contraception (e.g. oral, injectable, implantable),&#xD;
             intrauterine device (IUD) or intrauterine hormone-releasing system (IUS) in&#xD;
             combination with male condom, bilateral tubal occlusion, vasectomised partner, sexual&#xD;
             abstinence.&#xD;
&#xD;
          9. Legally capable to give their consent to participate in the study (including personal&#xD;
             data processing) and available to sign and date the written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Known hypersensitivity to trazodone or gabapentin or any excipients of the test drugs.&#xD;
&#xD;
          2. Any other form of non-diabetic distal symmetric polyneuropathy or any other pain&#xD;
             condition that can impair the study endpoint (e.g. painful conditions where the&#xD;
             intensity of pain is significantly more severe than the diabetic peripheral&#xD;
             neuropathic pain).&#xD;
&#xD;
          3. Concomitant treatment with medications for pain management that could not be&#xD;
             discontinued.&#xD;
&#xD;
          4. Concomitant treatment with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir,&#xD;
             indinavir) or drugs known to prolong QT interval.&#xD;
&#xD;
          5. Use of trazodone or gabapentin in the previous 3 months.&#xD;
&#xD;
          6. Known history of previous non-responder to gabapentin treatment.&#xD;
&#xD;
          7. Use of high dose morphine (e.g. &gt; 120 mg/day) at the Screening Visit.&#xD;
&#xD;
          8. Clinically significant abnormalities on physical examination, vital signs,&#xD;
             elettrocardiogram, laboratory tests at Screening Visit that in the opinion of&#xD;
             Investigator would compromise patient's participation in the study.&#xD;
&#xD;
          9. Active foot ulcer or previous major limb amputation.&#xD;
&#xD;
         10. Concurrent heart failure ≥ 4 class according to New York Heart Association (NYHA) or&#xD;
             myocardial infarction or angioplasty or by-pass graft procedures within the past 6&#xD;
             months.&#xD;
&#xD;
         11. Patient with increased risk of Torsade de Pointes (e.g. family history of long QT&#xD;
             syndrome) or QTcF value higher than 450 msec (male) and QTcF value higher than 470&#xD;
             msec (female) at Screening Visit.&#xD;
&#xD;
         12. Transient ischemic attack or cerebral vascular accident within the past 6 months.&#xD;
&#xD;
         13. Glomerular Filtration Rate value &lt; 50 ml/min calculated with Modification of Diet in&#xD;
             Renal Disease formula.&#xD;
&#xD;
         14. Significant liver disease, defined as known active hepatitis or elevated liver enzymes&#xD;
             over 3-fold the upper normal limit of laboratory normal ranges.&#xD;
&#xD;
         15. Patient with latent or known hereditary problems of galactose intolerance or the Lapp&#xD;
             lactase deficiency or glucose-galactose malabsorption.&#xD;
&#xD;
         16. Positive urine drug screen for Central Nervous System active drugs (cocaine, opioids,&#xD;
             amphetamines and cannabinoids) at Screening Visit.&#xD;
&#xD;
         17. Positive present history of glaucoma.&#xD;
&#xD;
         18. Hyperthyroidism, even if pharmacologically corrected.&#xD;
&#xD;
         19. Significant mental disorders.&#xD;
&#xD;
         20. Suicide risk score ≥ 2 on question 9 of the Beck Depression Inventory-II (BDI-II) at&#xD;
             Screening visit or Visit 0.&#xD;
&#xD;
         21. History of epilepsy or seizure events other than a single childhood febrile seizure.&#xD;
&#xD;
         22. History of alcohol or psychoactive substance abuse or addiction.&#xD;
&#xD;
         23. Use of neurological device (e.g. neurostimulation devices, etc).&#xD;
&#xD;
         24. Women during pregnancy or lactation period.&#xD;
&#xD;
         25. Inability to comply with the protocol requirements, instructions or study-related&#xD;
             restrictions (e.g. uncooperative attitude, inability to return for study visits,&#xD;
             improbability of completing the clinical study, etc).&#xD;
&#xD;
         26. Subject involved in the conduct of the study (e.g. Investigator or his/her deputy,&#xD;
             first grade relatives, pharmacist, assistant or other personnel, etc).&#xD;
&#xD;
         27. Participation to an interventional clinical trial within 3 months prior to Screening&#xD;
             Visit.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Solomon Tesfaye, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sheffield Teaching Hospitals NHS Foundation Trust</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Neurosanatio s.r.o.</name>
      <address>
        <city>Litomyšl, 570 01</city>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cerebrovaskulární poradna, s.r.o.</name>
      <address>
        <city>Ostrava - Poruba, 70800</city>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nemocnice Pardubického kraje a.s. Pardubická nemocnice Neurologická klinika</name>
      <address>
        <city>Pardubice, 532 03</city>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Diabetologická ambulance Milan Kvapil s.r.o.</name>
      <address>
        <city>Praha 4, 149 00</city>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Axon Clinical s.r.o</name>
