<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/NCT01694836</url>
  </required_header>
  <id_info>
    <org_study_id>603-PG-PSC-191</org_study_id>
    <secondary_id>2012-000414-11</secondary_id>
    <nct_id>NCT01694836</nct_id>
  </id_info>
  <brief_title>Depigoid Birch 5000 Longterm Study in Adults and Adolescents</brief_title>
  <official_title>Multicenter, Placebo-controlled, Long-term Study of Depigoid Birch 5000 in Adults and Adolescents With Allergic Rhinitis and/or Rhinoconjunctivitis With or Without Intermittent Asthma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Leti Pharma GmbH</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Leti Pharma GmbH</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Specific immunotherapy for IgE mediated sensitization to birch pollen. Long-term study to&#xD;
      assess safety and efficacy of Depigoid(R)Birch 5000 - a modified pollen extract of Betula&#xD;
      alba (Birch) - versus placebo.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Investigation of the long-term efficacy and safety of Depigoid Birch 5000 according to the&#xD;
      perennial treatment regimen in comparison to placebo in adult and adolescent patients with&#xD;
      birch pollen-induced allergic rhinitis and/or rhinoconjunctivitis to show superiority vs.&#xD;
      placebo.&#xD;
&#xD;
      As the study includes adolescent patients it is run under an approved PIP.&#xD;
&#xD;
      Total study duration per patient will be 5 years: 3 years of perennial treatment (application&#xD;
      of study medication at intervals of 4-6 weeks) followed by a treatment-free observational&#xD;
      phase of 2 years (seasons).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 17, 2012</start_date>
  <completion_date type="Actual">July 30, 2018</completion_date>
  <primary_completion_date type="Actual">July 30, 2018</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proof of efficacy (superiority vs. placebo) by means of the combined Symptom and Medication Score (SMS).</measure>
    <time_frame>after 5 years</time_frame>
    <description>For the primary outcome the SMS of nasal and ocular symptoms and their respective Rescue Medication score is used to assess efficacy of the perennial treatment regimen of Depigoid Birch 5000 DPP/mL versus placebo after 5 years (comprising 3 years of treatment plus 2 years treatment-free follow-up). An interim analysis will be conducted after 2 years.&#xD;
Data are captured via eDiary to be completed by the patients during each of the 5 pollen seasons within the duration of the study, starting prior to onset of pollen flight until after the end of the pollen seasons.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Symptom score (SS) during the 1st, 3rd, and 4th pollen seasons.</measure>
    <time_frame>after 1 year, 2 years, 3 years, 4 years and 5 years</time_frame>
    <description>Differences between treatment groups also including pulmonary symptoms and for asthmatic/non-asthmatic patients.&#xD;
Data are captured via eDiary to be completed by the patients during each of the 5 pollen seasons within the duration of the study, starting prior to onset of pollen flight until after the end of the pollen seasons.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rescue Medication Score (RMS) during the 1st, 3rd, and 4th pollen season (futility and interim analyses).</measure>
    <time_frame>after 1 year, 2 years, 3 years, 4 years and 5 years</time_frame>
    <description>Differences between treatment groups also including pulmonary symptoms and for asthmatic/non-asthmatic patients.&#xD;
Data are captured via eDiary to be completed by the patients during each of the 5 pollen seasons within the duration of the study, starting prior to onset of pollen flight until afte the end of the pollen seasons.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>combined Symptoms and Rescue Medication Score (SMS) during the 1st, 3rd, and 4th pollen season including pulmonary symptoms.</measure>
    <time_frame>after 1 year, 2 years, 3 years and 4 years</time_frame>
    <description>Differences between treatment groups, during all 5 pollen seasons also including pulmonary symptoms and for asthmatic/non-asthmatic patients.&#xD;
Data are captured via eDiary to be completed by the patients during each of the 5 pollen seasons within the duration of the study, starting prior to onset of pollen flight until after the end of the pollen seasons.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rhinitis Quality of Life Questionnaire (RQLQ) resp. RQLQ for adolescent patients (AdolRQLQ)</measure>
    <time_frame>Screening and after 1 year, 2 years, 3 years, 4 years and 5 years</time_frame>
    <description>Changes to baseline and difference between treatment groups during all 5 pollen seasons</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunology parameters (Total IgE, specific IgE, specific IgG1 and IgG4)</measure>
    <time_frame>Screening, after years 1, 2, 3 and 5 (resp. end of study)</time_frame>
    <description>Differences within patients and between treatment groups</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease modifying effect after 5 years</measure>
