- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03068910
Hyperandrogenemia and Altered Day-night LH Pulse Patterns (CRM008)
November 1, 2023 updated by: Chris McCartney, University of Virginia
Study to Evaluate if Androgen-receptor Blockade (Spironolactone) Improves Progesterone-suppression of Wake Luteinizing Hormone Pulse Frequency in Pubertal Girls With Hyperandrogenism
The purpose of this study is to determine if, in mid- to late pubertal girls with hyperandrogenism, androgen-receptor blockade (spironolactone) improves the ability of progesterone to acutely reduce waking luteinizing hormone pulse frequency (primary endpoint).
Study Overview
Status
Recruiting
Conditions
Intervention / Treatment
Detailed Description
This is a randomized, placebo-controlled, double-blinded crossover study to test the following hypothesis: In mid- to late pubertal girls with hyperandrogenism (HA), acute progesterone suppression of waking LH pulse frequency is greater after 2 weeks of spironolactone pretreatment compared to after 2 weeks of placebo pretreatment.
We will only study mid- to late pubertal girls with HA (i.e., girls who would be candidates for therapeutic spironolactone use).
Subjects will complete two 18-hour Clinical Research Unit (CRU) admissions in separate menstrual cycles.
Subjects will be randomized to be pretreated for 2 weeks with either oral spironolactone (50 mg twice daily) or placebo prior to the first CRU admission.
Immediately before and during each CRU admission, oral micronized progesterone (0.8 mg/kg/dose) will be given at 0700, 1500, 2300, and 0700 h.
During each CRU admission, blood will be obtained every 10 minutes through an indwelling iv catheter from 1800 to 1200 h.
This will allow full characterization of pulsatile LH secretion in addition to other hormone measurements.
Formal polysomnography will be performed during CRU admissions.
A second CRU admission (performed at least 2 months later given blood withdrawal limits) will be identical to the first except that placebo pretreatment will exchanged for spironolactone pretreatment or vice versa (treatment crossover).
The primary endpoint is LH pulse frequency while awake.
(LH pulse frequency while asleep is an important secondary endpoint.)
The wake LH pulse frequency data from the spironolactone and placebo admissions will be analyzed via a hierarchical linear mixed model (HLMM).
The admission (spironolactone vs. placebo) will represent the fixed effect factor of the HLMM.
Random effects will be utilized to account for the hierarchical variance-covariance structure of the two-period cross-over design.
Wake LH pulse frequency in response to exogenous progesterone will be compared between the spironolactone admission and the placebo admission via a linear contrast of the HLMM least squares LH pulse frequency means.
A similar analysis will be performed for sleep-related LH pulse frequency.
Using published and preliminary data, we determined that, if 16 mid- to late pubertal girls with HA complete both admissions, we should have at least an 80% chance of detecting a 0.35 pulse/hour mean within-subject difference in wake LH pulse frequency between the spironolactone and placebo admissions with a two-sided false positive rejection rate of no more than 0.05.
Study Type
Interventional
Enrollment (Estimated)
32
Phase
- Early Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Contact
- Name: Melissa Gilrain, MS
- Phone Number: 434-243-6911
- Email: MG7ZB@hscmail.mcc.virginia.edu
Study Contact Backup
- Name: Christopher R McCartney, M.D.
- Phone Number: 434-923-0329
- Email: cm2hq@hscmail.mcc.virginia.edu
Study Locations
-
-
Virginia
-
Charlottesville, Virginia, United States, 22908
- Recruiting
- University of Virginia Clinical Research Unit
-
Principal Investigator:
- Christopher R McCartney, M.D.
-
Sub-Investigator:
- Christine M Burt Solorzano, M.D.
-
Sub-Investigator:
- Jessica A Lundgren, M.D.
-
Sub-Investigator:
- Su H Kim, M.D
-
Contact:
- Melissa Gilrain, MS
- Phone Number: 434-243-6911
- Email: MG7ZB@hscmail.mcc.virginia.edu
-
Contact:
- Christopher R McCartney, M.D.
