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Estradiol/Norethindrone Acetate Tablets, 1/0.5 mg Under Fasting Conditions

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01157182
Recruitment Status : Completed
First Posted : July 5, 2010
Results First Posted : December 17, 2010
Last Update Posted : December 17, 2010
Sponsor:
Information provided by:
Teva Pharmaceuticals USA

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label)
Condition Healthy
Interventions Drug: Estradiol/Norethindrone acetate
Drug: Activella®
Enrollment 36
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Estradiol/Norethindrone Acetate (Test) First Activella® (Reference) First
Hide Arm/Group Description 1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in first period followed by 1/0.5 mg Activella® Tablets reference product dosed in the second period. 1/0.5 mg Activella® Tablets reference product dosed in first period followed by 1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in the second period.
Period Title: First Intervention
Started 18 18
Completed 18 18
Not Completed 0 0
Period Title: Washout of 28 Days
Started 18 18
Completed 16 18
Not Completed 2 0
Reason Not Completed
Adverse Event             2             0
Period Title: Second Intervention
Started 16 18
Completed 16 18
Not Completed 0 0
Arm/Group Title Estradiol/Norethindrone Acetate (Test) First Activella® (Reference) First Total
Hide Arm/Group Description 1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in first period followed by 1/0.5 mg Activella® Tablets reference product dosed in the second period. 1/0.5 mg Activella® Tablets reference product dosed in first period followed by 1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in the second period. Total of all reporting groups
Overall Number of Baseline Participants 18 18 36
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 18 participants 36 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
17
  94.4%
18
 100.0%
35
  97.2%
>=65 years
1
   5.6%
0
   0.0%
1
   2.8%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 18 participants 36 participants
Female
18
 100.0%
18
 100.0%
36
 100.0%
Male
0
   0.0%
0
   0.0%
0
   0.0%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 18 participants 18 participants 36 participants
Caucasian 12 14 26
Hispanic 0 3 3
Black 3 0 3
Asian 3 0 3
American Indian 0 1 1
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Canada Number Analyzed 18 participants 18 participants 36 participants
18 18 36
1.Primary Outcome
Title Cmax for Norethindrone(Maximum Observed Concentration of Drug Substance in Plasma)
Hide Description Bioequivalence based on Norethindrone Cmax.
Time Frame Blood samples collected over a 36 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: ng/mL
10.08  (3.32) 9.90  (3.68)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 102.94
Confidence Interval (2-Sided) 90%
97.63 to 108.55
Estimation Comments Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.
2.Primary Outcome
Title AUC0-t for Norethindrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Hide Description Bioequivalence based on Norethindrone AUC0-t.
Time Frame Blood samples collected over a 36 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: ng*h/mL
36.59  (19.54) 37.05  (18.07)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 98.40
Confidence Interval (2-Sided) 90%
95.15 to 101.76
Estimation Comments Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.
3.Primary Outcome
Title AUC0-inf for Norethindrone(Area Under the Concentration-time Curve From Time Zero to Infinity)
Hide Description Bioequivalence based on Norethindrone AUC0-inf.
Time Frame Blood samples collected over a 36 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: ng*h/mL
39.94  (20.14) 40.40  (18.90)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 98.73
Confidence Interval (2-Sided) 90%
95.33 to 102.26
Estimation Comments Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.
4.Primary Outcome
Title Cmax for Corrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma)
Hide Description Bioequivalence based on Corrected Total Estrone Cmax.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg/mL
43997.17  (10387.84) 47015.47  (9894.22)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 92.51
Confidence Interval (2-Sided) 90%
88.64 to 96.55
Estimation Comments Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.
5.Primary Outcome
Title AUC0-t for Corrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Hide Description Bioequivalence based on Corrected Total Estrone AUC0-t.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg*h/mL
365242.88  (155344.76) 374730.12  (145770.97)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 95.66
Confidence Interval (2-Sided) 90%
92.60 to 98.81
Estimation Comments Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.
6.Primary Outcome
Title AUC0-inf for Corrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity)
Hide Description Bioequivalence based on Corrected Total Estrone AUC0-inf.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg*h/mL
375439.71  (164404.58) 384535.16  (153333.46)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 95.71
Confidence Interval (2-Sided) 90%
92.62 to 98.91
Estimation Comments Bioequivalence is established if the 90% confidence interval for the ln-transformed geometric mean between the reference (R) and test (T) product fall within the interval of 80-125%.