      <address>
        <city>Praha 5, 15000</city>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>FORBELI s.r.o.</name>
      <address>
        <city>Praha 6, 160 00</city>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clintrial s.r.o.</name>
      <address>
        <city>Praha, 100 00</city>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fondation Hôtel Dieu Groupe SOS Service de Diabétologie</name>
      <address>
        <city>Le Creusot, 71200</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GHR MSA - Hôpital Emile Muller Service de Diabétologie-Endocrinologie-Nutrition</name>
      <address>
        <city>Mulhouse, 68100</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Nantes - Hôpital Guillaume-et-René-Laënnec Clinique d'Endocrinologie, maladies métaboliques et nutrition CIC Endocrino - Nutrition - UF 7015</name>
      <address>
        <city>Nantes Cedex 144 093</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre de Recherche Clinique G.H.M les Portes du Sud Departement d'Endocrinologie</name>
      <address>
        <city>Venissieux, 69200</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centrum Badań Klinicznych PI-House</name>
      <address>
        <city>Gdansk, 80-546</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Silmedic Sp. z o.o.</name>
      <address>
        <city>Katowice, 40-282</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Pro Familia Altera Poradnia Wielospecjalistyczna</name>
      <address>
        <city>Katowice, 40-648</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medyczne Centrum Diabetologiczno-Endokrynologiczno-Metaboliczne DIAB-ENDO-MET</name>
      <address>
        <city>Kraków, 31-261</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NZOZ Neuromed M. i M. Nastaj Sp. P.</name>
      <address>
        <city>Lublin, 20-064</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instytut Medycyny Wsi im. Witolda Chodźki Klinika Diabetologii</name>
      <address>
        <city>Lublin, 20-090</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centrum Medyczne HCP Sp. z o.o.</name>
      <address>
        <city>Poznań, 61-485</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>RCMed Oddział Sochaczew</name>
      <address>
        <city>Sochaczew, 96-500</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Nasz Lekarz Przychodnie Medyczne</name>
      <address>
        <city>Toruń, 87-100</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medycyna Kliniczna</name>
      <address>
        <city>Warszawa, 00-874</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instytut Diabetologii</name>
      <address>
        <city>Warszawa, 04-736</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>WroMedica I. Bielicka, A. Strzałkowska s.c.</name>
      <address>
        <city>Wrocław, 51- 685</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centrum Badań Klinicznych Ośrodek Badań Wczesnej Fazy</name>
      <address>
        <city>Wrocław, 51-162</city>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical Innovation Development and Research Unit (MIDRU) Heartlands Hospital</name>
      <address>
        <city>Birmingham</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Diabetes Centre Wythenshawe Hospital</name>
      <address>
        <city>Manchester</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Manchester Clinical Research Facility Manchester Royal Infirmary</name>
      <address>
        <city>Manchester</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Diabetes Centre George Eliot Hospital NHS Trust</name>
      <address>
        <city>Nuneaton</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lancashire Clinical Research Facility The Avondale Unit Royal Preston Hospital</name>
      <address>
        <city>Preston</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinical Research Facility Royal Hallamshire Hospital</name>
      <address>
        <city>Sheffield</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Czechia</country>
    <country>France</country>
    <country>Poland</country>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>November 20, 2018</study_first_submitted>
  <study_first_submitted_qc>November 20, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 21, 2018</study_first_posted>
  <last_update_submitted>May 26, 2021</last_update_submitted>
  <last_update_submitted_qc>May 26, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">May 27, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Trazodone</keyword>
  <keyword>Gabapentin</keyword>
  <keyword>Neuropathic pain</keyword>
  <keyword>Placebo</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetic Neuropathies</mesh_term>
    <mesh_term>Pain</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gabapentin</mesh_term>
    <mesh_term>Trazodone</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/NCT03749642
org study id: 039(1)PO16357
secondary id: 2018-000133-12
nct id: NCT03749642
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The primary objective of the study is to collect preliminary information on the effect of
      three doses of trazodone/gabapentin FDC products on pain intensity in patients with painful
      diabetic neuropathy after 8-week treatment period.
