<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/NCT03010202</url>
  </required_header>
  <id_info>
    <org_study_id>RGCH004</org_study_id>
    <nct_id>NCT03010202</nct_id>
  </id_info>
  <brief_title>The PROLONG Trial - Rituximab Maintenance Therapy in ITP</brief_title>
  <official_title>Prolonging the Response by Low-dose Rituximab Maintenance Therapy in Immune Thrombocytopenia: a Randomized Placebo-controlled Trial - the PROLONG Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ostfold Hospital Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Oslo University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>St. Olavs Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Helse Stavanger HF</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital of North Norway</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Haukeland University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Odense University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Centre Hôpital Universitaire Farhat Hached, Tunisia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Henri Mondor University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Hospital, Akershus</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hammersmith hospital, UK</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Cairo University Hospital, Egypt</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Ostfold Hospital Trust</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is a two phase study that aims to evaluate if low-dose Rituximab maintenance&#xD;
      therapy may prolong the the effect of Rituximab in immune thrombocytopenia.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a multi-center, international, randomized, two-phase study:&#xD;
&#xD;
      First phase (induction phase) is open-label, hypothesis-generating, involving 1:1&#xD;
      randomization into: rituximab (group 1) or rituximab plus dexamethasone (group 2) to&#xD;
      determine if the response to rituximab can be improved by the addition of dexamethasone.&#xD;
&#xD;
      Second Phase (maintenance phase) is the main part of the study, involving 1:1 double-blind&#xD;
      randomization into low dose rituximab or placebo to determine if the response achieved in the&#xD;
      first phase can be prolonged by administrating maintenance treatment with low dose rituximab.&#xD;
&#xD;
      Primary objective:&#xD;
&#xD;
      To determine if maintenance therapy with low-dose rituximab is superior to placebo in&#xD;
      prolonging responses among ITP patients who achieved an initial response with rituximab.&#xD;
&#xD;
      Secondary objectives:&#xD;
&#xD;
        1. To explore if the initial overall response rate, at week 24, can be improved by at least&#xD;
           10% by adding dexamethasone to rituximab (induction phase).&#xD;
&#xD;
        2. To assess the safety of study treatment, especially infectious episodes (induction &amp;&#xD;
           maintenance phases).&#xD;
&#xD;
        3. To assess bleeding complications during the study (induction &amp; maintenance phases).&#xD;
&#xD;
        4. To assess the use of rescue medications and other platelet-elevating therapies during&#xD;
           the study (induction &amp; maintenance phases).&#xD;
&#xD;
        5. To determine rate of Complete Response (CR) during induction phase and sustained CR&#xD;
           during maintenance phase (induction &amp; maintenance phases).&#xD;
&#xD;
        6. To determine the duration of overall response and CR (induction &amp; maintenance phases).&#xD;
&#xD;
        7. To assess health-related quality of life and fatigue (induction &amp; maintenance phases).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date>December 2016</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">December 2023</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Sustained of overall response</measure>
    <time_frame>52 weeks</time_frame>
    <description>sustained overall response during maintenance phase [loss of overall response is defined as: (1) two consecutive measurements with platelet counts &lt; 50 x 109/L taken at 1-8-week interval, and/or, (2) use of any ITP-directed therapies, other than study medication, because of bleeding or thrombocytopenia, except for preoperative elevation of platelet count] (this endpoint applies to maintenance phase only).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Improvement at overall response rate in week 24</measure>
    <time_frame>Week 24 (+/- 2 weeks)</time_frame>
    <description>Overall response during induction phase defined as mean platelet count, determined in week 24 (± 2 weeks) after induction therapy, &gt; 50 x 10E9/L , without use of any other ITP-directed therapies after week 12 following the first randomization (this endpoint applies to induction phase only).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety assessed by the frequency of &gt; grade II adverse events (this endpoint applies to both phases)</measure>