    <time_frame>after 5 years</time_frame>
    <description>Difference between treatment groups. Incidence of asthma and new sensitizations.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical chemistry: Number of patients with outside range values</measure>
    <time_frame>Screening, after years 2, 3 and 5</time_frame>
    <description>Differences between treatment groups</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events: number of patients with AEs/SAEs</measure>
    <time_frame>throughout the whole study duration</time_frame>
    <description>Including symptoms reported by patients in eDiary. Differences between treatment groups including but not limited to differences in severity levels of systemic reactions (SRs), immediate and local reaction including calculation of ratios per injection</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum levels of Aluminium hydroxide (Pharmacokinetics)</measure>
    <time_frame>prior and after 1st and 2nd application of IMP and after 1 year</time_frame>
    <description>Serum Aluminium hydroxide levels are assessed in a subgroup of 24 patients. Differences between treatment groups (adult patients only) Sampling: prior to 1st application of IMP, 4 time points after 1st, 2nd and 10th application (after 1 year). 24 hrs. urine at these 3 time points</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Vitamin D3 level</measure>
    <time_frame>baseline and end of study</time_frame>
    <description>Possible influence on specific immunotherapy. Exploratory evaluation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hematology: Number of patients with outside range values</measure>
    <time_frame>Screening, after years 2, 3 and 5</time_frame>
    <description>Differences between treatment groups</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">634</enrollment>
  <condition>Allergic Rhinitis/Rhinoconjunctivitis +-Intermittent Asthma</condition>
  <condition>Sensitization Against Betula Alba (Birch) Pollen</condition>
  <arm_group>
    <arm_group_label>Depigoid Birch 5.000 DPP/ml</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Suspension for s.c. injection. Treatment schedule:&#xD;
Build-up phase (1 day: 0,2 ml+0,3 ml at interval of 30 minutes)&#xD;
Maintenance phase (3 years: 0,5 ml at intervals of 4-6 weeks)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Suspension for s.c. injection. Treatment schedule:&#xD;
Build-up phase (1 day: 0,2 ml+0,3 ml at interval of 30 minutes)&#xD;
Maintenance phase (3 years: 0,5 ml at intervals of 4-6 weeks)</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>s.c. injection</intervention_name>
    <description>3 years of therapy followed by 2 years (seasons) of treatment-free observational period</description>
    <arm_group_label>Depigoid Birch 5.000 DPP/ml</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Depigoid(R)Birch</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Availability of an appropriately signed and dated informed consent before any study&#xD;
             specific examination,&#xD;
&#xD;
          -  Clinical history of at least 2 years of seasonal allergic rhinitis and/or&#xD;
             rhinoconjunctivitis with or without intermittent asthma due to birch pollen allergy&#xD;
             that has required repeated use of symptomatic treatment,&#xD;
&#xD;
          -  Patients must have a minimum level of perception of symptoms from previous seasons&#xD;
             defined as at least a moderate symptom level (i.e. a score of 2 on the 4-point-Likert&#xD;
             scale) in at least 2 symptom categories prior to randomization,&#xD;
&#xD;
          -  Lung function ≥ 80% of the predicted normal value,&#xD;
&#xD;
          -  IgE-mediated sensitization has to be verified by:&#xD;
&#xD;
               -  suggestive medical history, and&#xD;
&#xD;
               -  specific IgE reactivity to birch pollen (CAP-RAST ≥ 2), and&#xD;
&#xD;
               -  a positive SPT to birch pollen at screening or within 1 months prior to the&#xD;
                  screening visit. An SPT is considered positive if it results in a wheal diameter&#xD;
                  of at least 3.0 mm&#xD;
&#xD;
          -  Internet access so that patients can complete the eDiary daily via internet during all&#xD;
             5 pollen seasons covered by the study protocol.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of significant clinical manifestations of allergy as a result of sensitization&#xD;
             against co-allergies, particularly-but not limited to-grass or weed pollen and&#xD;
             perennial allergens (e.g. house dust mites, cat or dog).&#xD;
&#xD;
          -  History of anaphylactic reaction.&#xD;
&#xD;
          -  Moderate or severe persistent asthma (GINA 3 or 4).&#xD;
&#xD;
          -  Mild persistent asthma (GINA 2), according to the Global Initiative for Asthma&#xD;
             Guidelines, necessitating treatment with inhaled glucocorticoids at a daily dose level&#xD;
             of &gt; 400 µg budesonide dose equivalents.&#xD;
&#xD;
          -  Lung function &lt; 80% of the predicted normal value (for PEF: highest result of 3&#xD;
             measurements).&#xD;
