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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 fed conditions.
Criteria for Evaluation: FDA Bioequivalence Criteria
Statistical Methods: FDA Bioequivalence Statistical Methods
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Investigational Test Product | Experimental | Estradiol/Norethindrone Acetate Tablets, 1 mg/0.5 mg |
|
| Reference Listed Drug | Active Comparator | Activella® (1 mg estradiol/0.5 mg norethindrone acetate) Tablets |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Estradiol/Norethindrone acetate | Drug | 1 mg/0.5 mg Tablets |
|
| Measure | Description | Time Frame |
|---|---|---|
| Cmax of Norethindrone (Maximum Observed Concentration of Drug Substance in Plasma) | Bioequivalence based on Norethindrone Cmax. | Blood samples collected over a 36 hour period. |
| AUC0-t of Norethindrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Bioequivalence based on Norethindrone AUC0-t. | Blood samples collected over a 36 hour period. |
| AUC0-inf of Norethindrone(Area Under the Concentration-time Curve From Time Zero to Infinity) | Bioequivalence based on Norethindrone AUC0-inf. | Blood samples collected over a 36 hour period. |
| Cmax of Corrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma) | Bioequivalence based on Corrected Total Estrone Cmax. | Blood samples collected over a 72 hour period. |
| AUC0-t of Corrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Bioequivalence based on Corrected Total Estrone AUC0-t. | Blood samples collected over a 72 hour period. |
| AUC0-inf of Corrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity) | Bioequivalence based on Corrected Total Estrone AUC0-inf. | Blood samples collected over a 72 hour period. |
| Measure | Description | Time Frame |
|---|---|---|
| Cmax of Uncorrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma) | Informational comparison of Cmax values for Uncorrected Total Estrone. | Blood samples collected over a 72 hour period. |
| AUC0-t of Uncorrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Paul Y Tam, M.D., F.R.C.P., F.A.C.P. | Biovail Clinical Research | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Biovail Contract Research | Toronto | Ontario | M1L 4S4 | Canada |
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| ID | Title | Description |
|---|---|---|
| FG000 | Estradiol/Norethindrone Acetate (Test) First | 1 mg/0.5 mg Estradiol/Norethindrone Acetate Tablets test product dosed in first period followed by 1 mg/0.5 mg Activella® Tablets reference product dosed in the second period. |
| FG001 | Activella® (Reference) First | 1 mg/0.5 mg Activella® Tablets reference product dosed in first period followed by 1 mg/0.5 mg Estradiol/Norethindrone Acetate Tablets test product dosed in the second period. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention |
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| Washout of 28 Days |
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| Second Intervention |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Estradiol/Norethindrone Acetate (Test) First | 1 mg/0.5 mg Estradiol/Norethindrone Acetate Tablets test product dosed in first period followed by 1 mg/0.5 mg Activella® Tablets reference product dosed in the second period. |
| BG001 | Activella® (Reference) First |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Cmax of Norethindrone (Maximum Observed Concentration of Drug Substance in Plasma) | Bioequivalence based on Norethindrone Cmax. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | ng/mL | Blood samples collected over a 36 hour period. |
|
Adverse event data was collected over the course of the study, which was approximately 6 weeks in duration.
