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Primary Ovarian InsufficiencyPhase 3NCT03568708

Primary Ovarian Insufficiency: Phenotype and Optimal Treatment

A Phase 3 study testing Transdermal Estrogen in people with Primary Ovarian Insufficiency, run by Children's Hospital Medical Center, Cincinnati at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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 24 months. Read more about this study

Who is it for?
Ages 11 to 18 years, women onlyHealthy volunteers can take part
Conditions the study is for
Primary Ovarian Insufficiency
What is being tested?
Transdermal Estrogen
Could I receive a placebo?
No, everyone receives an active treatment
How many people
19 participants
Where
1 siteUnited States
Study dates
1 Nov 2018to 5 Jan 2023
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 11 to 18 years
  • Women only
  • Healthy volunteers accepted
  • Child, Adult

Who may be able to join

  • The participant must:
  • Be willing to give informed consent/assent
  • Have a diagnosis of POI based on 2 elevated serum follicle stimulating hormone (FSH) levels obtained >1 month apart.
  • Be English-speaking

Who cannot join

  • The participant must not:
  • Have other chronic disease known to affect bone health (e.g., cystic fibrosis, celiac disease, etc.)
  • Have an identified secondary cause of ovarian insufficiency
  • Have POI in the setting of Turner syndrome, Fanconi Anemia, galactosemia, or Perrault syndrome (as associated neurological/medical sequelae could confound baseline measures)
  • Have used medications known to affect bone metabolism over previous 3 months (e.g. anticonvulsants, chronic use of glucocorticoids, Depo-Provera, oral contraceptive pills)
  • Be currently pregnant (to be confirmed by pregnancy testing)
Show all 22Show fewer
  • Inclusion Criteria for Healthy Adolescent Control Participants
  • The participant must:
  • Be similar in age and race group to the idiopathic POI group
  • 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
  • Race of controls participants will be matched based on race of POI patient participants
  • Have a BMI within 20% of the BMI of the case-matched participant
  • If postmenarchal, will be regularly menstruating (cycles between 21-35 days)
  • if POI participant is <12.5yrs (mean age of menarche) will match with a pre- menarchal control participant
  • Be English-speaking
  • Exclusion Criteria for Healthy Adolescent Control Participants
  • The participant must not:
  • Have a chronic disease, known to affect bone metabolism (e.g., cystic fibrosis, celiac disease, sickle cell disease, inflammatory bowel disease etc.)
  • 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.)
  • Have a learning disability or a developmental delay
  • Be currently taking any selective serotonin reuptake inhibitors (SSRIs), antipsychotics or have any documented problems with anxiety or depression.
  • Be currently pregnant (as confirmed by pregnancy testing)

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Cincinnati Children's Hospital

    Cincinnati, Ohio, 45229

Other trials in United States

About this study

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 24 months.

Read the 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 Cincinnati Children's Hospital Medical Center (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.

Being tested
Transdermal Estrogen
Keywords
Primary Ovarian Insufficiency, Hormone Replacement Therapy, Estrogen Deficiency
Medical subject headings
Primary Ovarian Insufficiency

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Transdermal EstrogenDrug

    Also called Estradiol-estradiol patch

    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).

Study groups in NCT03568708
Study groupRoleWhat they receive
Control ParticipantsNo interventionThe 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.
POI ParticipantsExperimentalThis 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).
Receives: Drug: Transdermal Estrogen

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change in Dual Energy X-ray Absorptiometry (DXA) Measure of Bone Mineral Density (BMD) of the Lumbar Spine

    Change in height adjusted areal BMD Z-score of the lumbar spine from baseline to 24 months within groups. BMI Z-score, calcium intake, vitamin D intake and physical activity were included in the analysis. As DXA BMD Z-scores already include race, age, and sex, these variables were not included in the analysis.

    Z-scores ranging between -2.0 and 2.0 are considered normal. A Z-score <-2.0 is considered low. This analysis considers change in Z-score, therefore a high value reflects a greater increase in BMD Z-score.

    Measured: Change in bone mineral density and body composition from baseline to 24 months

Secondary outcomes (10)

  1. Change in Dual Energy X-ray Absorptiometry (DXA) Measure of Bone Mineral Density (BMD) at the Whole Body Less Head, Total Hip, and Femoral Neck

    To assess changes in bone mineral density DXA height adjusted BMD Z-scores of the whole body less head, total hip and femoral neck were measured. BMI, calcium intake, vitamin D intake and physical activity were included in the analysis. As DXA BMD Z-scores already include race, age, and sex, these variables were not included in the analysis.

    Z-scores ranging between -2.0 and 2.0 are considered normal. A Z-score <-2.0 is considered low. This analysis considers change in Z-score, therefore a high value reflects a greater increase in BMD Z-score.

    Measured: baseline to 24 months

  2. Change in Volumetric Bone Mineral Density (vBMD) at the Distal Radius as Measured by Peripheral Quantitative Computed Tomography (pQCT)

    To assess the appendicular (peripheral) skeleton, pQCT (Stratec XCT 2000, Orthometrix, Inc., White Plains, NY) bone measures were obtained of the non-dominant radius at the 3% and 66% sites. Measurements were acquired with a voxel size of 0.4 mm, slice thickness of 2.3 mm, and scan speed of 25 mm/sec, and analyzed with manufacturer software version 6.

    Measured: Change from baseline to 24 months

  3. Anthropometrics

    The mean BMI in kg/m^2 is presented for each study group at baseline and at the 24 months follow up visit to show that there was no significant difference between groups nor a significant change in BMI over the duration of the study.

