<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/NCT01669499</url>
  </required_header>
  <id_info>
    <org_study_id>ZonMW 11510009</org_study_id>
    <nct_id>NCT01669499</nct_id>
  </id_info>
  <brief_title>Dexamethasone for Pain Flare After Radiotherapy of Painful Bone metastasesZonMW 11510009</brief_title>
  <official_title>Dexamethasone for the Prevention of a Pain Flare After Palliative Radiotherapy for Painful Bone Metastases: a Multi-center Double-blind Placebo-controlled Randomized Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>UMC Utrecht</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>ZonMw: The Netherlands Organisation for Health Research and Development</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>UMC Utrecht</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Cancer patients with pain due to bone metastases are often treated with external irradiation&#xD;
      in order to reduce pain. However, patients may experience a temporary increase of pain&#xD;
      shortly after irradiation, a so-called pain flare. This study investigates whether a short&#xD;
      course of a drug called dexamethasone may prevent the occurrence of a pain flare. Patients,&#xD;
      who are irradiated for painful bone metastases are randomized into three groups. Group 1&#xD;
      receives placebo during four days, group 2 receives dexamethasone on the day of the&#xD;
      irradiation and placebo during three days, and group 3 receives dexamethasone during four&#xD;
      days. All patients complete a questionnaire on pain, side-effects of treatment and quality of&#xD;
      life during 14 days and after four weeks. This study will define whether dexamethasone&#xD;
      decreases the occurrence of a pain flare after irradiation for painful bone metastases, and,&#xD;
      if so, whether four days of treatment with dexamethasone is better dan one day of treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background of the study:&#xD;
&#xD;
      Patients with pain due to bone metastases are often treated with palliative short schedule&#xD;
      external beam radiotherapy. Dependent on the institutional protocols, single fraction (8 Gy)&#xD;
      or 5-6 fractions of 4 Gy are usually applied. Randomized studies have shown the equal&#xD;
      effectiveness of both schedules in treating pain, with almost 70% of patients experiencing&#xD;
      less or no pain within three to four weeks after treatment (Wu 2003). However, within 10 days&#xD;
      after treatment a short term transient progression of pain may occur, the so-called pain&#xD;
      flare (Chow 2005, Loblaw 2007, Hird 2009-1). Two prospective observational studies reported&#xD;
      patient-based daily pain scores after radiotherapy for painful bone metastases. Loblaw showed&#xD;
      a pain flare in 44% patients after 8 Gy and in 24% patients after 20 Gy in 4 fractions&#xD;
      (Loblaw 2007). The median duration of the pain flare was three days. A recent publication&#xD;
      found no difference in pain flare in 111 patients after single vs. multiple fractions (39%&#xD;
      vs. 41%, resp.) (Hird 2009-1). No data are available of the occurrence of pain flare in Dutch&#xD;
      patients. The largest trial to date on painful bone metastases, the Dutch Bone Metastasis&#xD;
      Study, was funded by OG and CKTO and randomized from 1996-1998 a total of 1157 patients&#xD;
      between 8 Gy single fraction and 24 Gy in 6 fractions (PhD thesis, van der Linden 2005).&#xD;
      Follow-up consisted of 12 weekly and thereafter monthly questionnaires on pain, pain&#xD;
      medication and quality of life. In this study, daily scoring of pain to asses pain flare was&#xD;
      not performed. When a pain flare occurs oral dexamethasone can be prescribed. The rationale&#xD;
      for administering steroids is to decrease edema that arises in the periostium of the affected&#xD;
      bone shortly after radiotherapy and thereby to reduce pain (de Graeff 2006). Two small&#xD;
      studies were performed to study the effectiveness of dexamethasone for treating a pain flare&#xD;
      (Chow 2007, Hird 2009-2). Chow et al. administered 8 mg dexamethasone to 23 patients one hour&#xD;
      before single fraction treatment and showed pain flare in only 24% of patients (95% CI&#xD;
      10-39%) within the first 10 days after radiotherapy (Chow 2007). Only one patient had a flare&#xD;
      within two days after treatment. Dexamethasone was well tolerated. In a fase 2 study of the&#xD;
      same research group 41 patients were administered 8 mg dexamethasone before and then for&#xD;
      three consecutive days after single fraction treatment. They showed a pain flare in 22% of&#xD;
      patients (with a median duration of one day), with 81% occurring within five days after&#xD;
      treatment, and 95% within 10 days (Hird 2009-2). Both studies concluded that randomized&#xD;
      studies are necessary to collect unbiased data on the occurrence and duration of pain flare&#xD;
      and the effectiveness of drug treatment. Until now, no randomized studies were performed&#xD;
      comparing dexamethasone with placebo or no treatment. The effectiveness of placebo vs.&#xD;
      dexamethasone in the treatment of pain flare in patients after radiotherapy for painful bone&#xD;
      metastases is the subject of this study.&#xD;
&#xD;
      Aim of the study To study the effectiveness and toxicity of dexamethasone to prevent the&#xD;
      occurrence of a pain flare after short schedule radiotherapy for painful bone metastases and&#xD;
      to define the optimal schedule of dosing.&#xD;
&#xD;
      Research questions:&#xD;
&#xD;
        1. What is the effectiveness of dexamethasone to prevent the occurrence of a pain flare&#xD;
           after short schedule radiotherapy for painful bone metastases?&#xD;
&#xD;
        2. Is there a difference in effectiveness between a single dose of 8 mg dexamethasone&#xD;
           before radiotherapy or a dose of 8 mg dexamethasone before radiotherapy in combination&#xD;
           with three additional doses during the three following days?&#xD;
&#xD;
        3. What are the side effects of dexamethasone and placebo in patients treated with&#xD;
           radiotherapy for painful bone metastases? 4. Does a pain flare predict for pain response&#xD;
           to radiotherapy?&#xD;
&#xD;
      Study design:&#xD;
&#xD;
      This study is a randomized, controlled, multicenter study in 411 patients with painful bone&#xD;
      metastases who are referred for a short course of palliative radiotherapy. Short course&#xD;
      radiotherapy encompasses all treatment schedules from one to six fractions of radiotherapy.&#xD;