The present phase II study is designed to collect preliminary data on the efficacy and safety
      of trazodone/gabapentin Fixed-Dose Combination (FDC)products for treatment of patients
      affected by painful diabetic neuropathy in a randomized controlled clinical trial. Diabetic
      peripheral neuropathic pain represents an important therapeutic challenge as its
      pathophysiology is not yet fully understood and pain relief is still unsatisfactory. The
      pharmacological treatments, with exception to those targeted to the glycemic control, are
      symptomatic and their use is limited by not universal efficacy, side effects or by the
      development of tolerance. A wide variety of drugs, used both alone and in combination, has
      shown to significantly reduce neuropathic pain when compared with placebo in randomized
      controlled trials, even though pain relief remains inadequate for most of the patients.

      In this contest, Angelini S.p.A is developing a fixed-dose combination medicinal product for
      the treatment of neuropathic pain containing low doses of active ingredients: trazodone, a
      widely used antidepressant drug, and gabapentin which is indicated for the treatment of
      neuropathic pain.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomized, double-blind, placebo and reference controlled, placebo unbalanced, double-dummy, dose finding, parallel group, multicentre, international, prospective study
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: The present study will be performed in double blind conditions. During the study neither the Investigator nor the patient will be aware of the treatment assigned.
measure: Change of the average daily pain score based on the 11-point Numeric Rating Scale (NRS).
time frame: Baseline - Day 56
description: The NRS is based on a 11-point from 0 for [no pain] to 10 [worst possible pain].
measure: Change of the average daily pain score based on the 11-point Numeric Rating Scale (NRS).
time frame: Baseline - Days 7, 14, 21, 28, 42
description: The NRS is based on a 11-point from 0 for [no pain] to 10 [worst possible pain].
measure: Percentage of responder patients
time frame: Baseline - Day 56
description: Responder patients are defined as ≥30% and ≥50% reduction from baseline of the average daily pain score based on the 11-point NRS.
measure: Change of the average daily pain score based on the 11-point NRS between gabapentin and placebo as assay sensitivity.
time frame: Baseline - Day 56
description: The NRS is based on a 11-point from 0 for [no pain] to 10 [worst possible pain].
measure: Change of Brief Pain Inventory Short Form (BPI-SF) items 3, 4, 5, 6, 8 and 9 score.
time frame: Baseline - Days 28, 56
description: The BPI-SF is a numeric rating scale that assesses the severity of pain, its impact on daily functioning and other aspects of pain (e.g. location of pain, relief from medications). Items use a 0-10 numeric rating scale anchored at zero for "no pain" and 10 for "pain as bad as you can imagine" for Severity, and "does not interfere" to "completely interferes" for Interference.
measure: Change of Neuropathic Pain Symptom Inventory (NPSI) total score.
time frame: Baseline - Days 28, 56
description: The NPSI is a self-questionnaire specifically designed to evaluate the different symptoms of neuropathic pain: It includes 10 descriptors plus two temporal items that allow discrimination and quantification of five distinct clinically relevant dimensions of neuropathic pain syndromes.
measure: Change of Beck Depression Inventory - Second Edition (BDI-II)
time frame: Baseline - Days 28, 56
description: The BDI-II consists of 21 items to assess the intensity of depression in clinical and normal patients. Each item is a list of four statements arranged in increasing severity about a particular symptom of depression and scored from 0 to 3.
