<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/NCT02197923</url>
  </required_header>
  <id_info>
    <org_study_id>2014/637b</org_study_id>
    <nct_id>NCT02197923</nct_id>
  </id_info>
  <brief_title>Norwegian Adenomyosis Study II: Gene Expression Profiling of Adenomyosis</brief_title>
  <acronym>NAPPED II</acronym>
  <official_title>Norwegian Adenomyosis Study: Pathophysiology, Peristalsis, Expression Profiling and Diagnosis, Part 2</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Oslo University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Oslo</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Helse Sor-Ost</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Oslo University Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Adenomyosis is characterized by the appearance of endometrial cells in the muscular layer of&#xD;
      the uterus. It affects about 15-20% of the female population.&#xD;
&#xD;
      The symptoms of adenomyosis are heavy menstrual bleedings and painful menstruation&#xD;
      (dysmenorrhea) and in addition chronic pelvic pain. Subfertility and infertility have been&#xD;
      correlated with adenomyosis.&#xD;
&#xD;
      Parity, age and uterine abrasion increase the risk of adenomyosis. Hormonal factors such as&#xD;
      local hyperestrogenism and elevated levels of prolactin (PRL) have been identified, but&#xD;
      autoimmune and mechanical factors are also hypothesized.&#xD;
&#xD;
      Regarding treatment, the most effective measure is hysterectomy. As this is a very drastic&#xD;
      measure in younger women, levonogestrel-releasing intrauterine devices, Gonadotropin&#xD;
      releasing hormone (GnRH)-analogues, Danazol, uterine embolization and endometrial ablation&#xD;
      have been tried, but studies are few in number, retrospective, and have small sample sizes.&#xD;
&#xD;
      Adenomyosis has so far not been subject to extensive research efforts. The pathogenesis of&#xD;
      adenomyosis remains still unclear, there are not many satisfying treatment options and&#xD;
      diagnostics include mostly magnetic resonance imaging (MRI) and histology.&#xD;
&#xD;
      The investigators designed a series of 3 studies with a broad approach in understanding&#xD;
      adenomyosis. This is part 2.&#xD;
&#xD;
      In this study the investigators take both tissue samples and blood samples that will be&#xD;
      investigated in order to understand the basic processes leading to adenomyosis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Biopsy of focal adenomyosis of the myometrium:&#xD;
&#xD;
      This will be an extension of the NAPPED1-study. The investigators will perform&#xD;
      ultrasound-guided transvaginal biopsies of the myometrium and collect venous blood samples.&#xD;
&#xD;
      As recent studies have suggested abnormalities in the regulation of specific genes in the&#xD;
      development of adenomyosis, the investigators want to investigate differentially expressed&#xD;
      genes in adenomyosis compared to eutopic endometrium. Using microarrays, the investigators&#xD;
      can simultaneously screen differences in expression of thousands of genes in samples from the&#xD;
      two groups. Profiling studies performed on endometrium of healthy individuals and of&#xD;
      endometriosis show results that enable identification of biological processes and molecular&#xD;
      mechanisms. Expression profiles can be used to identify molecular targets for therapeutic&#xD;
      purposes. There are some very interesting studies that investigate drug treatment on a&#xD;
      molecular level e.g. the effect of Danazol treatment on eutopic and ectopic endometrial&#xD;
      tissue, but intramural adenomyosis has not been subject to gene profiling yet.&#xD;
&#xD;
      Tissue samples can be easily obtained after hysterectomy, but those samples will only&#xD;
      represent older women, and cannot be used for consecutive monitoring of biochemical effects&#xD;
      of treatment, as the uterus is removed. In order to investigate the pathophysiology of&#xD;
      adenomyosis in younger women, and compare it to those in older individuals, as well as to&#xD;
      evaluate effects of treatment, it is necessary to be able to obtain in-vivo samples.&#xD;
&#xD;
      The plan is therefore to take transvaginal, ultrasound-guided biopsy-samples from the uterus&#xD;
      (myometrium) of all included patients at the beginning of their surgery, when the patient is&#xD;
      under full anesthesia. The safety of comparable procedures has been shown in prior studies,&#xD;
      but the investigators will further validate the safety of this method. The investigators&#xD;
      believe that an in-vivo biopsy is a safe measure, and that representative samples of&#xD;
      adenomyosis can be obtained.&#xD;
&#xD;
      The challenge with adenomyosis is that it is located intramyometrially. A transcervical&#xD;
      biopsy will contaminate the sample with eutopic endometria, therefore it is most meaningful&#xD;
      to take the biopsy transvaginally, but not through the cavity. After obtaining the biopsy&#xD;
      sample, it will be examined histologically by imprint, to confirm if glandular cells are&#xD;
      contained where expected. When good routines show a reliable level of specificity, the&#xD;
      investigators will go further by selecting approximately 10 patients for gene profiling of&#xD;
      adenomyosis. The investigators will also use endometrial biopsies (Pipelle) from those&#xD;
      patients to see if there is a difference between intramural adenomyosis and their eutopic&#xD;
      endometria. Most patients that undergo hysterectomy have taken a pipelle-biopsy routinely.&#xD;
&#xD;
      The levels of prolactin, Anti-müllerian hormone (AMH), Follicle stimulating hormone (FSH),&#xD;
      luteinizing hormone (LH) and estrogen will also be taken, in order to determine if the&#xD;