&#xD;
          -  Acute or chronic inflammatory or infectious airway diseases including recurrent acute&#xD;
             or chronic sinusitis.&#xD;
&#xD;
          -  Chronic structural diseases of the affected organs (e.g. eye, nose, lung).&#xD;
&#xD;
          -  History or presence of confirmed or potential diseases of the immune system including&#xD;
             autoimmune diseases and immune deficiencies of actual clinical relevance.&#xD;
&#xD;
          -  Any disease that prohibits the use of adrenaline (e.g. hyperthyroidism).&#xD;
&#xD;
          -  Atopic dermatitis with SCORAD &gt;30 in the past or at screening.&#xD;
&#xD;
          -  Ongoing or past full courses of SIT against birch pollen within the last 5 years.&#xD;
&#xD;
          -  Topical and systemic treatment with β-blockers.&#xD;
&#xD;
          -  Concomitant treatment with substances interfering with the immune system beginning 1&#xD;
             week prior to start of treatment.&#xD;
&#xD;
          -  Use of systemic corticosteroids within 3 months prior to Visit 1-1.&#xD;
&#xD;
          -  Immunization with vaccines within 7 days prior to Visit 1-1.&#xD;
&#xD;
          -  Treatment with antihistamines for any reason other than allergic symptoms due to birch&#xD;
             pollen allergy.&#xD;
&#xD;
          -  Changed residence between geographical regions since the last birch pollen season or&#xD;
             not staying in the geographical region during the pre-determined birch pollen season.&#xD;
&#xD;
          -  Nursing (lactating) women or women with a positive pregnancy test at the screening&#xD;
             visit. Women of childbearing potential must be using highly effective contraception&#xD;
             during participation in this clinical study. A highly effective method of birth&#xD;
             control is defined as one that results in a low failure rate (i.e. less than 1% per&#xD;
             year) when used consistently and correctly, such as implants, injectables, combined&#xD;
             oral contraceptives, some IUDs, sexual abstinence, or vasectomised partner.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Natalja Novak, Prof. Dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Klinik für Dermatologie und Allergologie der Universität Bonn</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Angelika Sager, Dr. med.</last_name>
    <role>Study Director</role>
    <affiliation>Leti Pharma GmbH</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hautarztpraxis</name>
      <address>
        <city>Berlin</city>
        <zip>13057</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinik und Poliklinik für Dermatologie und Allergologie der Universität</name>
      <address>
        <city>Bonn</city>
        <zip>53105</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>August 27, 2012</study_first_submitted>
  <study_first_submitted_qc>September 26, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 27, 2012</study_first_posted>
  <last_update_submitted>January 15, 2019</last_update_submitted>
  <last_update_submitted_qc>January 15, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">January 16, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Allergic rhinitis</keyword>
  <keyword>Allergic rhinoconjunctivitis</keyword>
  <keyword>Allergy induced asthma</keyword>
  <keyword>Birch (Betula alba)</keyword>
  <keyword>Hayfever</keyword>
  <keyword>Immunotherapy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rhinitis</mesh_term>
    <mesh_term>Asthma</mesh_term>
    <mesh_term>Rhinitis, Allergic</mesh_term>
    <mesh_term>Conjunctivitis</mesh_term>
  </condition_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/NCT01694836
org study id: 603-PG-PSC-191
secondary id: 2012-000414-11
nct id: NCT01694836
lead sponsor: 
has dmc: Yes
Specific immunotherapy for IgE mediated sensitization to birch pollen. Long-term study to
      assess safety and efficacy of Depigoid(R)Birch 5000 - a modified pollen extract of Betula
      alba (Birch) - versus placebo.
Investigation of the long-term efficacy and safety of Depigoid Birch 5000 according to the
      perennial treatment regimen in comparison to placebo in adult and adolescent patients with
      birch pollen-induced allergic rhinitis and/or rhinoconjunctivitis to show superiority vs.
      placebo.

      As the study includes adolescent patients it is run under an approved PIP.

      Total study duration per patient will be 5 years: 3 years of perennial treatment (application
      of study medication at intervals of 4-6 weeks) followed by a treatment-free observational
      phase of 2 years (seasons).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Proof of efficacy (superiority vs. placebo) by means of the combined Symptom and Medication Score (SMS).
time frame: after 5 years
description: For the primary outcome the SMS of nasal and ocular symptoms and their respective Rescue Medication score is used to assess efficacy of the perennial treatment regimen of Depigoid Birch 5000 DPP/mL versus placebo after 5 years (comprising 3 years of treatment plus 2 years treatment-free follow-up). An interim analysis will be conducted after 2 years.