    Measured: Baseline and 24 months

  4. Change in Lean Mass as Measured by DXA Body Composition

    Lean mass was obtained from the whole body DXA scan. Change in baseline to 24 months was assessed.

    Measured: Change in lean mass from baseline to 24 months

  5. Change in Symptoms of Anxiety as Measured by Screen for Child Anxiety Related Disorders (SCARED)

    A 41 item self-report tool to assess for anxiety where each question receives a score of either 0, 1 or 2. Range of scores is 0 to 82. A total score of ≥ 25 may indicate the presence of an Anxiety Disorder. A higher score indicates there are more endorsed symptoms of anxiety.

    Measured: Change from SCARED score baseline to 24 months

  6. Change in Symptoms of Depression as Measured by Child Depression Inventory-II (CDI-II)

    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. The total score is converted into a T-score (mean=50, standard deviation=10) where a result >64 is considered elevated. A higher score indicates there are more endorsed symptoms of depression.

    Measured: Change from CDI-II score from baseline to 24 months

  7. Change in Memory as Assessed by the Children and Adolescent Memory Profile (CHAMP) Total Memory Index Score

    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. The ChAMP includes 4 Subtests of visual and verbal memory to generate a total memory index score as a measure of overall memory. The total memory index score ranges from 50-150 with a mean=100 and standard deviation=15. Higher scores indicating better memory. The data presented here is the change in the total memory index score from baseline visit to the 24 month follow up time.

    Measured: Change from score from baseline to 24 months

  8. Change in Quality of Life as Assessed by the Child Health Questionnaire-Child Self-Report Form (CHQ-CF87)

    The CHQ-87 is an 87-item self-report survey is designed to measure the physical and psychosocial health of adolescents. The total score ranges from 0-100. Higher scores indicate better quality of life. This instrument is reliable and valid for evaluating aspects of health pertinent across age, gender, health condition, and socioeconomic status in adolescents.

    Measured: Change from baseline to 24 months

  9. Compliance With Transdermal Estrogen Patch

    Participants with primary ovarian insufficiency (POI) were prescribed weekly transdermal estrogen (TDE2) patches and asked to log on a patch calendar when they changed the patch. Patch calendars were reviewed for compliance and weeks where at least one patch was applied were considered to be in compliance. Weeks in compliance generated the numerator whereas total weeks of participation in the study constituted the numerator.

    Measured: Patch Calendars were collected at 6 months, 12 months, 18 months and 24 months. Data presented is through study completion.

  10. Study Medications - Serum Estradiol

    Mean serum estradiol levels as measured in participants with POI.

    Measured: Baseline, 12 months, 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Jun 2018
  2. Study start1 Nov 2018
  3. Primary completion5 Jan 2023
  4. Study completion5 Jan 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
19 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03568708
Sponsor's protocol ID
FP00000706
Status last verified
Jun 2024
First submitted
11 May 2018
Last updated
25 Jun 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Gordon CM, Kanaoka T, Nelson LM. Update on primary ovarian insufficiency in adolescents. Curr Opin Pediatr. 2015 Aug;27(4):511-9. doi: 10.1097/MOP.0000000000000236.

    PubMed 26087426

  • Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009 Feb 5;360(6):606-14. doi: 10.1056/NEJMcp0808697.

    PubMed 19196677

  • Committee opinion no. 605: primary ovarian insufficiency in adolescents and young women. Obstet Gynecol. 2014 Jul;124(1):193-197. doi: 10.1097/01.AOG.0000451757.51964.98.

    PubMed 24945456

  • Sadeghi MR. New hopes for the treatment of primary ovarian insufficiency/premature ovarian failure. J Reprod Infertil. 2013 Jan;14(1):1-2. No abstract available.

    PubMed 23926553

  • Gordon CM, Zemel BS, Wren TA, Leonard MB, Bachrach LK, Rauch F, Gilsanz V, Rosen CJ, Winer KK. The Determinants of Peak Bone Mass. J Pediatr. 2017 Jan;180:261-269. doi: 10.1016/j.jpeds.2016.09.056. Epub 2016 Nov 3. No abstract available.

    PubMed 27816219

  • Bakhsh H, Dei M, Bucciantini S, Balzi D, Bruni V. Premature ovarian insufficiency in young girls: repercussions on uterine volume and bone mineral density. Gynecol Endocrinol. 2015 Jan;31(1):65-9. doi: 10.3109/09513590.2014.958987. Epub 2014 Sep 9.

    PubMed 25203144

  • Popat VB, Calis KA, Vanderhoof VH, Cizza G, Reynolds JC, Sebring N, Troendle JF, Nelson LM. Bone mineral density in estrogen-deficient young women. J Clin Endocrinol Metab. 2009 Jul;94(7):2277-83. doi: 10.1210/jc.2008-1878. Epub 2009 Apr 28.

    PubMed 19401379

  • Zemel BS, Kalkwarf HJ, Gilsanz V, Lappe JM, Oberfield S, Shepherd JA, Frederick MM, Huang X, Lu M, Mahboubi S, Hangartner T, Winer KK. Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: results of the bone mineral density in childhood study. J Clin Endocrinol Metab. 2011 Oct;96(10):3160-9. doi: 10.1210/jc.2011-1111. Epub 2011 Sep 14.

    PubMed 21917867

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Transdermal Estrogen in people with Primary Ovarian Insufficiency, run by Children's Hospital Medical Center, Cincinnati at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 25 Jun 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 25 Jun 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change in Dual Energy X-ray Absorptiometry (DXA) Measure of Bone Mineral Density (BMD) of the Lumbar Spine (time frame: Change in bone mineral density and body composition from baseline to 24 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03568708, which also lists 8 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jun 2024.

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