      severity of adenomyosis is only related to age as shown before, or also to hormonal activity.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 6, 2014</start_date>
  <completion_date type="Anticipated">December 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">November 1, 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Sensitivity and specificity of biopsies for adenomyotic tissue in percent (%)</measure>
    <time_frame>At time of hysterectomy</time_frame>
    <description>Sensitivity and specificity of ultrasound guided myometrial biopsies for adenomyotic tissue</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>multiple comparison of gene expression, measured in fold</measure>
    <time_frame>at time of biopsy taking</time_frame>
    <description>Expression profile for proliferative and invasive genes in adenomyotic tissue and surrounding stromal cells compared to healthy individuals, in fold</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of complications related to biopsy taking in percent (%)</measure>
    <time_frame>through 1 hour after biopsytaking</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum levels of prolactin in mU/L</measure>
    <time_frame>at time of hysterectomy</time_frame>
    <description>Serum levels of prolactin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum level of ER, in nmol/L</measure>
    <time_frame>at time of hysterectomy</time_frame>
    <description>Serum level of estrogen.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum levels of FSH in U/L</measure>
    <time_frame>at time of hysterectomy</time_frame>
    <description>Levels of follicle stimulating hormone.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum levels of AMH in pmol/L</measure>
    <time_frame>at time of hysterectomy</time_frame>
    <description>Levels of Anti-Mullerian hormone.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum levels of LH in U/L</measure>
    <time_frame>at time of hysterectomy</time_frame>
    <description>Levels of luteinizing hormone.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>difference hormone serum-levels in fold</measure>
    <time_frame>at time of hysterectomy</time_frame>
    <description>Comparison of serum-levels of PRL, FSH, AMH, LH and ER in patients with and without adenomyosis</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Adenomyosis</condition>
  <arm_group>
    <arm_group_label>Biopsy: adenomyosis</arm_group_label>
    <description>Myometrial biopsy Pipelle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Biopsy: Healthy</arm_group_label>
    <description>Myometrial Biopsy Pipelle</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Myometrial biopsy</intervention_name>
    <description>transvaginal ultrasound guided biopsy of the myometria</description>
    <arm_group_label>Biopsy: Healthy</arm_group_label>
    <arm_group_label>Biopsy: adenomyosis</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>endometrial biopsy</intervention_name>
    <description>transcervical endometrial biopsy</description>
    <arm_group_label>Biopsy: Healthy</arm_group_label>
    <arm_group_label>Biopsy: adenomyosis</arm_group_label>
    <other_name>Pipelle</other_name>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      whole blood and biopsies from uterine myometria and uterine endometria&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        women referred to our clinic and volunteering to participate&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Premenopausal women aged 30 - 50 years old scheduled for vaginal, abdominal or laparoscopic&#xD;
        total hysterectomy one or more of the following clinical symptoms:&#xD;
&#xD;
          -  bleeding disorders (menorrhagia, irregular bleeding, hypermenorrhoea),&#xD;
&#xD;
          -  chronic pelvic pain,&#xD;
&#xD;
          -  dysmenorrhoea,&#xD;
&#xD;
          -  or dyspareunia junction zone definable&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  postmenopausal women,&#xD;
&#xD;
          -  pregnancy&#xD;
&#xD;
          -  gynecological cancer&#xD;
&#xD;
          -  GnRH analog therapy or systemic hormone therapy in the last three months prior to&#xD;
             hysterectomy&#xD;
&#xD;
          -  junctional zone not identifiable&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>30 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Erik Qvigstad, PhD, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Oslo University Hospital, Ullevål</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Tina Tellum, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Oslo University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Gynecological department, Oslo University Hospital, Ullevål</name>
      <address>
        <city>Oslo</city>
        <zip>0382</zip>
        <country>Norway</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Norway</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>July 17, 2014</study_first_submitted>
  <study_first_submitted_qc>July 22, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 23, 2014</study_first_posted>
  <last_update_submitted>March 22, 2023</last_update_submitted>
  <last_update_submitted_qc>March 22, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 23, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Oslo University Hospital</investigator_affiliation>
    <investigator_full_name>Tina Tellum</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </responsible_party>
  <keyword>Menorrhagia</keyword>
  <keyword>Dysmenorrhea</keyword>
  <keyword>Pelvic pain</keyword>
  <keyword>expression profiling</keyword>
  <keyword>uterine biopsies</keyword>
  <keyword>serum hormones</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Adenomyosis</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/NCT02197923
org study id: 2014/637b
nct id: NCT02197923
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
Adenomyosis is characterized by the appearance of endometrial cells in the muscular layer of
      the uterus. It affects about 15-20% of the female population.