measure: Change of Hospital Anxiety and Depression Scale (HADS).
time frame: Baseline - Days 28, 56
description: The HADS is used to assess the level of anxiety and depression that a patient is experiencing. This is 14-item scale: seven related to the anxiety and seven to depression. Each item is scored from 0 to 3.
measure: Change of Insomnia Severity Index (ISI).
time frame: Baseline - Days 28, 56
description: The ISI is a 7-item self-reported instrument measuring the patient's perception of his/her insomnia.Total score ranges from 0-28 and the following categorization is applicable: 0-7 = absence of insomnia; 8-14 = subthreshold insomnia; 15-21 = moderate insomnia; 22-28 = severe insomnia.
measure: Change of Euroqol-5D-5L (EQ-5D-5L)
time frame: Baseline - Days 28, 56
description: The EQ-5D-5L consists of the EQ-5D descriptive system (five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression assessed as no problems, slight problems, moderate problems, severe problems and extreme problems) and the EQ visual analogue scale (where the patient self-rates his/her health on a vertical visual analogue scale from 'The best health you can imagine' to 'The worst health you can imagine').
measure: Clinical Global Improvement or Change (CGI-C).
time frame: Baseline - Days 28, 56
description: CGI-C provides a global rating of patient's Improvement and scores range from "0 - not assessed" through to "7 - very much worse".
measure: Frequency of adverse events
time frame: 65 days
description: Monitoring of the treatment related adverse events.
arm group label: trazodone/gabapentin 2.5/25 mg
arm group type: Experimental
description: One capsule, three times a day, for 8 weeks. The total daily doses administered will be trazodone 7,5 mg and gabapentin 75 mg.
arm group label: trazodone/gabapentin 5/50 mg
arm group type: Experimental
description: One capsule, three times a day, for 8 weeks.
arm group label: trazodone/gabapentin 10/100 mg
arm group type: Experimental
description: One capsule, three times a day, for 8 weeks.
arm group label: placebo
arm group type: Placebo Comparator
description: Two capsules, three times a day, for 8 weeks.
arm group label: Gabapentin
arm group type: Active Comparator
description: according to the following scheduling dosage regimen:
100 mg (2 capsules) 3 times a day, from day 0 to day 6 (±1);
300 mg (1 capsule) 3 times a day, from day 7 (±1) to day 13 (±1);
400 mg (1 capsule) 3 times a day, from day 14 (±1) to day 20 (±1);
300 mg (2 capsules) 3 times a day, from day 21 (±1) to day 55 (±2).
intervention type: Drug
intervention name: trazodone/gabapentin 2.5/25 mg
description: The total daily doses administered will be trazodone 7,5 mg and gabapentin 75 mg.
arm group label: trazodone/gabapentin 2.5/25 mg
intervention type: Drug
intervention name: trazodone/gabapentin 5/50 mg
description: The total daily doses administered will be trazodone 15 mg and gabapentin 150 mg.
arm group label: trazodone/gabapentin 5/50 mg
intervention type: Drug
intervention name: trazodone/gabapentin 10/100
description: The total daily doses administered will be trazodone 30 mg and gabapentin 300 mg.
arm group label: trazodone/gabapentin 10/100 mg
intervention type: Drug
intervention name: Gabapentin
description: The total daily doses administered will be:
600 mg from day 0 to day 6 (±1)
900 mg from day 7 (±1) to day 13 (±1)
1200 mg from day 14 (±1) to day 20 (±1)
1800 mg from day 21 (±1) to day 56 (±2)
arm group label: Gabapentin
other name: Neurontin
intervention type: Drug
intervention name: Placebo oral capsule
description: Two capsules, three times a day, for 8 weeks.
arm group label: placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Solomon Tesfaye, MD
role: Principal Investigator
affiliation: Sheffield Teaching Hospitals NHS Foundation Trust
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country: Czechia
country: France
country: Poland
country: United Kingdom
responsible party type: Sponsor
mesh term: Diabetic Neuropathies
mesh term: Pain
mesh term: Gabapentin
mesh term: Trazodone
sharing ipd: No