    <time_frame>24 weeks and 52 weeks</time_frame>
    <description>Safety assessed by the frequency of &gt; grade II adverse events (this endpoint applies to both phases).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Grade of bleeding during the study (during both phases)</measure>
    <time_frame>24 weeks and 52 weeks</time_frame>
    <description>Grade of bleeding (this endpoint applies to both phases).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sustained Complete Response (CR) during maintenance phase</measure>
    <time_frame>52 weeks</time_frame>
    <description>Sustained Complete Response (CR) during maintenance phase defined as platelet count &gt; 100 x 109/L maintained during maintenance phase, without the use of any ITP-directed therapies</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complete Response during induction phase</measure>
    <time_frame>24 weeks (+/- 2 weeks)</time_frame>
    <description>Complete Response (CR) during induction phase defined as platelet count, determined in week 24 (± 2 weeks), &gt; 100 x 109/L without use of any other ITP-directed therapies after week 12 following the first randomization (induction phase)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rescue medication or other elevating platelet therapy</measure>
    <time_frame>after 12 weeks in induction phase and 40 weeks in maintenance phase</time_frame>
    <description>Administration of rescue medication or other elevating platelet therapy&#xD;
After week 12 (induction phase)&#xD;
During maintenance phase (maintenance phase).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Platelet count Levels &gt; 50 x 109/L during maintenance phase</measure>
    <time_frame>phase 2 (52 weeks)</time_frame>
    <description>Percentage of patients with more than 80% of platelet counts level &gt; 50 x 109/L during the maintenance phase (this endpoint applies to maintenance phase only).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Health related quality of life</measure>
    <time_frame>First phase at 24 weeks and second phase at 52 weeks</time_frame>
    <description>Health-related quality of life assessed by SF-36 questionnaire (this endpoint applies to both phases).</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Purpura, Thrombocytopenic, Idiopathic</condition>
  <arm_group>
    <arm_group_label>Induction phase: Rituximab+Dexamethasone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Open-label, intravenous infusions of rituximab 1000 mg and oral dexamethasone 20 mg daily for 4 days given on day 1 and day 15.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Induction phase: Rituximab</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Open-label, intravenous infusions of rituximab 1000 mg given on day 1 and day 15.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Maintenance phase: Rituximab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients who respond to rituximab in the induction phase will be proceed into the maintenance phase and randomized to rituximab infusion of 500 mg in week 1 and week 24, or</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Maintenance phase: Placebo</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Infusion of normal saline 0,9% in week 1 ande week 24 in second randomization.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dexamethasone</intervention_name>
    <description>Comparing the effect of Rituximab infusion With or without Dexamethasone</description>
    <arm_group_label>Induction phase: Rituximab+Dexamethasone</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Comparing maintenance dose of 500mg Rituximab at week 1 and week 24 to Placebo</description>
    <arm_group_label>Maintenance phase: Rituximab</arm_group_label>
    <other_name>Mabthera</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria First randomization (Induction phase):&#xD;
&#xD;
          1. Male or female aged ≥18 years.&#xD;
&#xD;
          2. Diagnosis of primary ITP of less than one year duration having a platelet count of ≤&#xD;
             30 x109/L measured within 4 weeks prior to inclusion with failure to achieve initial&#xD;
             response or relapse either after one cycle of dexamethasone (40 mg daily for 4 days)&#xD;
             or 4 weeks with any other steroid (prednisone or prednisolone). Platelet count between&#xD;
             31 to 50 x109/L is accepted if higher platelet count is required due to concomitant&#xD;
             antiplatelet therapy or bleeding.&#xD;
&#xD;
          3. Scheduled intravenous treatment of rituximab.&#xD;
&#xD;
          4. Signed and dated written informed consent.&#xD;
&#xD;
          5. Females of child-bearing potential accepting to follow effective contraceptive methods&#xD;
             for at least 12 months following the last administration of rituximab or placebo.&#xD;
&#xD;