      The symptoms of adenomyosis are heavy menstrual bleedings and painful menstruation
      (dysmenorrhea) and in addition chronic pelvic pain. Subfertility and infertility have been
      correlated with adenomyosis.

      Parity, age and uterine abrasion increase the risk of adenomyosis. Hormonal factors such as
      local hyperestrogenism and elevated levels of prolactin (PRL) have been identified, but
      autoimmune and mechanical factors are also hypothesized.

      Regarding treatment, the most effective measure is hysterectomy. As this is a very drastic
      measure in younger women, levonogestrel-releasing intrauterine devices, Gonadotropin
      releasing hormone (GnRH)-analogues, Danazol, uterine embolization and endometrial ablation
      have been tried, but studies are few in number, retrospective, and have small sample sizes.

      Adenomyosis has so far not been subject to extensive research efforts. The pathogenesis of
      adenomyosis remains still unclear, there are not many satisfying treatment options and
      diagnostics include mostly magnetic resonance imaging (MRI) and histology.

      The investigators designed a series of 3 studies with a broad approach in understanding
      adenomyosis. This is part 2.

      In this study the investigators take both tissue samples and blood samples that will be
      investigated in order to understand the basic processes leading to adenomyosis.
Biopsy of focal adenomyosis of the myometrium:

      This will be an extension of the NAPPED1-study. The investigators will perform
      ultrasound-guided transvaginal biopsies of the myometrium and collect venous blood samples.

      As recent studies have suggested abnormalities in the regulation of specific genes in the
      development of adenomyosis, the investigators want to investigate differentially expressed
      genes in adenomyosis compared to eutopic endometrium. Using microarrays, the investigators
      can simultaneously screen differences in expression of thousands of genes in samples from the
      two groups. Profiling studies performed on endometrium of healthy individuals and of
      endometriosis show results that enable identification of biological processes and molecular
      mechanisms. Expression profiles can be used to identify molecular targets for therapeutic
      purposes. There are some very interesting studies that investigate drug treatment on a
      molecular level e.g. the effect of Danazol treatment on eutopic and ectopic endometrial
      tissue, but intramural adenomyosis has not been subject to gene profiling yet.