Volunteers were monitored throughout the study for any adverse experiences. AEs were collected through both solicited and unsolicited methods. The volunteers were encouraged to report signs, symptoms, and any changes in health to the clinic staff.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Estradiol/Norethindrone Acetate (Test) | 1 mg/0.5 mg Estradiol/Norethindrone Acetate Tablets test product dosed in either period. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | General disorders | MedDRA (Unspecified) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Associate Director, Biopharmaceutics | TEVA Pharmaceuticals, USA | 1-866-384-5525 | clinicaltrialqueries@tevausa.com |
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| ID | Term |
|---|---|
| C418365 | estradiol, norethindrone drug combination |
| D004958 | Estradiol |
| D000077563 | Norethindrone Acetate |
| ID | Term |
|---|---|
| D004963 | Estrenes |
| D004962 | Estranes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
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| Activella® | Drug | 1 mg/0.5 mg Tablets |
|
|
Informational comparison of AUC0-t values for Uncorrected Total Estrone. |
| Blood samples collected over a 72 hour period. |
| AUC0-inf of Uncorrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity) | Informational comparison of AUC0-inf values for Uncorrected Total Estrone. | Blood samples collected over a 72 hour period. |
| Cmax of Uncorrected Unconjugated Estradiol(Maximum Observed Concentration of Drug Substance in Plasma) | Informational comparison of Cmax values for Uncorrected Unconjugated Estradiol. | Blood samples collected over a 72 hour period. |
| AUC0-t of Uncorrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Informational comparison of AUC0-t values for Uncorrected Unconjugated Estradiol. | Blood samples collected over a 72 hour period. |
| AUC0-inf of Uncorrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity) | Informational comparison of AUC0-inf values for Uncorrected Unconjugated Estradiol. | Blood samples collected over a 72 hour period. |
| Cmax of Uncorrected Unconjugated Estrone(Maximum Observed Concentration of Drug Substance in Plasma) | Informational comparison of Cmax values for Uncorrected Unconjugated Estrone. | Blood samples collected over a 72 hour period. |
| AUC0-t of Uncorrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Informational comparison of AUC0-t values for Uncorrected Unconjugated Estrone. | Blood samples collected over a 72 hour period. |
| AUC0-inf of Uncorrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity) | Informational comparison of AUC0-inf values for Uncorrected Unconjugated Estrone. | Blood samples collected over a 72 hour period. |
| Cmax of Corrected Unconjugated Estradiol(Maximum Observed Concentration of Drug Substance in Plasma) | Informational comparison of Cmax values for Corrected Unconjugated Estradiol. | Blood samples collected over a 72 hour period. |
| AUC0-t of Corrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Informational comparison of AUC0-t values for Corrected Unconjugated Estradiol. | Blood samples collected over a 72 hour period. |
| AUC0-inf of Corrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity) | Informational comparison of AUC0-inf values for Corrected Unconjugated Estradiol. | Blood samples collected over a 72 hour period. |
| Cmax of Corrected Unconjugated Estrone(Maximum Observed Concentration of Drug Substance in Plasma) | Informational comparison of Cmax values for Corrected Unconjugated Estrone. | Blood samples collected over a 72 hour period. |
| AUC0-t of Corrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Informational comparison of AUC0-t values for Corrected Unconjugated Estrone. | Blood samples collected over a 72 hour period. |
| AUC0-inf of Corrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity) | Informational comparison of AUC0-inf values for Corrected Unconjugated Estrone. | Blood samples collected over a 72 hour period. |
| NOT COMPLETED |
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| NOT COMPLETED |
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1 mg/0.5 mg Activella® Tablets reference product dosed in first period followed by 1 mg/0.5 mg Estradiol/Norethindrone Acetate Tablets test product dosed in the second period. |
| BG002 | Total | Total of all reporting groups |
| Participants |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Number | participants |
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| Region of Enrollment | Number | participants |
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| Units | Counts |
|---|---|
| Participants |
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|
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| Primary | AUC0-t of Norethindrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Bioequivalence based on Norethindrone AUC0-t. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | ng*h/mL | Blood samples collected over a 36 hour period. |
|
|
|
|
| Primary | AUC0-inf of Norethindrone(Area Under the Concentration-time Curve From Time Zero to Infinity) | Bioequivalence based on Norethindrone AUC0-inf. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | ng*h/mL | Blood samples collected over a 36 hour period. |
|
|
|
|
| Primary | Cmax of Corrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma) | Bioequivalence based on Corrected Total Estrone Cmax. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg/mL | Blood samples collected over a 72 hour period. |
|
|
|
|