        Inclusion criteria second randomization (maintenance phase):&#xD;
&#xD;
          1. Completion of the induction phase (phase 1) of the study.&#xD;
&#xD;
          2. Sustained response at the end of phase 1.&#xD;
&#xD;
          3. Randomization within 4 weeks after the completion of phase 1, i.e. between week 24 and&#xD;
             28.&#xD;
&#xD;
        Exclusion Criteria first randomization (Induction phase):&#xD;
&#xD;
          1. Previous treatment for ITP with: rituximab, other immune suppressants (including&#xD;
             mycophenolate mofetil, aziothioprin, cyclosporine), chemotherapy or splenectomy.&#xD;
&#xD;
          2. Pregnancy or lactation.&#xD;
&#xD;
          3. Known active gastro-duodenal ulcer.&#xD;
&#xD;
          4. Secondary ITP: ITP associated with lymphoma, chronic lymphocytic leukemia, autoimmune&#xD;
             disorders such as, common variable immune deficiency, human immunodeficiency virus, or&#xD;
             hepatitis C or thrombocytopenia associated with myeloid dysplasia.&#xD;
&#xD;
          5. Concomitant autoimmune hemolytic anemia.&#xD;
&#xD;
          6. History of any major cardiovascular event within the 6 months prior to randomization,&#xD;
             including but not limited to: myocardial infarction, unstable angina, cerebrovascular&#xD;
             accident, or New York Heart Association Class III or IV heart failure.&#xD;
&#xD;
          7. Active hepatitis B virus or patients with positive HBsAG or HBcAB.&#xD;
&#xD;
          8. Patients with active severe infection, including systemic mycotic infections or a&#xD;
             history of recurring or chronic infections or with underlying conditions which may&#xD;
             further predispose patients to serious infection.&#xD;
&#xD;
          9. Known allergy and/or sensitivity or contraindication to rituximab or dexamethasone or&#xD;
             any of the ingredients.&#xD;
&#xD;
         10. Patients in a severely immune compromised state.&#xD;
&#xD;
         11. Known contraindication to a treatment with any proton-pump inhibitor.&#xD;
&#xD;
         12. Active malignancy or history of malignant disease during the last 2 years except cured&#xD;
             skin cancer.&#xD;
&#xD;
         13. Patients with history of poor compliance or history of alcohol/drug abuse or excessive&#xD;
             alcohol beverage consumption that would interfere with the ability to comply with the&#xD;
             study protocol, or current or past psychiatric disease that might interfere with the&#xD;
             ability to comply with the study protocol or give informed consent.&#xD;
&#xD;
        Exclusion criteria second randomization (maintenance phase) 14. Severe allergic reaction or&#xD;
        serum sickness due to rituximab in phase 1 of the study.&#xD;
&#xD;
        15. Pregnancy. 16. Treatment with rescue medication after week 18. 17. Patients refusing to&#xD;
        continue in the study (withdrawal of consent). 18. Splenectomy performed for any cause.&#xD;
&#xD;
        -&#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>Waleed Ghanima, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ostfold Hospital Trust</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Waleed Ghanima, PhD</last_name>
    <phone>+47 41303440</phone>
    <email>wghanima@gmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Pål André Holme, PhD</last_name>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Ostfold Hospital Trust</name>
      <address>
        <city>Sarpsborg</city>
        <zip>1714</zip>
        <country>Norway</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Waleed Ghanima, PhD</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Norway</country>
  </location_countries>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>December 28, 2016</study_first_submitted>
  <study_first_submitted_qc>January 3, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 4, 2017</study_first_posted>
  <last_update_submitted>November 10, 2020</last_update_submitted>
  <last_update_submitted_qc>November 10, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 13, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>immune thrombocytopenia</keyword>
  <keyword>rituximab</keyword>
  <keyword>thrombocytopenia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thrombocytopenia</mesh_term>
    <mesh_term>Purpura</mesh_term>
    <mesh_term>Purpura, Thrombocytopenic, Idiopathic</mesh_term>
    <mesh_term>Purpura, Thrombocytopenic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Rituximab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03010202
org study id: RGCH004
nct id: NCT03010202
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
This study is a two phase study that aims to evaluate if low-dose Rituximab maintenance
      therapy may prolong the the effect of Rituximab in immune thrombocytopenia.
This is a multi-center, international, randomized, two-phase study:

      First phase (induction phase) is open-label, hypothesis-generating, involving 1:1
      randomization into: rituximab (group 1) or rituximab plus dexamethasone (group 2) to
      determine if the response to rituximab can be improved by the addition of dexamethasone.

      Second Phase (maintenance phase) is the main part of the study, involving 1:1 double-blind
      randomization into low dose rituximab or placebo to determine if the response achieved in the
      first phase can be prolonged by administrating maintenance treatment with low dose rituximab.

      Primary objective:

      To determine if maintenance therapy with low-dose rituximab is superior to placebo in
      prolonging responses among ITP patients who achieved an initial response with rituximab.

      Secondary objectives:

        1. To explore if the initial overall response rate, at week 24, can be improved by at least
           10% by adding dexamethasone to rituximab (induction phase).

        2. To assess the safety of study treatment, especially infectious episodes (induction &
           maintenance phases).

        3. To assess bleeding complications during the study (induction & maintenance phases).

        4. To assess the use of rescue medications and other platelet-elevating therapies during
           the study (induction & maintenance phases).

        5. To determine rate of Complete Response (CR) during induction phase and sustained CR
           during maintenance phase (induction & maintenance phases).

        6. To determine the duration of overall response and CR (induction & maintenance phases).

        7. To assess health-related quality of life and fatigue (induction & maintenance phases).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Sustained of overall response
time frame: 52 weeks
description: sustained overall response during maintenance phase [loss of overall response is defined as: (1) two consecutive measurements with platelet counts < 50 x 109/L taken at 1-8-week interval, and/or, (2) use of any ITP-directed therapies, other than study medication, because of bleeding or thrombocytopenia, except for preoperative elevation of platelet count] (this endpoint applies to maintenance phase only).
measure: Improvement at overall response rate in week 24
time frame: Week 24 (+/- 2 weeks)
description: Overall response during induction phase defined as mean platelet count, determined in week 24 (± 2 weeks) after induction therapy, > 50 x 10E9/L , without use of any other ITP-directed therapies after week 12 following the first randomization (this endpoint applies to induction phase only).
measure: Safety assessed by the frequency of > grade II adverse events (this endpoint applies to both phases)
time frame: 24 weeks and 52 weeks
description: Safety assessed by the frequency of > grade II adverse events (this endpoint applies to both phases).
measure: Grade of bleeding during the study (during both phases)
time frame: 24 weeks and 52 weeks
description: Grade of bleeding (this endpoint applies to both phases).
measure: Sustained Complete Response (CR) during maintenance phase
time frame: 52 weeks
description: Sustained Complete Response (CR) during maintenance phase defined as platelet count > 100 x 109/L maintained during maintenance phase, without the use of any ITP-directed therapies
measure: Complete Response during induction phase
time frame: 24 weeks (+/- 2 weeks)
description: Complete Response (CR) during induction phase defined as platelet count, determined in week 24 (± 2 weeks), > 100 x 109/L without use of any other ITP-directed therapies after week 12 following the first randomization (induction phase)
measure: Rescue medication or other elevating platelet therapy
time frame: after 12 weeks in induction phase and 40 weeks in maintenance phase
description: Administration of rescue medication or other elevating platelet therapy
After week 12 (induction phase)
During maintenance phase (maintenance phase).
measure: Platelet count Levels > 50 x 109/L during maintenance phase
time frame: phase 2 (52 weeks)
description: Percentage of patients with more than 80% of platelet counts level > 50 x 109/L during the maintenance phase (this endpoint applies to maintenance phase only).
measure: Health related quality of life
time frame: First phase at 24 weeks and second phase at 52 weeks
description: Health-related quality of life assessed by SF-36 questionnaire (this endpoint applies to both phases).
arm group label: Induction phase: Rituximab+Dexamethasone
arm group type: Experimental
description: Open-label, intravenous infusions of rituximab 1000 mg and oral dexamethasone 20 mg daily for 4 days given on day 1 and day 15.
arm group label: Induction phase: Rituximab
arm group type: No Intervention
description: Open-label, intravenous infusions of rituximab 1000 mg given on day 1 and day 15.
arm group label: Maintenance phase: Rituximab
arm group type: Experimental
description: Patients who respond to rituximab in the induction phase will be proceed into the maintenance phase and randomized to rituximab infusion of 500 mg in week 1 and week 24, or
arm group label: Maintenance phase: Placebo
arm group type: No Intervention
description: Infusion of normal saline 0,9% in week 1 ande week 24 in second randomization.
intervention type: Drug
intervention name: Dexamethasone
description: Comparing the effect of Rituximab infusion With or without Dexamethasone
arm group label: Induction phase: Rituximab+Dexamethasone
intervention type: Drug
intervention name: Rituximab
description: Comparing maintenance dose of 500mg Rituximab at week 1 and week 24 to Placebo
arm group label: Maintenance phase: Rituximab
other name: Mabthera
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Waleed Ghanima, PhD
role: Principal Investigator
affiliation: Ostfold Hospital Trust
last name: Waleed Ghanima, PhD
phone: +47 41303440
email: wghanima@gmail.com
last name: Pål André Holme, PhD
facility: 
status: Recruiting
contact: 
country: Norway
responsible party type: Sponsor
mesh term: Thrombocytopenia
mesh term: Purpura
mesh term: Purpura, Thrombocytopenic, Idiopathic
mesh term: Purpura, Thrombocytopenic
mesh term: Dexamethasone
mesh term: Rituximab
sharing ipd: Undecided