Metformin for the Treatment of Premature Pubarche in Girls

A Double Blind Randomized Controlled 12 Month Trial of Metformin for the Treatment of Premature Pubarche in Girls

The primary objective of this study is to determine the safety and efficacy of metformin in lowering serum DHEAS levels in girls with premature pubarche and secondary, to observe changes in hormones associated with pubertal development including gonadotropins, sex steroids, insulin, adipocytokines, and growth factors.

Study Overview

• Status: Terminated
• Conditions: Premature Pubarche
• Intervention / Treatment: Drug: sugar pill; Drug: Metformin, glucophage

• Study Type: Interventional
• Enrollment (Actual): 4
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children, Indiana University School of Medicine
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh at the University of Pittsburgh Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 10 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

1. Girls aged 4-10 with pubic hair prior to 8 years of age
2. Elevated DHEAS level above age normal levels
3. Informed consent from parents and assent from the girl

Exclusion Criteria:

1. Diagnosis of incomplete precocious puberty, peripheral precocious puberty, or evidence of any abnormal pituitary, hypothalamic, adrenal, thyroid, and gonadal function other than premature secretion of adrenal androgens.
2. Chronic illness requiring treatment that may interfere with growth and development, i.e. chronic steroid use, renal failure, etc.
3. 21-hydroxylase deficiency or other enzyme deficiency leading to the phenotype of congenital adrenal hyperplasia. 21-hydroxylase deficiency will be excluded in all patients by a fasting 17-hydroxyprogesterone (17-OHP) level < 2 ng/mL. In the case of elevated fasting 17-OHP levels, an ACTH stimulation test will be performed. A 1-hour stimulated value > 10 ng/mL will be an exclusion 82. As 21 hydroxylase deficiency is a congenital condition, any normal level in the past of 17-hydroxyprogesterone allows entry into this study.
4. Uncorrected thyroid disease (defined as TSH < 0.2 mIU/ML or > 5.5 mIU/mL). A normal level within the last year is adequate for entry.
5. Type I or Type II diabetes (defined as a fasting serum glucose > 125mg/dL on two occasions 83), or patients receiving anti-diabetic medications such as insulin, thiazolidinediones, acarbose, or sulfonylureas; patients currently receiving metformin XR for a diagnosis of Type I or Type II diabetes or for PCOS are also specifically excluded.
6. Liver disease defined as AST or ALT > 2 times normal or total bilirubin > 2.5 mg/dL.
7. Renal disease defined as BUN > 30 mg/dL or serum creatinine > 1.4 mg/dL.
8. Significant anemia (Hemoglobin < 10 mg/dL).
9. History of deep venous thrombosis, pulmonary embolus, or cerebrovascular accident.
10. Known heart disease (New York Heart Association Class II or higher).
11. Enrolled simultaneously into other investigative studies that require medications, proscribe the study medications, or otherwise prevent compliance with the protocol. Patients who anticipate taking longer than a one month break during the protocol should not be enrolled.
12. Concomitant use other medications known to affect reproductive function or metabolism. These medications include growth hormone, IGF-1, medroxyprogesterone acetate, oral contraceptives, GnRH agonists and antagonists, anti-androgens, gonadotropins, anti-obesity drugs, somatostatin, diazoxide, ACE inhibitors, and calcium channel blockers. The washout period on all these medications will be three months.
13. Suspected adrenal or ovarian tumor secreting androgens or other ectopic steroid secreting tumor.
14. Suspected Cushing's syndrome.
15. Lactose intolerance (the placebo filler is lactose).
16. Known hypersensitivity to study medication, including ACTH and GnRH, or their excipients.
17. Any concomitant medical condition that in the opinion of the investigator, may expose a subject to unacceptable level of safety risk, or that affects subject compliance.
18. Subjects who anticipate having any surgery associated with restricted intake of fluids or radiological studies with contrast dye during the study period.
19. Any concomitant medical condition that in the opinion of the investigator, may expose a subject to unacceptable level of safety risk, or that affects subject compliance.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: sugar pill; 2 pills per day for 12 months	Drug: sugar pill; 2 pills per day for 12 months
Active Comparator: Metformin; 2 212.5mg pill/day for 12 months	Drug: Metformin, glucophage; 2 212.5mg pills/day for 12 months; Other Names: metformin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Serum DHEAS Levels	Change in DHEAS level was constructed per subject as the 1-year measurement minus the baseline measurement. Only descriptive statistics are provided, statistical tests were not conducted given the extremely small sample size per group.	1 year

Collaborators and Investigators

• Sponsor: Milton S. Hershey Medical Center
• Investigators: Principal Investigator: Richard S Legro, MD, Milton S. Hershey Medical Center

Publications and helpful links

Helpful Links

• departmental website

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): December 1, 2013
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: March 15, 2011
• First Submitted That Met QC Criteria: March 15, 2011
• First Posted (Estimate): March 16, 2011

Study Record Updates

• Last Update Posted (Estimate): May 12, 2016
• Last Update Submitted That Met QC Criteria: April 7, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Keywords: Puberty; Hormones
• Additional Relevant MeSH Terms: Endocrine System Diseases; Gonadal Disorders; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Puberty, Precocious; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin
• Other Study ID Numbers: 35865