<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/NCT03834363</url>
  </required_header>
  <id_info>
    <org_study_id>MoreFoRCOPD</org_study_id>
    <nct_id>NCT03834363</nct_id>
  </id_info>
  <brief_title>Morphine or Fentanyl for Refractory Dyspnea in COPD</brief_title>
  <acronym>MoreFoRCOPD</acronym>
  <official_title>Morphine or Fentanyl for Refractory Dyspnea in COPD</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Huib A.M. Kerstjens</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Dutch Foundation for Asthma Prevention</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Innovatiefonds Zorgverzekeraars</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Medical Center Groningen</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Rationale: The most important complaint in severe COPD is dyspnea which is associated with a&#xD;
      diminished exercise tolerance, reduced quality of life and can lead to anxiety and&#xD;
      depression. If dyspnea continues to exist despite optimal therapy it is called refractory&#xD;
      dyspnea. There is evidence that morphine is effective and can safely be prescribed for&#xD;
      treating refractory dyspnea.&#xD;
&#xD;
      However, a Dutch study recently showed that few pulmonologists actually prescribe opioids for&#xD;
      this indication. The main reasons for this are concerns about side effects and respiratory&#xD;
      insufficiency as well as negative emotions for the patient and families at the thought of&#xD;
      using morphine.&#xD;
&#xD;
      Most studies investigating opioids for treatment of dyspnea are conducted with morphine&#xD;
      tablets, and only a part of these patients suffered from COPD. To our knowledge there has not&#xD;
      been a randomized controlled trial investigating fentanyl patches for refractory dyspnea in&#xD;
      COPD patients. However, studies comparing fentanyl and morphine in pain management show that&#xD;
      patients may prefer fentanyl patches and have less problems with obstipation.&#xD;
&#xD;
      Objective: There are three main objectives for this study.&#xD;
&#xD;
      First, the investigators will investigate the following hypothesis: Both fentanyl and&#xD;
      morphine provide a reduction of dyspnea which is better than placebo. Fentanyl has less side&#xD;
      effects than morphine.&#xD;
&#xD;
      Secondly, with this Dutch multi-center study the investigators would like to enlarge the&#xD;
      evidence base and contribute to the experience with opioids for refractory dyspnea in COPD&#xD;
      thereby greatly facilitating its implementation in the Netherlands.&#xD;
&#xD;
      Finally, the investigators will develop and evaluate educational material about opioid use&#xD;
      for dyspnea in COPD.&#xD;
&#xD;
      Study design: This is a multi-center double blind, double-dummy cross-over randomized&#xD;
      placebo-controlled trial with three study arms. A total of 60 COPD patients will be included&#xD;
      in this study.&#xD;
&#xD;
      Participants will be treated sequentially with three combinations of medication and/or&#xD;
      placebo medication in a random order. They will receive either a Fentanyl patch in&#xD;
      combination with placebo tablets, a placebo patch with Morphine Slow release tablets or a&#xD;
      placebo patch with placebo tablets. Main study parameters/endpoints: The primary endpoint is&#xD;
      change in dyspnea sensation Secondary endpoints are change in HR-QoL, anxiety, sleep quality,&#xD;
      hypercapnia and the number and seriousness of side effect.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 15, 2019</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">October 2023</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>Crossover, double blind, double dummy Randomized Controlled Trial</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>For both morphine retard capsules as fentanyl patches there is a placebo available. Participants will be treated in each period with both tablets and a patch. (morphine capsules+placebo patch, placebo capsules+fentanyl patch, placebo capsules+ placebo patch.)</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in dyspnea sensation</measure>
    <time_frame>Daily during the six week treatment period</time_frame>
    <description>Change in dyspnea sensation measured on a Numeric Rating Scale from 0 to 10. A lower score represents a better outcome.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in CCQ (HR-QoL)</measure>
