Primary Ovarian Insufficiency: Phenotype and Optimal Treatment
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|ClinicalTrials.gov Identifier: NCT03568708|
Recruitment Status : Recruiting
First Posted : June 26, 2018
Last Update Posted : May 20, 2020
|Condition or disease||Intervention/treatment||Phase|
|Primary Ovarian Insufficiency||Drug: Transdermal Estrogen||Phase 3|
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, 12, 18, and 24 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||20 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Primary Ovarian Insufficiency: Phenotype and Optimal Treatment|
|Actual Study Start Date :||November 1, 2018|
|Estimated Primary Completion Date :||May 31, 2022|
|Estimated Study Completion Date :||May 31, 2022|
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 12, and 18 months (to 37.5, 50, 75, and 100 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 12, and 18 months (to 37.5, 50, 75, and 100 µg/patch).
Other Name: Estradiol-estradiol patch
- DXA Measure of Bone Mineral Density [ Time Frame: Change in bone mineral density and body composition from baseline to 24 months ]DXA measures of the lumbar spine
- Study Medications [ Time Frame: Change in serum estradiol levels from baseline to 24 months ]Compliance with study medications as assessed by patch count at study visits and serum estradiol levels.
- pQCT [ Time Frame: Change from baseline to 24 months ]To assess the appendicular (peripheral) skeleton, bone measures of the non-dominant radius will be obtained by pQCT
- Bone age [ Time Frame: Change from baseline to 24 months ]Radiograph of the left wrist to assess bone age for POI participants
- Anthropometrics [ Time Frame: Change from baseline to 24 months ]weight and height will be combined to report BMI in kg/m^2
- Youth/Adolescent Questionnaire (YAQ) [ Time Frame: Change from baseline to 24 months ]Nutrition survey
- Child Health Questionnaire-Child Self-Report Form (CHQ-CF87) [ Time Frame: Change from baseline to 24 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
- Menopause Rating Scale (MRS) [ Time Frame: Change from baseline to 24 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).
- Child Depression Inventory-II (CDI-II) [ Time Frame: Change from CDI-II score from baseline to 24 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.
- Screen for Child Anxiety Related Disorders (SCARED) [ Time Frame: Change from SCARED score baseline to 24 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.
- Children and Adolescent Memory Profile (CHAMP) [ Time Frame: Change from score from baseline to 24 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.
- DXA Measure of Bone Mineral Density [ Time Frame: Change from baseline bone mineral density to 24 months ]To assess the axial (central) skeleton, DXA measure of the whole body
- DXA Measure of Body Composition [ Time Frame: Change from baseline body composition to 24 months ]To assess the axial (central) skeleton, DXA measure of the whole body
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
|Contact: Emily Smith, BS||1-800-344-2462 ext email@example.com|
|Contact: Halley Wasserman, MD, MSc||1-800-344-2462 ext firstname.lastname@example.org|
|Principal Investigator:||Catherine Gordon, MD,Msc||Boston Children's Hospital and Cincinnati Children's Hospital Medical Center|
|Principal Investigator:||Halley Wasserman, MD, MSc||Children's Hospital Medical Center, Cincinnati|