Data are captured via eDiary to be completed by the patients during each of the 5 pollen seasons within the duration of the study, starting prior to onset of pollen flight until after the end of the pollen seasons.
measure: Symptom score (SS) during the 1st, 3rd, and 4th pollen seasons.
time frame: after 1 year, 2 years, 3 years, 4 years and 5 years
description: Differences between treatment groups also including pulmonary symptoms and for asthmatic/non-asthmatic patients.
Data are captured via eDiary to be completed by the patients during each of the 5 pollen seasons within the duration of the study, starting prior to onset of pollen flight until after the end of the pollen seasons.
measure: Rescue Medication Score (RMS) during the 1st, 3rd, and 4th pollen season (futility and interim analyses).
time frame: after 1 year, 2 years, 3 years, 4 years and 5 years
description: Differences between treatment groups also including pulmonary symptoms and for asthmatic/non-asthmatic patients.
Data are captured via eDiary to be completed by the patients during each of the 5 pollen seasons within the duration of the study, starting prior to onset of pollen flight until afte the end of the pollen seasons.
measure: combined Symptoms and Rescue Medication Score (SMS) during the 1st, 3rd, and 4th pollen season including pulmonary symptoms.
time frame: after 1 year, 2 years, 3 years and 4 years
description: Differences between treatment groups, during all 5 pollen seasons also including pulmonary symptoms and for asthmatic/non-asthmatic patients.
Data are captured via eDiary to be completed by the patients during each of the 5 pollen seasons within the duration of the study, starting prior to onset of pollen flight until after the end of the pollen seasons.
measure: Rhinitis Quality of Life Questionnaire (RQLQ) resp. RQLQ for adolescent patients (AdolRQLQ)
time frame: Screening and after 1 year, 2 years, 3 years, 4 years and 5 years
description: Changes to baseline and difference between treatment groups during all 5 pollen seasons
measure: Immunology parameters (Total IgE, specific IgE, specific IgG1 and IgG4)
time frame: Screening, after years 1, 2, 3 and 5 (resp. end of study)
description: Differences within patients and between treatment groups
measure: Disease modifying effect after 5 years
time frame: after 5 years
description: Difference between treatment groups. Incidence of asthma and new sensitizations.
measure: Clinical chemistry: Number of patients with outside range values
time frame: Screening, after years 2, 3 and 5
description: Differences between treatment groups
measure: Adverse events: number of patients with AEs/SAEs
time frame: throughout the whole study duration
description: Including symptoms reported by patients in eDiary. Differences between treatment groups including but not limited to differences in severity levels of systemic reactions (SRs), immediate and local reaction including calculation of ratios per injection
measure: Serum levels of Aluminium hydroxide (Pharmacokinetics)
time frame: prior and after 1st and 2nd application of IMP and after 1 year
description: Serum Aluminium hydroxide levels are assessed in a subgroup of 24 patients. Differences between treatment groups (adult patients only) Sampling: prior to 1st application of IMP, 4 time points after 1st, 2nd and 10th application (after 1 year). 24 hrs. urine at these 3 time points
measure: Vitamin D3 level
time frame: baseline and end of study
description: Possible influence on specific immunotherapy. Exploratory evaluation
measure: Hematology: Number of patients with outside range values
time frame: Screening, after years 2, 3 and 5
description: Differences between treatment groups
arm group label: Depigoid Birch 5.000 DPP/ml
arm group type: Experimental
description: Suspension for s.c. injection. Treatment schedule:
Build-up phase (1 day: 0,2 ml+0,3 ml at interval of 30 minutes)
Maintenance phase (3 years: 0,5 ml at intervals of 4-6 weeks)
arm group label: Placebo
arm group type: Placebo Comparator
description: Suspension for s.c. injection. Treatment schedule:
Build-up phase (1 day: 0,2 ml+0,3 ml at interval of 30 minutes)
Maintenance phase (3 years: 0,5 ml at intervals of 4-6 weeks)
intervention type: Biological
intervention name: s.c. injection
description: 3 years of therapy followed by 2 years (seasons) of treatment-free observational period
arm group label: Depigoid Birch 5.000 DPP/ml
arm group label: Placebo
other name: Depigoid(R)Birch
criteria: 
gender: All
minimum age: 12 Years
maximum age: 70 Years
healthy volunteers: No
last name: Natalja Novak, Prof. Dr.
role: Principal Investigator
affiliation: Klinik für Dermatologie und Allergologie der Universität Bonn
last name: Angelika Sager, Dr. med.
role: Study Director
affiliation: Leti Pharma GmbH
facility: 
facility: 
country: Germany
responsible party type: Sponsor
mesh term: Rhinitis
mesh term: Asthma
mesh term: Rhinitis, Allergic
mesh term: Conjunctivitis