    <time_frame>Daily during the six week treatment period</time_frame>
    <description>Change in HR-QoL measured with the Clinical COPD Questionnaire. Scores range from 0 to 6. Lower values represent a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in CRQ (HR-QoL)</measure>
    <time_frame>4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.</time_frame>
    <description>Change in HR-QoL measured with Chronic Respiratory Disease Questionnare. Scores range from 1 to 7. A higher score represents a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in CRQ mastery (HR-QoL)</measure>
    <time_frame>4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.</time_frame>
    <description>Change in HR-QoL measured with Chronic Respiratory Disease Questionnare, domain Mastery. Scores range from 1 to 7. A higher score represents a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change on the HADS-A questionnaire (Anxiety)</measure>
    <time_frame>4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.</time_frame>
    <description>Change on the Hospital Anxiety and Depression Scale-anxiety subscale. Scores range from 0 to 21. A lower score represents a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Side effects</measure>
    <time_frame>Daily during the six week treatment period</time_frame>
    <description>Reported spontaneously in a daily patient diary and specifically, both open and named side effects at planned visits.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hypercapnia</measure>
    <time_frame>4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.</time_frame>
    <description>Change in pCO2 in capillary blood gas analysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sleep quality</measure>
    <time_frame>Daily during the six week treatment period</time_frame>
    <description>Change on a Numeric Rating Scale from 0 to 10. A lower score represents a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Continued opioid use</measure>
    <time_frame>Once, three months after the end of the treatment period</time_frame>
    <description>Asked three months after the end of the treatment period</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Survival</measure>
    <time_frame>One week after the end of the treatment period, which is 7 weeks after start of the study.</time_frame>
    <description>Measured one week after the end of the treatment period</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>COPD</condition>
  <arm_group>
    <arm_group_label>Morphine capsules and Placebo patch</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Morphine retard 10 mg twice daily Placebo patch, change every three days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo capsules and Fentanyl patch</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Placebo capsules twice daily Fentanyl patch 12 mcg/hr, change every three days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo capsules and Placebo patch</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo capsules twice daily Placebo patch, change every three days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fentanyl</intervention_name>
    <description>Fentanylpatch 12 mcg/hr, change patch every three days.</description>
    <arm_group_label>Placebo capsules and Fentanyl patch</arm_group_label>
    <other_name>Fentanyl Matrix</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Morphine Retard</intervention_name>
    <description>Morphine retard capsules 10 mg bid.</description>
    <arm_group_label>Morphine capsules and Placebo patch</arm_group_label>
    <other_name>Morphine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo patch</intervention_name>
    <description>Placebo patch, change patch every three days.</description>
    <arm_group_label>Morphine capsules and Placebo patch</arm_group_label>
    <arm_group_label>Placebo capsules and Placebo patch</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo oral capsule</intervention_name>
    <description>Placebo oral capsule bid</description>
    <arm_group_label>Placebo capsules and Fentanyl patch</arm_group_label>
    <arm_group_label>Placebo capsules and Placebo patch</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 40 years.&#xD;
&#xD;
          -  Read, understood and signed the Informed Consent form.&#xD;
&#xD;
          -  COPD GOLD class III or IV, according to GOLD criteria (Post-bronchodilation FEV/FVC&#xD;
             &lt;70% and FEV1 &lt; 50%pred.&#xD;
&#xD;
