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Primary Ovarian Insufficiency: Phenotype and Optimal Treatment

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ClinicalTrials.gov Identifier: NCT03568708
Recruitment Status : Recruiting
First Posted : June 25, 2018
Last Update Posted : December 13, 2018
Sponsor:
Information provided by (Responsible Party):
Catherine Gordon, MD, MSc, Children's Hospital Medical Center, Cincinnati

Brief Summary:
This pilot study will observe the progression of newly diagnosed POI patients physical and psychology outcomes after initiating standard of care HRT treatment in comparison to healthy female control participants' physical and psychology health over 12 months.

Condition or disease Intervention/treatment Phase
Primary Ovarian Insufficiency Drug: Transdermal Estrogen Phase 3

Detailed Description:

Background: Primary ovarian insufficiency (POI) is an enigmatic condition that affects ~1/10,000 women by age 20. Sometimes referred to as "early menopause," POI is characterized by estrogen deficiency among other hormonal abnormalities that resemble the menopause. POI is a serious chronic condition with no cure. The clinical presentation or 'phenotype' in adolescents is not well understood. Health consequences may include delayed or arrested puberty, skeletal losses, and the threat to reproductive health. Both the metabolic and emotional sequelae are substantial, and one of the most concerning is compromised bone health. The optimal hormone replacement therapy (HRT) regimen for these young women is debated and practice varies among health providers. Importantly only sparse data exist to guide clinicians to make evidence-based decisions regarding the management of these patients. If initiated early, HRT may prevent estrogen-associated bone loss.

Impact: Better understanding of POI may lead to improved treatments for this underserved population and have significant implications for the treatment of estrogen deficiency in other populations of adolescents and young women, and for all women going though natural menopause later in life. Little is known about the effects of HRT on bone health, body composition, cognition, and health-related quality of life, especially among adolescents. Understanding how this therapy affects these multiple health outcomes will fill knowledge gaps regarding treatment for young patients with POI, with potential implications for adolescents and young women with estrogen deficiency in other clinical settings. We will define the clinical presentation (i.e., phenotype) of adolescent POI. The pilot data collected will be used in a future application to the National Institutes of Health, to fund a larger trial that builds on observations from this initial study. The information gained from this pediatric model may also provide insights on management of the natural menopause that occurs in all women later in life.

Methods: Ten adolescents with idiopathic POI (i.e., from unexplained causes) will be recruited through the CCHMC Teen Health Center, Endocrine or Pediatric/Adolescent Gynecology Clinics. Ten healthy controls will be recruited from the Teen Health Center. Participants with POI will receive transdermal estrogen replacement (beginning at 25 µg/patch applied weekly), with the dose increased at subsequent study visits that will occur at 3, 6, and 12 months. All data collection will take place at the CCHMC Schubert Research Clinic. The investigators will measure bone density of the central skeleton and body composition by dual-energy x-ray absorptiometry. To evaluate the peripheral skeleton, bone and muscle measures will be obtained by peripheral quantitative computed tomography. At each visit, the participants will have blood drawn to measure circulating hormone levels that are characteristically altered in adolescents with POI, along with safety assays. Cognitive functioning will be assessed using standardized tools. Participants will complete quality of life assessments, along with nutrition and physical activity surveys. Lastly, all participants will also complete a detailed medical history and health assessment.

Implications/Future Directions: Once the phenotype of adolescent POI is more clearly defined, a logical next question will be to determine whether negative health outcomes can be prevented or modified. Data from the proposed trial will guide the design of future prospective studies that evaluate the effects of traditional treatments (e.g., HRT), including a longer study to monitor HRT therapy, as well as more experimental treatments (e.g., skeletal agents) that may benefit young women with this rare condition. In addition, findings are expected to open avenues of research for adolescents and women with estrogen deficiency in other clinical settings.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Primary Ovarian Insufficiency: Phenotype and Optimal Treatment
Actual Study Start Date : November 1, 2018
Estimated Primary Completion Date : May 31, 2021
Estimated Study Completion Date : May 31, 2021


Arm Intervention/treatment
No Intervention: Control Participants
The control group will reflect a comparison group similar to the POI patient group. As bone density, body composition, and cognitive domains continue to mature throughout the teenage years, this comparison group will provide an important metric of normal growth and development.
Experimental: POI Participants
This group will be participants who have been recently diagnosed with POI. In an open-label fashion, participants with POI will receive Transdermal Estrogen(beginning at a dose of 25 μg/patch applied weekly), with the dose increased at 3, 6 and 12 months (to 37.5, 50, and 75 μg/patch).
Drug: Transdermal Estrogen
In an open-label fashion, participants with POI will receive transdermal estradiol (beginning at a dose of 25 µg/patch applied weekly), with the dose increased at 3, 6 and 12 months (to 37.5, 50, and 75 µg/patch).
Other Name: Estradiol-estradiol patch




Primary Outcome Measures :
  1. DXA Measure of Bone Mineral Density [ Time Frame: Change in bone mineral density and body composition from baseline to 12 months ]
    DXA measures of the lumbar spine


Secondary Outcome Measures :
  1. Study Medications [ Time Frame: Change in serum estradiol levels from baseline to 12 months ]
    Compliance with study medications as assessed by patch count at study visits and serum estradiol levels.