- Phone Number: 434-923-0329
- Email: cm2hq@virginia.edu
-
Sub-Investigator:
- John C Marsahll, M.D.
-
-
Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
10 years to 17 years (Child)
Accepts Healthy Volunteers
Yes
Description
Inclusion Criteria:
- Mid- to late pubertal adolescent girl (at least Tanner breast stage 3, but no more than 2 years postmenarcheal)
- Hyperandrogenism, defined as a serum (calculated) free testosterone concentration greater than the Tanner stage-specific reference range and/or unequivocal evidence for hirsutism
- General good health (excepting overweight, obesity, hyperandrogenism, and adequately-treated hypothyroidism)
- Capable of and willing to provide informed assent (adolescents under age 16 years) and/or consent (adolescents over age 16 years; custodial parents or guardians of all adolescent volunteers)
- Willing to strictly avoid pregnancy with use of reliable non-hormonal methods during the study period
Exclusion Criteria:
- Inability/incapacity to provide informed consent
- Males will be excluded (hyperandrogenism is unique to females)
- Obesity resulting from a well-defined endocrinopathy or genetic syndrome
- Positive pregnancy test or current lactation
- Evidence for non-physiologic or non-PCOS causes of hyperandrogenism and/or anovulation
- Evidence of virilization (e.g., rapidly progressive hirsutism, deepening of the voice, clitoromegaly)
- Total testosterone > 150 ng/dl, which suggests the possibility of virilizing ovarian or adrenal tumor
- DHEA-S elevation > 1.5 times the upper reference range limit. Mild elevations may be seen in adolescent HA and in PCOS, and will be accepted in these groups.
- Early morning 17-hydroxyprogesterone > 200 ng/dl measured in the follicular phase, which suggests the possibility of congenital adrenal hyperplasia (if elevated during the luteal phase, the 17-hydroxyprogesterone will be repeated during the follicular phase). NOTE: If a 17-hydroxyprogesterone > 200 ng/dl is confirmed on repeat testing, an ACTH stimulated 17-hydroxyprogesterone < 1000 ng/dl will be required for study participation.
- Abnormal thyroid stimulating hormone (TSH): Note that subjects with stable and adequately treated primary hypothyroidism, reflected by normal TSH values, will not be excluded.
- Hyperprolactinemia > 20% higher than the upper limit of normal. Mild prolactin elevations may be seen in adolescents and women with HA/PCOS, and elevations within 20% higher than the upper limit of normal will be accepted in this group.
- History and/or physical exam findings suggestive of Cushing's syndrome, adrenal insufficiency, or acromegaly
- History and/or physical exam findings suggestive of hypogonadotropic hypogonadism (e.g., symptoms of estrogen deficiency) including functional hypothalamic amenorrhea (which may be suggested by a constellation of symptoms including restrictive eating patterns, excessive exercise, psychological stress, etc.)
- Persistent hematocrit < 36% and hemoglobin < 12 g/dl.
- Severe thrombocytopenia (platelets < 50,000 cells/microliter) or leukopenia (total white blood count < 4,000 cells/microliter)
- Previous diagnosis of diabetes, fasting glucose > or = 126 mg/dl, or a hemoglobin A1c > or = 6.5%
- Persistent liver panel abnormalities, with two exceptions. Mild bilirubin elevations will be accepted in the setting of known Gilbert's syndrome. Also, mild transaminase elevations may be seen in obesity/HA/PCOS; therefore, elevations < 1.5 times the upper limit of normal will be accepted in this group.
- Significant history of cardiac or pulmonary dysfunction (e.g., known or suspected congestive heart failure, asthma requiring intermittent systemic corticosteroids, etc.)