          -  Complaints of refractory dyspnea as established by patient and doctor.&#xD;
&#xD;
          -  mMRC score ≥ 3.&#xD;
&#xD;
          -  Life expectancy of ≥ 2 months.&#xD;
&#xD;
          -  Optimized standard therapy according to Dutch LAN guideline for diagnosis and&#xD;
             treatment of COPD.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Other severe disease with chronic pain or chronic dyspnea (a non substantial component&#xD;
             of left sided heart failure is acceptable).&#xD;
&#xD;
          -  Current use of opioids for whatever indication.&#xD;
&#xD;
          -  Allergy / intolerance for opioids&#xD;
&#xD;
          -  Psychiatric disease, not related to severe COPD.&#xD;
&#xD;
          -  Exacerbation of COPD 8 weeks prior to inclusion or between screening and&#xD;
             randomization.&#xD;
&#xD;
          -  Problematic (leading to medical help or social problems) substance abuse during the&#xD;
             last five years.&#xD;
&#xD;
          -  Active malignancy, with the exception of planocellular or basal cell carcinoma of the&#xD;
             skin.&#xD;
&#xD;
          -  eGFR &lt;15 ml/min&#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>Huib AM Kerstjens, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Medical Center Groningen</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Marlies van Dijk, MD</last_name>
    <phone>+31503612357</phone>
    <email>m.van.dijk05@umcg.nl</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Huib AM Kerstjens, MD PhD</last_name>
    <phone>+31503610280</phone>
    <email>h.a.m.kerstjens@umcg.nl</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Wilhelmina Ziekenhuis Assen</name>
      <address>
        <city>Assen</city>
        <state>Drenthe</state>
        <zip>9401 RK</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sander De Hosson, MD</last_name>
    </contact>
    <investigator>
      <last_name>Sander De Hosson, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Ommelander Ziekenhuis Groningen</name>
      <address>
        <city>Scheemda</city>
        <state>Groningen</state>
        <zip>9676 BJ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <investigator>
      <last_name>Jan Willem De Jong, MD PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Elkerliek Ziekenhuis</name>
      <address>
        <city>Helmond</city>
        <state>Noord-Brabant</state>
        <zip>5707 HA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Wai Yee Lam, MD PhD</last_name>
    </contact>
    <investigator>
      <last_name>Wai Yee Lam, MD PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Noordwest Ziekenhuisgroep Alkmaar</name>
      <address>
        <city>Alkmaar</city>
        <state>Noord-Holland</state>
        <zip>1815 JD</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Liesbeth Peters, MD</last_name>
    </contact>
    <investigator>
      <last_name>Liesbeth Peters, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Rode Kruis Ziekenhuis</name>
      <address>
        <city>Beverwijk</city>
        <state>Noord-Holland</state>
        <zip>1942 LE</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Karin Pool, MD</last_name>
    </contact>
    <investigator>
      <last_name>Karin Pool, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Spaarne Gasthuis</name>
      <address>
        <city>Haarlem</city>
        <state>Noord-Holland</state>
        <zip>2035 RC</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kris Mooren, MD</last_name>
    </contact>
    <investigator>
      <last_name>Kris Mooren, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Medisch Spectrum Twente</name>
      <address>
        <city>Enschede</city>
        <state>Overijssel</state>
        <zip>7512 KZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Wendy Van Beurden, MD</last_name>
    </contact>
    <investigator>
      <last_name>Wendy van Beurden, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Isala Klinieken</name>
      <address>
        <city>Zwolle</city>
        <state>Overijssel</state>
        <zip>8025 AB</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jan Willem Van den Berg, MD PhD</last_name>
    </contact>
    <investigator>
      <last_name>Jan WIllem Van den Berg, MD PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Ikazia Ziekenhuis</name>
      <address>
        <city>Rotterdam</city>
        <state>Zuid-Holland</state>
        <zip>3083 AN</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Roxane Heller-Baan, MD</last_name>