      The study consists of three arms:&#xD;
&#xD;
        -  Arm 1: day 0: placebo, day 1, 2 en 3: placebo&#xD;
&#xD;
        -  Arm 2: day 0: 8 mg dexamethasone, day 1, 2 en 3: placebo&#xD;
&#xD;
        -  Arm 3: day 0: 8 mg dexamethasone, day 1, 2 en 3: 8 mg dexamethasone Day 0 is the first&#xD;
           day of radiotherapy treatment. On day 0 the tablet of placebo or dexamethasone will be&#xD;
           administered one hour before radiotherapy. On day 1, 2, and 3 the tablet of placebo or&#xD;
           dexamethasone will be taken in the morning at about 8 a.m.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2012</start_date>
  <completion_date type="Actual">April 2016</completion_date>
  <primary_completion_date type="Actual">April 2016</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>Supportive Care</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The occurrence of a pain flare.</measure>
    <time_frame>Within 2 weeks after irradiation</time_frame>
    <description>A pain flare is defined by a two-point increase after radiotherapy of the worst pain score on Pain flare is defined as an 11-point scale of 0 (no pain) to 10 (worst imaginable pain) compared to baseline without a decrease in analgesic intake, or a 25% increase in analgesic intake without decrease in worst pain score (according to international bone metastases consensus guidelines) (Chow 2007).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pain scores</measure>
    <time_frame>Days 1-14 and 28</time_frame>
    <description>Pain scores as measured by BPI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life</measure>
    <time_frame>Days 7, 14 and 28</time_frame>
    <description>As measured by the quality of life scale of the EORTC PAL15</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Side effects</measure>
    <time_frame>Day 1-14</time_frame>
    <description>As measured by questionnaire</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">411</enrollment>
  <condition>Bone Metastases</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo on day 0-3</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dexamethasone acetate day 0</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>8 mg dexamethasone on day 0</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dexamethasone acetate day 0-3</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>8 mg dexamethasone on day 0-3</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dexamethasone acetate</intervention_name>
    <arm_group_label>Dexamethasone acetate day 0</arm_group_label>
    <arm_group_label>Dexamethasone acetate day 0-3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Dexamethasone acetate day 0</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients of 18 years or older&#xD;
&#xD;
          -  Uncomplicated painful bone metastases&#xD;
&#xD;
          -  Primary malignancy is a solid tumour • Pain intensity on a numeric rating scale of 2-8&#xD;
&#xD;
          -  No immediately expected change in the analgesic regimen.&#xD;
&#xD;
          -  Indication for single or short course radiotherapy&#xD;
&#xD;
          -  Able to fill out Dutch questionnaires&#xD;
&#xD;
          -  Able to follow instructions&#xD;
&#xD;
          -  Informed consent provided&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with hematological malignancy&#xD;
&#xD;
          -  Multliple sites to be irradiated&#xD;
&#xD;
          -  Patients who have been treated before with palliative radiotherapy for painful bone&#xD;
             metastases&#xD;
&#xD;
          -  Current use of steroids (dexamethasone, prednisolone or other), or use up to less than&#xD;
             a week before randomization&#xD;
&#xD;
          -  Long-term schedule radiotherapy (&gt;6 fractions)&#xD;
&#xD;
          -  Life expectancy shorter than 8 weeks&#xD;
&#xD;
          -  Karnofsky Performance Score of 40 or less&#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>Alexander de Graeff, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical Oncologist</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Leiden University Medical Centre</name>
      <address>
        <city>Leiden</city>
        <state>Zuid-Holland</state>
        <zip>2333 ZA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Medical Center Utrecht</name>
      <address>
        <city>Utrecht</city>
        <zip>3485 CX</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>November 2016</verification_date>
  <study_first_submitted>August 16, 2012</study_first_submitted>
  <study_first_submitted_qc>August 20, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 21, 2012</study_first_posted>
  <last_update_submitted>November 15, 2016</last_update_submitted>
  <last_update_submitted_qc>November 15, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">November 16, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>UMC Utrecht</investigator_affiliation>
    <investigator_full_name>A. de Graeff</investigator_full_name>
    <investigator_title>Associate professor</investigator_title>
  </responsible_party>
  <keyword>Bone metastases, radiotherapy, dexamethasone, pain flare</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Bone Neoplasms</mesh_term>
    <mesh_term>Bone Marrow Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Dexamethasone acetate</mesh_term>
    <mesh_term>BB 1101</mesh_term>
  </intervention_browse>
  <!-- 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/NCT01669499
org study id: ZonMW 11510009
nct id: NCT01669499
lead sponsor: 
collaborator: 
has dmc: Yes
Cancer patients with pain due to bone metastases are often treated with external irradiation
      in order to reduce pain. However, patients may experience a temporary increase of pain
      shortly after irradiation, a so-called pain flare. This study investigates whether a short
      course of a drug called dexamethasone may prevent the occurrence of a pain flare. Patients,
      who are irradiated for painful bone metastases are randomized into three groups. Group 1
      receives placebo during four days, group 2 receives dexamethasone on the day of the
      irradiation and placebo during three days, and group 3 receives dexamethasone during four
      days. All patients complete a questionnaire on pain, side-effects of treatment and quality of
      life during 14 days and after four weeks. This study will define whether dexamethasone
      decreases the occurrence of a pain flare after irradiation for painful bone metastases, and,
      if so, whether four days of treatment with dexamethasone is better dan one day of treatment.
Background of the study:

