Official Title: “Double Blind Placebo Controlled Evaluation of Bioidentical Hormones”

Double blind placebo controlled pilot study comparing bioidentical 'natural' hormones to low-dose PremPro. Forty participants will be enrolled. The purpose of this study is to try to gather early information about safety when "natural" or bioidentical hormones are used during early menopause.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Investigator), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: October 2008

In spite of warnings regarding safety and adverse events widely publicized after the Women's Health Initiative (WHI), women continue to seek hormone replacement therapy for a variety of reasons. Increased cardiovascular events identified in WHI are an important concern for considering menopausal hormone replacement. There is the belief the 'natural' or bioidentical hormone replacement therapy could provide a safe alternative to widely used synthetic hormone replacement therapy. However, this has never been studied with any rigor and health care providers can not adequately advise patients seeking 'natural' bioidentical hormone therapy.

This feasibility pilot study is designed as a prospective double blind, placebo controlled study comparing 4 groups of women who are within 7 years of menopause. There will be 10 women in each of the 4 groups with a total of 40 women enrolled and these women will be treated for 12 months.

The Long-Term Goal is to provide health care practitioners and consumers with evidence-based recommendations for the use of bioidentical hormone replacement. The Short-Term Goal of this pilot study is to determine if it is feasible to conduct a study in bioidentical hormones and obtain information that could lead to a larger more definitive study. We would like to provide safety information for bioidentical hormone use by evaluating surrogate markers for cardiovascular disease (lipid levels), with secondary evaluation of breast (mammogram) and uterus (endovaginal ultrasound), and to collect information about bone preservation.

The information gained from this trial will provide information for a future trial to test the hypothesis that bioidentical hormone replacement therapy provides a safe alternative to standard hormone replacement therapy: To determine if bioidentical hormone replacement therapy is associated with improved lipid profiles (surrogate marker for cardiovascular disease) when compared to Prempro. This will be determined by evaluating lipid levels at baseline and during the 12-month treatment period.

Secondary hypotheses will also be evaluated in the future to include:

1. To determine if bioidentical hormone replacement therapy provides improved short-term risk profiles for uterine and breast health when compared to Prempro. This will be accomplished by requiring mammograms and endovaginal ultrasounds at baseline and the end of each of the 12-month treatment period.

2. To determine if there is bone loss when using bioidentical hormone replacement when compared to Prempro. This aim will be evaluated by Dexa bone scan at baseline and at 12 months.

Subjects will randomly be assigned to one of the four arms of the study for the 12 months of treatment. The standard of care arm will consist of 10 women receiving in a double blind placebo controlled fashion low-dose Prempro. There will be 3 treatment arms consisting of different combinations of E2 estradiol and/or E3 estriol, all combined with bioidentical progesterone. These 3 arms will each have 10 subjects randomized and the bioidentical hormone delivered in a double blind placebo controlled fashion. Since the gold standard for treatment is the conventional arm (Prempro), we will compare each bioidentical arms to the gold standard. This comparison will occur at the end of 12 months of treatment. In this pilot study, we also wish to collect preliminary data about the comparisons between the 3 bioidentical hormone arm and the conventional arm. This is necessary because there is currently anecdotal evidence that E3 alone without combination with E2 may constitute adequate therapy in spite of its low biological activity at the estrogen receptor. The use of high doses of E3 with or without E2 is in common use by complementary and alternative practitioners.

It is expected in this small pilot study that bioidentical hormone will provide an adequate short-term safety profile for cardiovascular, breast and uterine health that will provide guidance for a larger trial that is longer in duration. It is also expected that bone density may be maintained by bioidentical hormone replacement when compared to Prempro. There may not be sufficient numbers to determine significance between the control arm and the treatment arms; however, we expect to collect useful information for future trials. It is assumed that equivalence will not likely be determined based on the sample size.