    </contact>
    <investigator>
      <last_name>Roxane Heller-Baan, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>University Medical Center Groningen</name>
      <address>
        <city>Groningen</city>
        <zip>9713GZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Huib A.M. Kerstjens, MD PhD</last_name>
    </contact>
    <investigator>
      <last_name>Huib A.M. Kerstjens, MD PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Marlies van Dijk, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <reference>
    <citation>Blinderman CD, Homel P, Billings JA, Tennstedt S, Portenoy RK. Symptom distress and quality of life in patients with advanced chronic obstructive pulmonary disease. J Pain Symptom Manage. 2009 Jul;38(1):115-23. doi: 10.1016/j.jpainsymman.2008.07.006. Epub 2009 Feb 20.</citation>
    <PMID>19232893</PMID>
  </reference>
  <reference>
    <citation>Wiseman R, Rowett D, Allcroft P, Abernethy A, Currow DC. Chronic refractory dyspnoea--evidence based management. Aust Fam Physician. 2013 Mar;42(3):137-40.</citation>
    <PMID>23529525</PMID>
  </reference>
  <reference>
    <citation>Abernethy AP, Currow DC, Frith P, Fazekas BS, McHugh A, Bui C. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ. 2003 Sep 6;327(7414):523-8. doi: 10.1136/bmj.327.7414.523.</citation>
    <PMID>12958109</PMID>
  </reference>
  <reference>
    <citation>Jennings AL, Davies AN, Higgins JP, Gibbs JS, Broadley KE. A systematic review of the use of opioids in the management of dyspnoea. Thorax. 2002 Nov;57(11):939-44. doi: 10.1136/thorax.57.11.939.</citation>
    <PMID>12403875</PMID>
  </reference>
  <reference>
    <citation>Janssen DJ, de Hosson SM, bij de Vaate E, Mooren KJ, Baas AA. Attitudes toward opioids for refractory dyspnea in COPD among Dutch chest physicians. Chron Respir Dis. 2015 May;12(2):85-92. doi: 10.1177/1479972315571926. Epub 2015 Feb 12.</citation>
    <PMID>25676931</PMID>
  </reference>
  <reference>
    <citation>Simon ST, Koskeroglu P, Gaertner J, Voltz R. Fentanyl for the relief of refractory breathlessness: a systematic review. J Pain Symptom Manage. 2013 Dec;46(6):874-86. doi: 10.1016/j.jpainsymman.2013.02.019. Epub 2013 Jun 4.</citation>
    <PMID>23742735</PMID>
  </reference>
  <reference>
    <citation>Payne R, Mathias SD, Pasta DJ, Wanke LA, Williams R, Mahmoud R. Quality of life and cancer pain: satisfaction and side effects with transdermal fentanyl versus oral morphine. J Clin Oncol. 1998 Apr;16(4):1588-93. doi: 10.1200/JCO.1998.16.4.1588.</citation>
    <PMID>9552070</PMID>
  </reference>
  <reference>
    <citation>Allan L, Hays H, Jensen NH, de Waroux BL, Bolt M, Donald R, Kalso E. Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. BMJ. 2001 May 12;322(7295):1154-8. doi: 10.1136/bmj.322.7295.1154.</citation>
    <PMID>11348910</PMID>
  </reference>
  <reference>
    <citation>Johnson MJ, Bland JM, Oxberry SG, Abernethy AP, Currow DC. Clinically important differences in the intensity of chronic refractory breathlessness. J Pain Symptom Manage. 2013 Dec;46(6):957-63. doi: 10.1016/j.jpainsymman.2013.01.011. Epub 2013 Apr 19.</citation>
    <PMID>23608121</PMID>
  </reference>
  <reference>
    <citation>Currow DC, McDonald C, Oaten S, Kenny B, Allcroft P, Frith P, Briffa M, Johnson MJ, Abernethy AP. Once-daily opioids for chronic dyspnea: a dose increment and pharmacovigilance study. J Pain Symptom Manage. 2011 Sep;42(3):388-99. doi: 10.1016/j.jpainsymman.2010.11.021. Epub 2011 Mar 31.</citation>
    <PMID>21458217</PMID>
  </reference>
  <reference>
    <citation>Jensen D, Alsuhail A, Viola R, Dudgeon DJ, Webb KA, O'Donnell DE. Inhaled fentanyl citrate improves exercise endurance during high-intensity constant work rate cycle exercise in chronic obstructive pulmonary disease. J Pain Symptom Manage. 2012 Apr;43(4):706-19. doi: 10.1016/j.jpainsymman.2011.05.007. Epub 2011 Dec 14.</citation>
    <PMID>22168961</PMID>
  </reference>
  <reference>
    <citation>Hui D, Kilgore K, Frisbee-Hume S, Park M, Liu D, Balachandran DD, Bruera E. Effect of Prophylactic Fentanyl Buccal Tablet on Episodic Exertional Dyspnea: A Pilot Double-Blind Randomized Controlled Trial. J Pain Symptom Manage. 2017 Dec;54(6):798-805. doi: 10.1016/j.jpainsymman.2017.08.001. Epub 2017 Aug 10.</citation>
    <PMID>28803087</PMID>
  </reference>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>January 11, 2019</study_first_submitted>
  <study_first_submitted_qc>February 6, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 7, 2019</study_first_posted>