  2. pQCT [ Time Frame: Change from baseline to 12 months ]
    To assess the appendicular (peripheral) skeleton, bone measures of the non-dominant radius will be obtained by pQCT

  3. Bone age [ Time Frame: Change from baseline to 12 months ]
    Radiograph of the left wrist to assess bone age for POI participants

  4. Anthropometrics [ Time Frame: Change from baseline to 12 months ]
    weight and height will be combined to report BMI in kg/m^2

  5. Youth/Adolescent Questionnaire (YAQ) [ Time Frame: Change from baseline to 12 months ]
    Nutrition survey

  6. Child Health Questionnaire-Child Self-Report Form (CHQ-CF87) [ Time Frame: Change from baseline to 12 months ]
    The tool consists of 12 summated subscales and is designed to measure the physical and psychosocial health of adolescents. The subscales include change in health in the last year, bodily pain, behavior, mental health, among others. Items are scored from 0-100, except for the change in health during the last year, and family cohesion variables, which are scored from 1-5. Higher scores on all other variables indicate better quality of life. This instrument has a record of reliability and validity for evaluating aspects of health that are pertinent across age, gender, health condition, and socioeconomic status in adolescents

  7. Menopause Rating Scale (MRS) [ Time Frame: Change from baseline to 12 months ]
    11-item self-report validated measure to assess symptoms associated with menopause. The composite scores for each of the dimensions (sub-scales) is based on adding up the scores of the items of the respective dimensions. The composite score (total score) is the sum of the dimension scores. The three dimensions, their corresponding questions and the evaluation are detailed and summarized. The total score of the MRS ranges between 0 (asymptomatic) and 44 (highest degree of complaints). psychological symptoms: 0 to 16 scoring points ( 4 symptoms: depressed, irritable, anxious, exhausted) somato-vegetative symptoms: 0 to 16 points (4 symptoms: sweating/flush, cardiac complaints, sleeping disorders, joint & muscle complaints) urogenital symptoms: 0 to 12 points (3 symptoms: sexual problems, urinary complaints, vaginal dryness).

  8. Child Depression Inventory-II (CDI-II) [ Time Frame: Change from CDI-II score from baseline to 12 months ]
    A brief self-report test that helps assess cognitive, affective and behavioral signs of depression in children and adolescents 7 to 17 years old. Scales include Emotional and Functional Problems, along with subscales of Negative mood/Physical symptoms, Negative Self-Esteem, Interpersonal Problems, and Ineffectiveness. Higher scores indicate more depressive symptoms for total scoring and subscale scores.

  9. Screen for Child Anxiety Related Disorders (SCARED) [ Time Frame: Change from SCARED score baseline to 12 months ]
    A 41 item self-report tool to assess for anxiety. A total score of ≥ 25 may indicate the presence of an Anxiety Disorder. Scores higher than 30 are more specific.A score of 7 for items 1, 6, 9, 12, 15, 18, 19, 22, 24, 27, 30, 34, 38 may indicate Panic Disorder or Significant Somatic Symptoms.A score of 9 for items 5, 7, 14, 21, 23, 28, 33, 35, 37 may indicate Generalized Anxiety Disorder. A score of 5 for items 4, 8, 13, 16, 20, 25, 29, 31 may indicate Separation Anxiety SOC. A score of 8 for items 3, 10, 26, 32, 39, 40, 41 may indicate Social Anxiety Disorder.

  10. Children and Adolescent Memory Profile (CHAMP) [ Time Frame: Change from score from baseline to 12 months ]
    The ChAMP is a norm-referenced test of memory and learning that was designed for use with children, adolescents, and young adults ranging from 5 through 21 years. This test is administered directly to the participant by a trained examiner. The survey is a comprehensive screen that allows both memory screening and in-depth memory evaluation. The ChAMP includes 4 Subtests (Lists, Objects, Instructions, Places), each with immediate and delayed evaluation modules. Composite scores yielded from this measure include: verbal memory index, visual memory index, immediate memory index, delayed memory index, and total memory index. The ChAMP takes approximately 35 minutes to administer. A score of 3 for items 2, 11, 17, 36 may indicate Significant School Avoidance.