      Tissue samples can be easily obtained after hysterectomy, but those samples will only
      represent older women, and cannot be used for consecutive monitoring of biochemical effects
      of treatment, as the uterus is removed. In order to investigate the pathophysiology of
      adenomyosis in younger women, and compare it to those in older individuals, as well as to
      evaluate effects of treatment, it is necessary to be able to obtain in-vivo samples.

      The plan is therefore to take transvaginal, ultrasound-guided biopsy-samples from the uterus
      (myometrium) of all included patients at the beginning of their surgery, when the patient is
      under full anesthesia. The safety of comparable procedures has been shown in prior studies,
      but the investigators will further validate the safety of this method. The investigators
      believe that an in-vivo biopsy is a safe measure, and that representative samples of
      adenomyosis can be obtained.

      The challenge with adenomyosis is that it is located intramyometrially. A transcervical
      biopsy will contaminate the sample with eutopic endometria, therefore it is most meaningful
      to take the biopsy transvaginally, but not through the cavity. After obtaining the biopsy
      sample, it will be examined histologically by imprint, to confirm if glandular cells are
      contained where expected. When good routines show a reliable level of specificity, the
      investigators will go further by selecting approximately 10 patients for gene profiling of
      adenomyosis. The investigators will also use endometrial biopsies (Pipelle) from those
      patients to see if there is a difference between intramural adenomyosis and their eutopic
      endometria. Most patients that undergo hysterectomy have taken a pipelle-biopsy routinely.

      The levels of prolactin, Anti-müllerian hormone (AMH), Follicle stimulating hormone (FSH),
      luteinizing hormone (LH) and estrogen will also be taken, in order to determine if the
      severity of adenomyosis is only related to age as shown before, or also to hormonal activity.
observational model: Case-Control
time perspective: Prospective
measure: Sensitivity and specificity of biopsies for adenomyotic tissue in percent (%)
time frame: At time of hysterectomy
description: Sensitivity and specificity of ultrasound guided myometrial biopsies for adenomyotic tissue
measure: multiple comparison of gene expression, measured in fold
time frame: at time of biopsy taking
description: Expression profile for proliferative and invasive genes in adenomyotic tissue and surrounding stromal cells compared to healthy individuals, in fold
measure: Frequency of complications related to biopsy taking in percent (%)
time frame: through 1 hour after biopsytaking
measure: Serum levels of prolactin in mU/L
time frame: at time of hysterectomy
description: Serum levels of prolactin
measure: Serum level of ER, in nmol/L
time frame: at time of hysterectomy
description: Serum level of estrogen.
measure: Serum levels of FSH in U/L
time frame: at time of hysterectomy
description: Levels of follicle stimulating hormone.
measure: Serum levels of AMH in pmol/L
time frame: at time of hysterectomy
description: Levels of Anti-Mullerian hormone.
measure: Serum levels of LH in U/L
time frame: at time of hysterectomy
description: Levels of luteinizing hormone.
measure: difference hormone serum-levels in fold
time frame: at time of hysterectomy
description: Comparison of serum-levels of PRL, FSH, AMH, LH and ER in patients with and without adenomyosis
arm group label: Biopsy: adenomyosis
description: Myometrial biopsy Pipelle
arm group label: Biopsy: Healthy
description: Myometrial Biopsy Pipelle
intervention type: Procedure
intervention name: Myometrial biopsy
description: transvaginal ultrasound guided biopsy of the myometria
arm group label: Biopsy: Healthy
arm group label: Biopsy: adenomyosis
intervention type: Procedure
intervention name: endometrial biopsy
description: transcervical endometrial biopsy
arm group label: Biopsy: Healthy
arm group label: Biopsy: adenomyosis
other name: Pipelle
whole blood and biopsies from uterine myometria and uterine endometria
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 30 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Erik Qvigstad, PhD, MD
role: Study Chair
affiliation: Oslo University Hospital, Ullevål
last name: Tina Tellum, MD
role: Principal Investigator
affiliation: Oslo University Hospital
facility: 
country: Norway
responsible party type: Principal Investigator
investigator affiliation: Oslo University Hospital
investigator full name: Tina Tellum
investigator title: MD
mesh term: Adenomyosis