  <last_update_submitted>November 16, 2022</last_update_submitted>
  <last_update_submitted_qc>November 16, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 17, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University Medical Center Groningen</investigator_affiliation>
    <investigator_full_name>Huib A.M. Kerstjens</investigator_full_name>
    <investigator_title>Full professor pulmonology, head of department pulmonology and tuberculosis, principal investigator.</investigator_title>
  </responsible_party>
  <keyword>COPD</keyword>
  <keyword>Refractory Dyspnea</keyword>
  <keyword>Morphine</keyword>
  <keyword>Fentanyl</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dyspnea</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fentanyl</mesh_term>
    <mesh_term>Morphine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Upon request</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>After publication of results Unlimited</ipd_time_frame>
    <ipd_access_criteria>Clear description of goals for asking</ipd_access_criteria>
  </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/NCT03834363
org study id: MoreFoRCOPD
nct id: NCT03834363
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Rationale: The most important complaint in severe COPD is dyspnea which is associated with a
      diminished exercise tolerance, reduced quality of life and can lead to anxiety and
      depression. If dyspnea continues to exist despite optimal therapy it is called refractory
      dyspnea. There is evidence that morphine is effective and can safely be prescribed for
      treating refractory dyspnea.

      However, a Dutch study recently showed that few pulmonologists actually prescribe opioids for
      this indication. The main reasons for this are concerns about side effects and respiratory
      insufficiency as well as negative emotions for the patient and families at the thought of
      using morphine.

      Most studies investigating opioids for treatment of dyspnea are conducted with morphine
      tablets, and only a part of these patients suffered from COPD. To our knowledge there has not
      been a randomized controlled trial investigating fentanyl patches for refractory dyspnea in
      COPD patients. However, studies comparing fentanyl and morphine in pain management show that
      patients may prefer fentanyl patches and have less problems with obstipation.

      Objective: There are three main objectives for this study.

      First, the investigators will investigate the following hypothesis: Both fentanyl and
      morphine provide a reduction of dyspnea which is better than placebo. Fentanyl has less side
      effects than morphine.

      Secondly, with this Dutch multi-center study the investigators would like to enlarge the
      evidence base and contribute to the experience with opioids for refractory dyspnea in COPD
      thereby greatly facilitating its implementation in the Netherlands.

      Finally, the investigators will develop and evaluate educational material about opioid use
      for dyspnea in COPD.

      Study design: This is a multi-center double blind, double-dummy cross-over randomized
      placebo-controlled trial with three study arms. A total of 60 COPD patients will be included
      in this study.

      Participants will be treated sequentially with three combinations of medication and/or
      placebo medication in a random order. They will receive either a Fentanyl patch in
      combination with placebo tablets, a placebo patch with Morphine Slow release tablets or a
      placebo patch with placebo tablets. Main study parameters/endpoints: The primary endpoint is
      change in dyspnea sensation Secondary endpoints are change in HR-QoL, anxiety, sleep quality,
      hypercapnia and the number and seriousness of side effect.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: Crossover, double blind, double dummy Randomized Controlled Trial
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: For both morphine retard capsules as fentanyl patches there is a placebo available. Participants will be treated in each period with both tablets and a patch. (morphine capsules+placebo patch, placebo capsules+fentanyl patch, placebo capsules+ placebo patch.)
measure: Change in dyspnea sensation
time frame: Daily during the six week treatment period
description: Change in dyspnea sensation measured on a Numeric Rating Scale from 0 to 10. A lower score represents a better outcome.
