Clinical trial NCT01157182: Estradiol/Norethindrone Acetate Tablets, 1/0.5 mg Under Fasting Conditions
Official title: A Two-Way Crossover, Open-Label, Single-Dose, Fasting, Bioequivalence Study of Estradiol/Norethindrone Acetate Tablets, 1 mg/0.5 mg Versus Activella® (1 mg Estradiol/0.5 mg Norethindrone Acetate) Tablets in Normal, Healthy, Post-Menopausal Female Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Healthy
Bioequivalence
Post-Menopausal
Lead sponsor: Teva Pharmaceuticals USA
Sponsor class: INDUSTRY
First posted: 2010-07-05
Enrollment: 36
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER

Brief summary: The objective of this study was to determine and compare the rate and extent of absorption of norethindrone and unconjugated estradiol from a test formulation of Estradiol/Norethindrone Acetate Tablets, 1 mg/0.5 mg versus the reference Activella® (1 mg estradiol/0.5 mg norethindrone acetate) Tablets under fasting conditions.

Detailed description: Criteria for Evaluation: FDA Bioequivalence Criteria

Statistical Methods: FDA Bioequivalence Statistical Methods

Eligibility criteria: Inclusion Criteria:

* Non-smoking or smoking (up to 10 cigarettes/day), physiologically or surgically post-menopausal female within the age range of 18-65 years.
* 17β-estradiol serum levels of \< 90 pmol/L and follicle-stimulating hormone (FSH) of \> 40 IU/L.
* Body Mass Index greater than or equal to 19.0 and less than or equal to 32.0.
* Normal findings in the physical examination, 12-lead electrocardiogram (ECG) and vital signs.
* Hemoglobin \> 115 g/L
* Normal Pap smear within 6 months.
* Normal mammogram within 1 year for subjects who are over the age of 50 years.
* Negative for drugs of abuse and alcohol.
* Negative for hepatitis B surface antigen, hepatitis C and Human Immunodeficiency Virus (HIV).
* No clinical laboratory values outside of the acceptable range as defined by BCR, unless the Principal Investigator or Sub-investigator decides that they are not clinically significant.
* Negative for pregnancy.
* Subjects who are surgically post-menopausal with an intact uterus (i.e. bilateral oophorectomy) for at least 6 months, or physiologically post-menopausal (i.e. spontaneous amenorrhea) for at least 1 year, and who will adhere to contraceptive requirements from at least 10 days before Period I check in, during the study and up to 1 month after the end of the study.
* Availability of the subject for the entire study period and willingness of the subject to adhere to protocol requirements, as evidence by a signed ICF.

Exclusion Criteria:

* Known history of hypersensitivity to norethindrone and estradiol combinations and/or norethindrone, and/or estradiol.
* Known history or presence of cardiac, pulmonary, gastrointestinal, endocrine, musculoskeletal, neurological, or hematological diseases, malignancies, or migraines, unless deemed NCS by the Principal Investigator or Sub-investigator.
* Known history of liver, kidney, and/or gallbladder dysfunction/disease, chronic diarrhea or inflammatory bowel disease.
* Known history or presence of cerebrovascular diseases or venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis.
* Any history of stroke.
* Presence of any significant physical or organ abnormality.
* History of osteoporosis.
* History or presence of fibrocystic breast disease.
* History or presence of breast, endometrial, cervical, and/or uterine carcinoma.
* Any illness during the 4 weeks before the study, unless deemed NCS by the Principal Investigator or Sub-investigator.
* Any history or evidence of psychiatric or psychological disease, unless deemed NCS by the Principal Investigator or Sub-investigator.
* Any history of abnormal vaginal bleeding, unless deemed NCS by the Principal Investigator or Sub-investigator.
* Any history of asthma (after 12 years of age).
* Evidence of pregnancy or lactation.
* Any history of severe allergic reaction (including drugs, food, insect bites, environmental allergens).
* Known history or presence of food allergies, or any condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
* Any history of drug abuse.
* Any recent history of alcohol abuse (less than 1 year).
* Use of any prescription medication within 30 days preceding this study.
* Use of hormone replacement therapy within 30 days before drug administration.
* Use of over-the-counter medication or any herbal supplement within the 7 days preceding this study (except for spermicidal/barrier contraceptive products).
* Use of hormonal contraceptives within the 30 days before drug administration or a depot injection of progestogen drug within 1 year before drug administration.
* Depot injection of any drug (other than progestogen) within 6 months.
* Blood draws within 56 days preceding this study, during the conduct of any clinical study at a facility other than BCR, or within the lockout period specified by a previous study conducted at BCR.
* Blood donations within 56 days preceding this study.
* Participation as a plasma donor in a plasmapheresis program within 7 days preceding this study.
* Participation in a clinical trial with an investigational drug within 30 days preceding this study.
* Intolerance to venipuncture.