  11. DXA Measure of Bone Mineral Density [ Time Frame: Change from baseline bone mineral density to 12 months ]
    To assess the axial (central) skeleton, DXA measure of the whole body

  12. DXA Measure of Body Composition [ Time Frame: Change from baseline body composition to 12 months ]
    To assess the axial (central) skeleton, DXA measure of the whole body



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Ages Eligible for Study:   11 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria for POI patients

The participant must:

  1. Be willing to give informed consent/assent
  2. Have a diagnosis of POI based on 2 elevated serum FSH levels obtained >1 month apart
  3. Be English-speaking

Exclusion Criteria for POI patients

The participant must not:

  1. Have other chronic disease known to affect bone health (e.g., cystic fibrosis, celiac disease, etc.)
  2. Have an identified secondary cause of ovarian insufficiency
  3. Have POI in the setting of Turner syndrome, Fanconi Anemia, galactosemia, or Perrault syndrome (as associated neurological/medical sequelae could confound baseline measures)
  4. Have used medications known to affect bone metabolism over previous 3 months (e.g. anticonvulsants, chronic use of glucocorticords, Depo-Provera, oral contraceptive pills)
  5. Be currently pregnant (to be confirmed by pregnancy testing)

Inclusion Criteria for Healthy Adolescent Control Participants

The participant must:

  1. Be similar in age and race group to the idiopathic POI group

    1. Control participants age must be within one year of age from the POI participant at the time of enrollment. Age may be within one year older or one year younger
    2. Race of controls participants will be matched based on race of POI patient participants
  2. Have a BMI within 20% of the BMI of the case-matched participant
  3. If postmenarchal, will be regularly menstruating (cycles between 21-35 days)

    a. if POI participant is <12.5yrs (mean age of menarche) will match with a pre- menarchal control participant

  4. Be English-speaking

Exclusion Criteria for Healthy Adolescent Control Participants

The participant must not:

  1. Have a chronic disease, known to affect bone metabolism (e.g., cystic fibrosis, celiac disease, sickle cell disease, inflammatory bowel disease etc.)
  2. Be receiving medications known to affect bone metabolism over previous three months (e.g. anticonvulsants, chronic use of glucocorticoids, Depo-Provera, oral contraceptive pills, etc.)
  3. Have a learning disability or a developmental delay
  4. Be currently taking any SSRIs, antipsychotics or have any documented problems with anxiety or depression.
  5. Be currently pregnant (as confirmed by pregnancy testing)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03568708


Contacts
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Contact: Andrea Meisman, MA 1-800-344-2462 ext 3-3132 andrea.meisman@cchmc.org

Locations
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United States, Ohio
Cincinnati Children's Hospital Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Catherine Gordon, MD, Msc    800-344-2462 ext 6-8602    catherine.gordon@cchmc.org   
Contact: Andrea Meisman, MA    1-800-344-2462 ext 3-3132    andrea.meisman@cchmc.org   
Sponsors and Collaborators
Children's Hospital Medical Center, Cincinnati
Investigators
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Principal Investigator: Catherine Gordon, MD,Msc Children's Hospital Medical Center, Cincinnati
Study Director: Halley Wasserman, MD Children's Hospital Medical Center, Cincinnati

Publications:
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Responsible Party: Catherine Gordon, MD, MSc, Director, Division of Adolescent and Transition Medicine Rauh Chair of Adolescent Medicine Professor, Dept. of Pediatrics, University of Cincinnati College of Medicine, Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier: NCT03568708     History of Changes
Other Study ID Numbers: FP00000706
First Posted: June 25, 2018    Key Record Dates
Last Update Posted: December 13, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Catherine Gordon, MD, MSc, Children's Hospital Medical Center, Cincinnati:
Primary Ovarian Insufficiency
Hormone Replacement Therapy
Estrogen Deficiency

Additional relevant MeSH terms:
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Primary Ovarian Insufficiency
Menopause, Premature
Gonadal Dysgenesis
Turner Syndrome
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Gonadal Disorders
Endocrine System Diseases
Disorders of Sex Development
Urogenital Abnormalities
Congenital Abnormalities
Sex Chromosome Disorders of Sex Development
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Sex Chromosome Disorders
Chromosome Disorders
Genetic Diseases, Inborn
Estradiol
Polyestradiol phosphate
Estrogens
Estradiol 3-benzoate
Estradiol 17 beta-cypionate
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Contraceptive Agents
Reproductive Control Agents