measure: Change in CCQ (HR-QoL)
time frame: Daily during the six week treatment period
description: Change in HR-QoL measured with the Clinical COPD Questionnaire. Scores range from 0 to 6. Lower values represent a better outcome.
measure: Change in CRQ (HR-QoL)
time frame: 4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.
description: Change in HR-QoL measured with Chronic Respiratory Disease Questionnare. Scores range from 1 to 7. A higher score represents a better outcome.
measure: Change in CRQ mastery (HR-QoL)
time frame: 4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.
description: Change in HR-QoL measured with Chronic Respiratory Disease Questionnare, domain Mastery. Scores range from 1 to 7. A higher score represents a better outcome.
measure: Change on the HADS-A questionnaire (Anxiety)
time frame: 4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.
description: Change on the Hospital Anxiety and Depression Scale-anxiety subscale. Scores range from 0 to 21. A lower score represents a better outcome.
measure: Side effects
time frame: Daily during the six week treatment period
description: Reported spontaneously in a daily patient diary and specifically, both open and named side effects at planned visits.
measure: Hypercapnia
time frame: 4 times during the six week treatment period: baseline, 2 weeks, 4 weeks, 6 weeks.
description: Change in pCO2 in capillary blood gas analysis
measure: Sleep quality
time frame: Daily during the six week treatment period
description: Change on a Numeric Rating Scale from 0 to 10. A lower score represents a better outcome.
measure: Continued opioid use
time frame: Once, three months after the end of the treatment period
description: Asked three months after the end of the treatment period
measure: Survival
time frame: One week after the end of the treatment period, which is 7 weeks after start of the study.
description: Measured one week after the end of the treatment period
arm group label: Morphine capsules and Placebo patch
arm group type: Active Comparator
description: Morphine retard 10 mg twice daily Placebo patch, change every three days.
arm group label: Placebo capsules and Fentanyl patch
arm group type: Experimental
description: Placebo capsules twice daily Fentanyl patch 12 mcg/hr, change every three days
arm group label: Placebo capsules and Placebo patch
arm group type: Placebo Comparator
description: Placebo capsules twice daily Placebo patch, change every three days
intervention type: Drug
intervention name: Fentanyl
description: Fentanylpatch 12 mcg/hr, change patch every three days.
arm group label: Placebo capsules and Fentanyl patch
other name: Fentanyl Matrix
intervention type: Drug
intervention name: Morphine Retard
description: Morphine retard capsules 10 mg bid.
arm group label: Morphine capsules and Placebo patch
other name: Morphine
intervention type: Drug
intervention name: Placebo patch
description: Placebo patch, change patch every three days.
arm group label: Morphine capsules and Placebo patch
arm group label: Placebo capsules and Placebo patch
intervention type: Drug
intervention name: Placebo oral capsule
description: Placebo oral capsule bid
arm group label: Placebo capsules and Fentanyl patch
arm group label: Placebo capsules and Placebo patch
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Huib AM Kerstjens, MD PhD
role: Principal Investigator
affiliation: University Medical Center Groningen
last name: Marlies van Dijk, MD
phone: +31503612357
email: m.van.dijk05@umcg.nl
last name: Huib AM Kerstjens, MD PhD
phone: +31503610280
email: h.a.m.kerstjens@umcg.nl
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status: Recruiting
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country: Netherlands
citation: Blinderman CD, Homel P, Billings JA, Tennstedt S, Portenoy RK. Symptom distress and quality of life in patients with advanced chronic obstructive pulmonary disease. J Pain Symptom Manage. 2009 Jul;38(1):115-23. doi: 10.1016/j.jpainsymman.2008.07.006. Epub 2009 Feb 20.
PMID: 19232893
citation: Wiseman R, Rowett D, Allcroft P, Abernethy A, Currow DC. Chronic refractory dyspnoea--evidence based management. Aust Fam Physician. 2013 Mar;42(3):137-40.
PMID: 23529525
citation: Abernethy AP, Currow DC, Frith P, Fazekas BS, McHugh A, Bui C. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ. 2003 Sep 6;327(7414):523-8. doi: 10.1136/bmj.327.7414.523.