- Decreased renal function evidenced by GFR < 60 ml/min/1.73m2
- A personal history of breast, ovarian, or endometrial cancer
- History of any other cancer diagnosis and/or treatment (with the exception of basal cell or squamous cell skin carcinoma) unless they have remained clinically disease free (based on appropriate surveillance) for five years
- History of allergy to micronized progesterone or spironolactone
- Body mass index (BMI)-for-age percentile < 5% (underweight)
- Due to the amount of blood being drawn, adolescent volunteers with body weight < 25 kg will be excluded.
- Restrictions on use of other drugs or treatments: No medications known to affect the reproductive system, glucose metabolism, lipid metabolism, or blood pressure can be taken in the 2 months prior to the screening visit and in the 3 months prior to the start of the study medications. Such medications include oral contraceptive pills, progestins, metformin, systemic glucocorticoids, some antipsychotic medications, and sympathomimetics/stimulants (e.g., methylphenidate).
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Placebo Comparator: Placebo
Prior to the first or the second admission (randomly determined), participants will be pretreated for 2 weeks with placebo (twice daily).
|
Spironolactone is an androgen-receptor blocker commonly used (off-label) for hyperandrogenism.
The spironolactone dose will be 50 mg taken orally twice daily (for two weeks before admission to the Clinical Research Unit).
Placebo contains only inert ingredients and is not expected to exert any direct physiological effects.
|
Experimental: Spironolactone
Prior to the first or the second admission (randomly determined), participants will be pretreated for 2 weeks with spironolactone (50 mg twice daily).
|
Placebo contains only inert ingredients and is not expected to exert any direct physiological effects.
Micronized progesterone 0.8 mg/kg at 0700, 1500, 2300 and 0700 h.
Progesterone is a natural hormone.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Luteinizing hormone (LH) pulse frequency
Time Frame: During first CRU admission and during the second CRU admission (which occurs at least 2 months after the first)
|
LH pulse frequency while awake vs. while asleep
|
During first CRU admission and during the second CRU admission (which occurs at least 2 months after the first)
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Sponsor
Collaborators
Investigators
- Principal Investigator: Christopher R McCartney, M.D., University of Virginia Center for Research in Reproduction
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
July 21, 2016
Primary Completion (Estimated)
April 1, 2025
Study Completion (Estimated)
December 1, 2025
Study Registration Dates
First Submitted
February 23, 2017
First Submitted That Met QC Criteria
February 27, 2017
First Posted (Actual)
March 3, 2017
Study Record Updates
Last Update Posted (Actual)
November 2, 2023
Last Update Submitted That Met QC Criteria
November 1, 2023
Last Verified
November 1, 2023
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms
- Endocrine System Diseases
- Ovarian Cysts
- Cysts
- Ovarian Diseases
- Adnexal Diseases
- Gonadal Disorders
- 46, XX Disorders of Sex Development
- Disorders of Sex Development
- Urogenital Abnormalities
- Adrenogenital Syndrome
- Congenital Abnormalities
- Female Urogenital Diseases
- Female Urogenital Diseases and Pregnancy Complications
- Urogenital Diseases
- Male Urogenital Diseases
- Genital Diseases
- Genital Diseases, Female
- Polycystic Ovary Syndrome
- Hyperandrogenism
- Physiological Effects of Drugs
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Natriuretic Agents
- Diuretics
- Hormone Antagonists
- Mineralocorticoid Receptor Antagonists
- Diuretics, Potassium Sparing
- Progestins
- Spironolactone
- Progesterone
Other Study ID Numbers
- 18489
- P50HD028934 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
UNDECIDED
IPD Plan Description
We plan to share IPD.
Data from this study will be deposited in the NICHD Data and Specimen Hub "DASH."
We also plan to provide raw study data (de-identified) as supplementary materials in the resulting manuscript as was done for Kim SH, et al.
Progesterone-mediated inhibition of the GnRH pulse generator: differential sensitivity as a function of sleep status.
J Clin Endocrinol Metab 2018; 103: 1112-1121 [PMCID in process].
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Yes
Studies a U.S. FDA-regulated device product
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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