Administrative information
Title {1} | Perimenopausal Effects of Estradiol on Anhedonia and Psychosis Study (PEEPs): Study Protocol for a Neural and Molecular Mechanistic Clinical Trial |
Trial registration {2a} | ClinicalTrials.gov Identifier: NCT05282277 |
Trial registration: data set {2a} | n/a; the register used for registration does not collect all items from the World Health Organization Trial Registration Data Set. |
Protocol version {3} | This is version 1.6 of the study protocol (06/09/2022). |
Funding {4} | National Institute of Mental Health (R01 MH128238 to DL, CES, and GSD and K23 MH113733 to EW). |
Author details {5a} | 1) Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27510, USA. *to whom correspondence should be addressed: melissa_walsh@med.unc.edu 2) Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA. 3) Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA. 4) Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA. 5) Department of Obstetrics and Gynecology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. 6) North Carolina Psychiatric Research Center, Raleigh, NC, 27610, USA 7) Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, USA |
Name and contact information for the trial sponsor {5b} | National Institute of Mental Health; nimhinfo@nih.gov |
Role of sponsor {5c} | The National Institute of Mental Health has no role in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, or any ultimate authority over any of these activities. |
Introduction
Background and rationale {6a}
Approach novelty
Objectives {7}
Trial design {8}
Methods: participants, interventions, and outcomes
Study setting {9}
Eligibility criteria {10}
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At least mild perimenopausal-onset anhedonia (SHAPS≥20) (Snaith et al. [38])
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Pregnancy or sensitivities to ingredients in the Climara® patch or Prometrium®, or their generics
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Bilateral oophorectomy
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Body mass index (BMI) extremes (<18 or >45 kg/m2) due to its cardiovascular risk
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PET-MR contraindications
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Use of psychotropic, hormonal preparations, or medication with unknown mood effects
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No axis I disorder history during the 2 years prior to perimenopause onset
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History of mood episodes requiring hospitalization
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Current mania
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History of suicide attempts within the past year or active suicidal ideation with intent or plan
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Neurological conditions (e.g., seizure/traumatic brain injury/stroke) or brain stimulation in past 6 months
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Endometriosis, undiagnosed ovary enlargement or vaginal bleeding, liver disease, breast cancer, cardiovascular disease, history of blood clots in legs or lungs, porphyria, type I or II diabetes mellitus, malignant melanoma, gallbladder or pancreatic or kidney disease, cigarette smoking, recurrent migraines with aura
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First-degree relative with premenopausal breast cancer, breast cancer in both breasts, or multiple relatives (>3) with breast cancer
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Poor cardiovascular health as determined by review of medical records and symptoms to rule out chronic, uncontrolled hypertension, history/presence of any heart conditions, dyspnea with or without exertion, orthopnea, chest pain/pressure, sense of rapid or irregular heartbeat/palpitations, exercise intolerance (i.e., METS <4), paroxysmal nocturnal dyspnea, unexplained syncope, unexplained lower extremity edema
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Current substance use disorder or history of moderate-to-severe substance use disorder within the past 2 years
Who will take informed consent {26a}
Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies {26b}
Interventions
Explanation for the choice of comparators {6b}
Intervention description {11a}
Treatment arms
Dose justification
Criteria for discontinuing or modifying the allocated intervention {11b}
Safety assessments
Strategies to improve adherence to interventions {11c}
Relevant concomitant care permitted or prohibited during the trial {11d}
Provisions for post-trial care {30}
Outcomes {12}
Mechanistic outcomes
Clinical outcomes
Participant timeline {13}
Sample size {14}
Recruitment {15}
Assignment of interventions: allocation
Sequence generation {16a}
Concealment mechanism {16b}
Implementation {16c}
Assignment of interventions: blinding
Who will be blinded {17a}
Procedure for unblinding if needed {17b}
Data collection and management
Plans for assessment and collection of outcomes {18a}
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Inventory of Depression and Anxiety Symptoms (IDAS-II [56]), a 64-item self-report measure with good psychometric properties that has been validated for use with reproductive mood disorder samples
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Clinical Global Impression (CGI) scale [57]: assessment of functional impairment to be collected at pre-treatment, week one, week two, and post-treatment
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Green Climacteric Scale [60]: 21-item gold-standard self-report measure for assessment of climacteric symptoms (vasomotor, somatic, anxiety, depression)
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Pittsburgh Sleep Quality Index (PSQI [61]): 9-item self-report questionnaire measuring sleep quality/patterns in older adults
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DSM-5 Self-Rated Level 1 Cross-Cutting Symptom Measure—Adult [62]: self-report questionnaire assessing symptoms relevant across different mental health diagnoses
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The 7-item anxiety scale (GAD-7) [63]: brief self-report anxiety scale
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Patient Health Questionnaire (PHQ)-9 [64]: brief 9-item questionnaire to assess depression severity
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World Health Organization Disability Assessment Schedule 2.0 [65]: self-report assessment of functioning across six domains (cognition, mobility, self-care, social interaction, life activities, participation)
Plans to promote participant retention and complete follow-up {18b}
Compliance monitoring
Data management {19}
Confidentiality {27}
Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
Case report form
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Methods for additional analyses (e.g., subgroup analyses) {20b}
Interim analyses {21b}
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Plans to give access to the full protocol, participant-level data, and statistical code {31c}
Oversight and monitoring
Composition of the coordinating center and trial steering committee {5d}
Composition of the data monitoring committee, its role, and reporting structure {21a}
Adverse events reporting and harms {22}
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Participation in study procedures poses unexpected, significant, or unacceptable risk (e.g., three or more serious adverse events reported).
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There are findings of (a) insufficient compliance with the study protocol, (b) data are not sufficiently complete or evaluable, or (c) trial progress is determined insufficient.
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There has been a clear demonstration of trial (a) efficacy or (b) futility.