PMID: 12958109
citation: Jennings AL, Davies AN, Higgins JP, Gibbs JS, Broadley KE. A systematic review of the use of opioids in the management of dyspnoea. Thorax. 2002 Nov;57(11):939-44. doi: 10.1136/thorax.57.11.939.
PMID: 12403875
citation: Janssen DJ, de Hosson SM, bij de Vaate E, Mooren KJ, Baas AA. Attitudes toward opioids for refractory dyspnea in COPD among Dutch chest physicians. Chron Respir Dis. 2015 May;12(2):85-92. doi: 10.1177/1479972315571926. Epub 2015 Feb 12.
PMID: 25676931
citation: Simon ST, Koskeroglu P, Gaertner J, Voltz R. Fentanyl for the relief of refractory breathlessness: a systematic review. J Pain Symptom Manage. 2013 Dec;46(6):874-86. doi: 10.1016/j.jpainsymman.2013.02.019. Epub 2013 Jun 4.
PMID: 23742735
citation: Payne R, Mathias SD, Pasta DJ, Wanke LA, Williams R, Mahmoud R. Quality of life and cancer pain: satisfaction and side effects with transdermal fentanyl versus oral morphine. J Clin Oncol. 1998 Apr;16(4):1588-93. doi: 10.1200/JCO.1998.16.4.1588.
PMID: 9552070
citation: Allan L, Hays H, Jensen NH, de Waroux BL, Bolt M, Donald R, Kalso E. Randomised crossover trial of transdermal fentanyl and sustained release oral morphine for treating chronic non-cancer pain. BMJ. 2001 May 12;322(7295):1154-8. doi: 10.1136/bmj.322.7295.1154.
PMID: 11348910
citation: Johnson MJ, Bland JM, Oxberry SG, Abernethy AP, Currow DC. Clinically important differences in the intensity of chronic refractory breathlessness. J Pain Symptom Manage. 2013 Dec;46(6):957-63. doi: 10.1016/j.jpainsymman.2013.01.011. Epub 2013 Apr 19.
PMID: 23608121
citation: Currow DC, McDonald C, Oaten S, Kenny B, Allcroft P, Frith P, Briffa M, Johnson MJ, Abernethy AP. Once-daily opioids for chronic dyspnea: a dose increment and pharmacovigilance study. J Pain Symptom Manage. 2011 Sep;42(3):388-99. doi: 10.1016/j.jpainsymman.2010.11.021. Epub 2011 Mar 31.
PMID: 21458217
citation: Jensen D, Alsuhail A, Viola R, Dudgeon DJ, Webb KA, O'Donnell DE. Inhaled fentanyl citrate improves exercise endurance during high-intensity constant work rate cycle exercise in chronic obstructive pulmonary disease. J Pain Symptom Manage. 2012 Apr;43(4):706-19. doi: 10.1016/j.jpainsymman.2011.05.007. Epub 2011 Dec 14.
PMID: 22168961
citation: Hui D, Kilgore K, Frisbee-Hume S, Park M, Liu D, Balachandran DD, Bruera E. Effect of Prophylactic Fentanyl Buccal Tablet on Episodic Exertional Dyspnea: A Pilot Double-Blind Randomized Controlled Trial. J Pain Symptom Manage. 2017 Dec;54(6):798-805. doi: 10.1016/j.jpainsymman.2017.08.001. Epub 2017 Aug 10.
PMID: 28803087
responsible party type: Sponsor-Investigator
investigator affiliation: University Medical Center Groningen
investigator full name: Huib A.M. Kerstjens
investigator title: Full professor pulmonology, head of department pulmonology and tuberculosis, principal investigator.
mesh term: Dyspnea
mesh term: Fentanyl
mesh term: Morphine
sharing ipd: Yes
ipd description: Upon request
ipd info type: Study Protocol
ipd info type: Informed Consent Form (ICF)
ipd time frame: After publication of results Unlimited
ipd access criteria: Clear description of goals for asking