7.Secondary Outcome
Title Cmax for Uncorrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma)
Hide Description Informational comparison of Cmax values for Uncorrected Total Estrone.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg/mL
43723.53  (10562.40) 47170.59  (9913.52)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 92.41
Confidence Interval (2-Sided) 90%
88.65 to 96.33
Estimation Comments This analysis was for informational purposes only and was not used to establish bioequivalence.
8.Secondary Outcome
Title AUC0-t for Uncorrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Hide Description Informational comparison of AUC0-t values for Uncorrected Total Estrone.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg*h/mL
372088.37  (159941.67) 385829.05  (150207.71)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 95.67
Confidence Interval (2-Sided) 90%
92.68 to 98.77
Estimation Comments This analysis was for informational purposes only and was not used to establish bioequivalence.
9.Secondary Outcome
Title AUC0-inf for Uncorrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity)
Hide Description Informational comparison of AUC0-inf values for Uncorrected Total Estrone.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg*h/mL
387085.29  (172021.74) 400726.94  (160336.60)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 95.73
Confidence Interval (2-Sided) 90%
92.68 to 98.88
Estimation Comments This analysis was for informational purposes only and was not used to establish bioequivalence.
10.Secondary Outcome
Title Cmax for Uncorrected Unconjugated Estradiol(Maximum Observed Concentration of Drug Substance in Plasma)
Hide Description Informational comparison of Cmax values for Uncorrected Unconjugated Estradiol.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg/mL
52.09  (19.78) 56.26  (18.96)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 91.21
Confidence Interval (2-Sided) 90%
84.62 to 98.31
Estimation Comments This analysis was for informational purposes only and was not used to establish bioequivalence.
11.Secondary Outcome
Title AUC0-t for Uncorrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Hide Description Informational comparison of AUC0-t values for Uncorrected Unconjugated Estradiol.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg*h/mL
1575.01  (670.36) 1656.16  (680.55)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 94.11
Confidence Interval (2-Sided) 90%
89.04 to 99.47
Estimation Comments This analysis was for informational purposes only and was not used to establish bioequivalence.
12.Secondary Outcome
Title AUC0-inf for Uncorrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity)
Hide Description Informational comparison of AUC0-inf values for Uncorrected Unconjugated Estradiol.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg*h/mL
1739.31  (671.74) 1905.28  (865.43)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 97.48
Confidence Interval (2-Sided) 90%
90.70 to 104.76
Estimation Comments This analysis was for informational purposes only and was not used to establish bioequivalence.
13.Secondary Outcome
Title Cmax for Uncorrected Unconjugated Estrone(Maximum Observed Concentration of Drug Substance in Plasma)
Hide Description Informational comparison of Cmax values for Uncorrected Unconjugated Estrone.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg/mL
475.44  (155.40) 502.24  (163.45)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 94.19
Confidence Interval (2-Sided) 90%
89.78 to 98.81
Estimation Comments This analysis was for informational purposes only and was not used to establish bioequivalence.
14.Secondary Outcome
Title AUC0-t for Uncorrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Hide Description Informational comparison of AUC0-t values for Uncorrected Unconjugated Estrone.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg*h/mL
10870.03  (4207.05) 11252.64  (4220.20)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 95.99
Confidence Interval (2-Sided) 90%
92.73 to 99.36
Estimation Comments This analysis was for informational purposes only and was not used to establish bioequivalence.
15.Secondary Outcome
Title AUC0-inf for Uncorrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity)
Hide Description Informational comparison of AUC0-inf values for Uncorrected Unconjugated Estrone.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg*h/mL
12387.14  (4715.23) 12646.49  (4673.97)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 97.22
Confidence Interval (2-Sided) 90%
93.62 to 100.96
Estimation Comments This analysis was for informational purposes only and was not used to establish bioequivalence.
16.Secondary Outcome
Title Cmax for Corrected Unconjugated Estradiol(Maximum Observed Concentration of Drug Substance in Plasma)
Hide Description Informational comparison of Cmax values for Corrected Unconjugated Estradiol.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg/mL
47.80  (19.05) 51.59  (18.77)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 91.73
Confidence Interval (2-Sided) 90%
84.46 to 99.62
Estimation Comments This analysis was for informational purposes only and was not used to establish bioequivalence.
17.Secondary Outcome
Title AUC0-t for Corrected Unconjugated Estradiol.(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Hide Description Informational comparison of AUC0-t values for Corrected Unconjugated Estradiol.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg*h/mL
1267.50  (574.02) 1323.70  (615.33)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 95.47
Confidence Interval (2-Sided) 90%
88.37 to 103.14
Estimation Comments This analysis was for informational purposes only and was not used to establish bioequivalence.
18.Secondary Outcome
Title AUC0-inf for Corrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity)
Hide Description Informational comparison of AUC0-inf values for Corrected Unconjugated Estradiol.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg*h/mL
1359.50  (664.41) 1410.51  (695.23)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 95.63
Confidence Interval (2-Sided) 90%
88.10 to 103.81
Estimation Comments This analysis was for informational purposes only and was not used to establish bioequivalence.
19.Secondary Outcome
Title Cmax for Corrected Unconjugated Estrone(Maximum Observed Concentration of Drug Substance in Plasma)
Hide Description Informational comparison of Cmax values for Corrected Unconjugated Estrone.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg/mL
455.16  (153.38) 481.46  (163.19)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 94.15
Confidence Interval (2-Sided) 90%
89.56 to 98.98
Estimation Comments This analysis was for informational purposes only and was not used to establish bioequivalence.
20.Secondary Outcome
Title AUC0-t for Corrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)
Hide Description Informational comparison of AUC0-t values for Corrected Unconjugated Estrone.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg*h/mL
9409.59  (4029.75) 9762.49  (4170.35)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 96.01
Confidence Interval (2-Sided) 90%
92.14 to 100.04
Estimation Comments This analysis was for informational purposes only and was not used to establish bioequivalence.
21.Secondary Outcome
Title AUC0-inf for Corrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity)
Hide Description Informational comparison of AUC0-inf values for Corrected Unconjugated Estrone.
Time Frame Blood samples collected over a 72 hour period.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Estradiol/Norethindrone Acetate (Test) Activella® (Reference)
Hide Arm/Group Description:
1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
1/0.5 mg Activella® Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: pg*h/mL
10267.03  (4156.10) 10214.23  (4497.68)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Estradiol/Norethindrone Acetate (Test), Activella® (Reference)
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments ANOVA is to be used to identify the source contributions by factors including subjects, period, formulation and potential interactions. The geometric mean ratio together with the ANOVA residual mean error term are used to identify the statistical basis for the 90% confidence interval for the ratio of the population means (Test [T]/Reference[R]) of the identified metrics (e.g. AUC, Cmax).
Method of Estimation Estimation Parameter Ratio of the T/R geometric mean x 100
Estimated Value 96.75
Confidence Interval (2-Sided) 90%
92.75 to 100.93
Estimation Comments This analysis was for informational purposes only and was not used to establish bioequivalence.
Time Frame Adverse event data was collected over the course of the study, which was approximately 6 weeks in duration.
Adverse Event Reporting Description 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.
 
Arm/Group Title Estradiol/Norethindrone Acetate (Test) First Activella® (Reference) First
Hide Arm/Group Description 1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in first period followed by 1/0.5 mg Activella® Tablets reference product dosed in the second period. 1/0.5 mg Activella® Tablets reference product dosed in first period followed by 1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in the second period.
All-Cause Mortality
Estradiol/Norethindrone Acetate (Test) First Activella® (Reference) First
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Estradiol/Norethindrone Acetate (Test) First Activella® (Reference) First
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/36 (0.00%)      0/36 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Estradiol/Norethindrone Acetate (Test) First Activella® (Reference) First
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/36 (8.33%)      0/36 (0.00%)    
General disorders     
Headache * 1  3/36 (8.33%)  4 0/36 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (Unspecified)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The Principal Investigator is not permitted to discuss or publish trial results.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Associate Director, Biopharmaceutics
Organization: TEVA Pharmaceuticals, USA
Phone: 1-866-384-5525
EMail: clinicaltrialqueries@tevausa.com
Layout table for additonal information
Responsible Party: Associate Director, Biopharmaceutics, TEVA Pharmaceuticals, USA
ClinicalTrials.gov Identifier: NCT01157182     History of Changes
Other Study ID Numbers: 3251
First Submitted: July 2, 2010
First Posted: July 5, 2010
Results First Submitted: September 15, 2010
Results First Posted: December 17, 2010
Last Update Posted: December 17, 2010