| Primary | AUC0-t of Corrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Bioequivalence based on Corrected Total Estrone AUC0-t. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg*h/mL | Blood samples collected over a 72 hour period. |
|
|
|
|
| Primary | AUC0-inf of Corrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity) | Bioequivalence based on Corrected Total Estrone AUC0-inf. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg*h/mL | Blood samples collected over a 72 hour period. |
|
|
|
|
| Secondary | Cmax of Uncorrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma) | Informational comparison of Cmax values for Uncorrected Total Estrone. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg/mL | Blood samples collected over a 72 hour period. |
|
|
|
|
| Secondary | AUC0-t of Uncorrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Informational comparison of AUC0-t values for Uncorrected Total Estrone. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg*h/mL | Blood samples collected over a 72 hour period. |
|
|
|
|
| Secondary | AUC0-inf of Uncorrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity) | Informational comparison of AUC0-inf values for Uncorrected Total Estrone. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg*h/mL | Blood samples collected over a 72 hour period. |
|
|
|
|
| Secondary | Cmax of Uncorrected Unconjugated Estradiol(Maximum Observed Concentration of Drug Substance in Plasma) | Informational comparison of Cmax values for Uncorrected Unconjugated Estradiol. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg/mL | Blood samples collected over a 72 hour period. |
|
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|
|
| Secondary | AUC0-t of Uncorrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Informational comparison of AUC0-t values for Uncorrected Unconjugated Estradiol. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg*h/mL | Blood samples collected over a 72 hour period. |
|
|
|
|
| Secondary | AUC0-inf of Uncorrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity) | Informational comparison of AUC0-inf values for Uncorrected Unconjugated Estradiol. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg*h/mL | Blood samples collected over a 72 hour period. |
|
|
|
|
| Secondary | Cmax of Uncorrected Unconjugated Estrone(Maximum Observed Concentration of Drug Substance in Plasma) | Informational comparison of Cmax values for Uncorrected Unconjugated Estrone. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg/mL | Blood samples collected over a 72 hour period. |
|
|
|
|
| Secondary | AUC0-t of Uncorrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Informational comparison of AUC0-t values for Uncorrected Unconjugated Estrone. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg*h/mL | Blood samples collected over a 72 hour period. |
|
|
|
|
| Secondary | AUC0-inf of Uncorrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity) | Informational comparison of AUC0-inf values for Uncorrected Unconjugated Estrone. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg*h/mL | Blood samples collected over a 72 hour period. |
|
|
|
|
| Secondary | Cmax of Corrected Unconjugated Estradiol(Maximum Observed Concentration of Drug Substance in Plasma) | Informational comparison of Cmax values for Corrected Unconjugated Estradiol. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg/mL | Blood samples collected over a 72 hour period. |
|
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|
|
| Secondary | AUC0-t of Corrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Informational comparison of AUC0-t values for Corrected Unconjugated Estradiol. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg*h/mL | Blood samples collected over a 72 hour period. |
|
|
|
|
| Secondary | AUC0-inf of Corrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity) | Informational comparison of AUC0-inf values for Corrected Unconjugated Estradiol. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg*h/mL | Blood samples collected over a 72 hour period. |
|
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|
|
| Secondary | Cmax of Corrected Unconjugated Estrone(Maximum Observed Concentration of Drug Substance in Plasma) | Informational comparison of Cmax values for Corrected Unconjugated Estrone. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg/mL | Blood samples collected over a 72 hour period. |
|
|
|
|
| Secondary | AUC0-t of Corrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration) | Informational comparison of AUC0-t values for Corrected Unconjugated Estrone. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg*h/mL | Blood samples collected over a 72 hour period. |
|
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|
|
| Secondary | AUC0-inf of Corrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity) | Informational comparison of AUC0-inf values for Corrected Unconjugated Estrone. | All participants that completed the study had their samples analyzed. | Posted | Mean | Standard Deviation | pg*h/mL | Blood samples collected over a 72 hour period. |
|
|
|
|
| 0 |
| 40 |
| 1 |
| 40 |
| EG001 | Activella® (Reference) | 1 mg/0.5 mg Activella® Tablets reference product dosed in either period. | 0 | 40 | 2 | 40 |
The Principal Investigator is not permitted to discuss or publish trial results.
| D011083 |
| Polycyclic Compounds |
| D045166 | Estradiol Congeners |
| D012739 | Gonadal Steroid Hormones |
| D042341 | Gonadal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D009640 | Norethindrone |
| D009652 | Norpregnenes |
| D009650 | Norpregnanes |
| D009654 | Norsteroids |