      Patients with pain due to bone metastases are often treated with palliative short schedule
      external beam radiotherapy. Dependent on the institutional protocols, single fraction (8 Gy)
      or 5-6 fractions of 4 Gy are usually applied. Randomized studies have shown the equal
      effectiveness of both schedules in treating pain, with almost 70% of patients experiencing
      less or no pain within three to four weeks after treatment (Wu 2003). However, within 10 days
      after treatment a short term transient progression of pain may occur, the so-called pain
      flare (Chow 2005, Loblaw 2007, Hird 2009-1). Two prospective observational studies reported
      patient-based daily pain scores after radiotherapy for painful bone metastases. Loblaw showed
      a pain flare in 44% patients after 8 Gy and in 24% patients after 20 Gy in 4 fractions
      (Loblaw 2007). The median duration of the pain flare was three days. A recent publication
      found no difference in pain flare in 111 patients after single vs. multiple fractions (39%
      vs. 41%, resp.) (Hird 2009-1). No data are available of the occurrence of pain flare in Dutch
      patients. The largest trial to date on painful bone metastases, the Dutch Bone Metastasis
      Study, was funded by OG and CKTO and randomized from 1996-1998 a total of 1157 patients
      between 8 Gy single fraction and 24 Gy in 6 fractions (PhD thesis, van der Linden 2005).
      Follow-up consisted of 12 weekly and thereafter monthly questionnaires on pain, pain
      medication and quality of life. In this study, daily scoring of pain to asses pain flare was
      not performed. When a pain flare occurs oral dexamethasone can be prescribed. The rationale
      for administering steroids is to decrease edema that arises in the periostium of the affected
      bone shortly after radiotherapy and thereby to reduce pain (de Graeff 2006). Two small
      studies were performed to study the effectiveness of dexamethasone for treating a pain flare
      (Chow 2007, Hird 2009-2). Chow et al. administered 8 mg dexamethasone to 23 patients one hour
      before single fraction treatment and showed pain flare in only 24% of patients (95% CI
      10-39%) within the first 10 days after radiotherapy (Chow 2007). Only one patient had a flare
      within two days after treatment. Dexamethasone was well tolerated. In a fase 2 study of the
      same research group 41 patients were administered 8 mg dexamethasone before and then for
      three consecutive days after single fraction treatment. They showed a pain flare in 22% of
      patients (with a median duration of one day), with 81% occurring within five days after
      treatment, and 95% within 10 days (Hird 2009-2). Both studies concluded that randomized
      studies are necessary to collect unbiased data on the occurrence and duration of pain flare
      and the effectiveness of drug treatment. Until now, no randomized studies were performed
      comparing dexamethasone with placebo or no treatment. The effectiveness of placebo vs.
      dexamethasone in the treatment of pain flare in patients after radiotherapy for painful bone
      metastases is the subject of this study.

      Aim of the study To study the effectiveness and toxicity of dexamethasone to prevent the
      occurrence of a pain flare after short schedule radiotherapy for painful bone metastases and
      to define the optimal schedule of dosing.

      Research questions:

        1. What is the effectiveness of dexamethasone to prevent the occurrence of a pain flare
           after short schedule radiotherapy for painful bone metastases?

        2. Is there a difference in effectiveness between a single dose of 8 mg dexamethasone
           before radiotherapy or a dose of 8 mg dexamethasone before radiotherapy in combination
           with three additional doses during the three following days?

        3. What are the side effects of dexamethasone and placebo in patients treated with
           radiotherapy for painful bone metastases? 4. Does a pain flare predict for pain response
           to radiotherapy?

      Study design:

      This study is a randomized, controlled, multicenter study in 411 patients with painful bone
      metastases who are referred for a short course of palliative radiotherapy. Short course
      radiotherapy encompasses all treatment schedules from one to six fractions of radiotherapy.
      The study consists of three arms:

        -  Arm 1: day 0: placebo, day 1, 2 en 3: placebo

        -  Arm 2: day 0: 8 mg dexamethasone, day 1, 2 en 3: placebo

        -  Arm 3: day 0: 8 mg dexamethasone, day 1, 2 en 3: 8 mg dexamethasone Day 0 is the first
           day of radiotherapy treatment. On day 0 the tablet of placebo or dexamethasone will be
           administered one hour before radiotherapy. On day 1, 2, and 3 the tablet of placebo or
           dexamethasone will be taken in the morning at about 8 a.m.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Supportive Care
masking: Triple (Participant, Care Provider, Investigator)
measure: The occurrence of a pain flare.
time frame: Within 2 weeks after irradiation
description: A pain flare is defined by a two-point increase after radiotherapy of the worst pain score on Pain flare is defined as an 11-point scale of 0 (no pain) to 10 (worst imaginable pain) compared to baseline without a decrease in analgesic intake, or a 25% increase in analgesic intake without decrease in worst pain score (according to international bone metastases consensus guidelines) (Chow 2007).
measure: Pain scores
time frame: Days 1-14 and 28
description: Pain scores as measured by BPI
measure: Quality of life
time frame: Days 7, 14 and 28
description: As measured by the quality of life scale of the EORTC PAL15
measure: Side effects
time frame: Day 1-14
description: As measured by questionnaire
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo on day 0-3
arm group label: Dexamethasone acetate day 0
arm group type: Active Comparator
description: 8 mg dexamethasone on day 0
arm group label: Dexamethasone acetate day 0-3
arm group type: Active Comparator
description: 8 mg dexamethasone on day 0-3
intervention type: Drug
intervention name: Dexamethasone acetate
arm group label: Dexamethasone acetate day 0
arm group label: Dexamethasone acetate day 0-3
intervention type: Drug
intervention name: Placebo
arm group label: Dexamethasone acetate day 0
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Alexander de Graeff, MD, PhD
role: Principal Investigator
affiliation: Medical Oncologist
facility: 
facility: 
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: UMC Utrecht
investigator full name: A. de Graeff
investigator title: Associate professor
mesh term: Neoplasm Metastasis
mesh term: Bone Neoplasms
mesh term: Bone Marrow Diseases
mesh term: Dexamethasone
mesh term: Dexamethasone acetate
mesh term: BB 1101