Intervention(s) in this Clinical Trial

• Drug: Prempro
  • premarin .45 mg, provera 1.5 mg
• Drug: estradiol, estriol, progesterone
  • estradiol 0.5 mg, estriol 2.0 mg, progesterone 100 mg
• Drug: estriol, progesterone
  • estriol 2.5 mg, progesterone 100 mg
• Drug: estradiol, progesterone
  • estradiol 0.5 mg, progesterone 100 mg

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • Prempro
• Experimental: 2
  • Estradiol, estriol, progesterone
• Experimental: 3
  • estriol, progesterone
• Experimental: 4
  • estradiol,progesterone

Primary Measures

• evaluating surrogate markers for cardiovascular disease (lipid levels)
  • Time Frame: baseline, 6 months, and at 12-month completion
    Safety Issue?: Yes

Secondary Measures

• Surrogate markers for cardiovascular disease (lipid levels and ECG)
  • Time Frame: baseline, 6 months, and at 12-month completion
    Safety Issue?: Yes
• Secondary: short-term risk profiles for uterine (ultrasound) and breast health (mammogram) and evaluation of bone mass (bone scan)
  • Time Frame: baseline and at 12 months.
    Safety Issue?: Yes

Inclusion Criteria:

• Female
• Ambulatory
• Within 7 years post menopause
• Positive history of menopausal symptoms such as vasomotor symptoms or osteoporosis in a study subject unable to tolerate bisphosphonates
• FSH greater than 20 mIU/mL
• Intact uterus and at least one intact ovary
• Amenorrhea for 3 months or greater up to 7 years
• Normal pap smear results within 12 months
• Normal mammogram result within 12 months
• Agreeable to a 3 month washout period with no hormones prior to entering the trial
• Women who have no language barrier, are cooperative, and who can give informed consent before entering this study

Exclusion Criteria:

• Unwilling to take hormone replacement for the 12 month period
• Evidence of clinically significant psychiatric disorder by history/examination that would prevent the patient from completing the study.
• Active deep venous thrombosis, pulmonary embolism, or a history of these conditions
• Active or recent arterial thromboembolic disease
• Undiagnosed vaginal bleeding
• Hypersensitivity to ingredients in Prempro
• Patients with known current bone disorders other than primary osteoporosis
• Patients with pathological fractures
• Patients with suspected or history of carcinoma of the breast or estrogen dependent neoplasms such as endometrial carcinoma.
• Patients who have ≥ 5mm endometrial thickness by endovaginal (transvaginal) ultrasound.
• Patients who have impaired renal function evidenced by serum creatinine greater than 2.5 mg/dL.
• Patients who have impaired hepatic function evidenced by transaminase (AST/ALT) ≥2.5X upper limit
• Patients with severe malabsorption syndromes.
• Patients who consume an excess of alcohol or abuse drugs (an excess of alcohol is defined as more than four of any one or combination of the following per day: 30 mL distilled spirits, 340 mL beer, or 120 mL wine).
• Treatment with therapeutic doses of any of the following medications more recently than 3 months:
• Estrogen
• Calcitonin
• Corticosteroids
• Progestins
• Progesterone
• Lithium
• Androgen
• Heparin
• Herbal menopause treatments
• SERMS
• Fluorides
• Phosphate binding antacids
• Bisphosphonates
• Vitamin D 50,000IU
• Anticonvulsants
• Patients who received any investigational drug within the proceeding month
• Tobacco use will not be allowed

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 40 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: Accepts Healthy Volunteers

Lead Sponsor: University of Kansas

Overall Clinical Trial Officials and Contacts

Jeanne A Drisko, MD Principal Investigator University of Kansas  

Overall Contact: Jeanne A Drisko, MD 913-588-6208 jdrisko@kumc.edu

Information obtained from ClinicalTrials.gov on August 20, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00302731

Study ID Number: 9941

ClinicalTrials.gov Identifier: NCT00302731

Health Authority: United States: Food and Drug Administration