Primary outcomes:
measure: Cmax for Norethindrone(Maximum Observed Concentration of Drug Substance in Plasma)
timeFrame: Blood samples collected over a 36 hour period.
measure: AUC0-t for Norethindrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
timeFrame: Blood samples collected over a 36 hour period.
measure: AUC0-inf for Norethindrone(Area Under the Concentration-time Curve From Time Zero to Infinity)
timeFrame: Blood samples collected over a 36 hour period.
measure: Cmax for Corrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma)
timeFrame: Blood samples collected over a 72 hour period.
measure: AUC0-t for Corrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
timeFrame: Blood samples collected over a 72 hour period.
measure: AUC0-inf for Corrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity)
timeFrame: Blood samples collected over a 72 hour period.
Secondary outcomes:
measure: Cmax for Uncorrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma)
timeFrame: Blood samples collected over a 72 hour period.
measure: AUC0-t for Uncorrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
timeFrame: Blood samples collected over a 72 hour period.
measure: AUC0-inf for Uncorrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity)
timeFrame: Blood samples collected over a 72 hour period.
measure: Cmax for Uncorrected Unconjugated Estradiol(Maximum Observed Concentration of Drug Substance in Plasma)
timeFrame: Blood samples collected over a 72 hour period.
measure: AUC0-t for Uncorrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
timeFrame: Blood samples collected over a 72 hour period.
measure: AUC0-inf for Uncorrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity)
timeFrame: Blood samples collected over a 72 hour period.
measure: Cmax for Uncorrected Unconjugated Estrone(Maximum Observed Concentration of Drug Substance in Plasma)
timeFrame: Blood samples collected over a 72 hour period.
measure: AUC0-t for Uncorrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
timeFrame: Blood samples collected over a 72 hour period.
measure: AUC0-inf for Uncorrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity)
timeFrame: Blood samples collected over a 72 hour period.
measure: Cmax for Corrected Unconjugated Estradiol(Maximum Observed Concentration of Drug Substance in Plasma)
timeFrame: Blood samples collected over a 72 hour period.
measure: AUC0-t for Corrected Unconjugated Estradiol.(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
timeFrame: Blood samples collected over a 72 hour period.
measure: AUC0-inf for Corrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity)
timeFrame: Blood samples collected over a 72 hour period.
measure: Cmax for Corrected Unconjugated Estrone(Maximum Observed Concentration of Drug Substance in Plasma)
timeFrame: Blood samples collected over a 72 hour period.
measure: AUC0-t for Corrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
timeFrame: Blood samples collected over a 72 hour period.
measure: AUC0-inf for Corrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity)
timeFrame: Blood samples collected over a 72 hour period.
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Biovail Clinical Research
state: Ontario
Study officials:
affiliation: Biovail Contract Research
name: Paul Y Tam, M.D., F.R.C.P., F.A.C.P.
role: PRINCIPAL_INVESTIGATOR
References: