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

This study has been completed.
Sponsor:
Information provided by:
Teva Pharmaceuticals USA
ClinicalTrials.gov Identifier:
NCT01157182
First received: July 2, 2010
Last updated: November 22, 2010
Last verified: November 2010
Results First Received: September 15, 2010  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Bio-equivalence Study;   Intervention Model: Crossover Assignment;   Masking: Open Label
Condition: Healthy
Interventions: Drug: Estradiol/Norethindrone acetate
Drug: Activella®

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Estradiol/Norethindrone Acetate (Test) First 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.
Activella® (Reference) First 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.

Participant Flow for 3 periods

Period 1:   First Intervention
    Estradiol/Norethindrone Acetate (Test) First   Activella® (Reference) First
STARTED   18   18 
COMPLETED   18   18 
NOT COMPLETED   0   0 

Period 2:   Washout of 28 Days
    Estradiol/Norethindrone Acetate (Test) First   Activella® (Reference) First
STARTED   18   18 
COMPLETED   16   18 
NOT COMPLETED   2   0 
Adverse Event                2                0 

Period 3:   Second Intervention
    Estradiol/Norethindrone Acetate (Test) First   Activella® (Reference) First
STARTED   16   18 
COMPLETED   16   18 
NOT COMPLETED   0   0 



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Estradiol/Norethindrone Acetate (Test) First 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.
Activella® (Reference) First 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 Total of all reporting groups

Baseline Measures
   Estradiol/Norethindrone Acetate (Test) First   Activella® (Reference) First   Total 
Overall Participants Analyzed 
[Units: Participants]
 18   18   36 
Age 
[Units: Participants]
     
<=18 years   0   0   0 
Between 18 and 65 years   17   18   35 
>=65 years   1   0   1 
Gender 
[Units: Participants]
     
Female   18   18   36 
Male   0   0   0 
Race/Ethnicity, Customized 
[Units: 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 
[Units: Participants]
     
Canada   18   18   36 


  Outcome Measures
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1.  Primary:   Cmax for Norethindrone(Maximum Observed Concentration of Drug Substance in Plasma)   [ Time Frame: Blood samples collected over a 36 hour period. ]

2.  Primary:   AUC0-t for Norethindrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)   [ Time Frame: Blood samples collected over a 36 hour period. ]

3.  Primary:   AUC0-inf for Norethindrone(Area Under the Concentration-time Curve From Time Zero to Infinity)   [ Time Frame: Blood samples collected over a 36 hour period. ]

4.  Primary:   Cmax for Corrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma)   [ Time Frame: Blood samples collected over a 72 hour period. ]
  Hide Outcome Measure 4

Measure Type Primary
Measure Title Cmax for Corrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma)
Measure Description Bioequivalence based on Corrected Total Estrone Cmax.
Time Frame Blood samples collected over a 72 hour period.  
Safety Issue No  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All participants that completed the study had their samples analyzed.

Reporting Groups
  Description
Estradiol/Norethindrone Acetate (Test) 1/0.5 mg Estradiol/Norethindrone acetate Tablets test product dosed in either period.
Activella® (Reference) 1/0.5 mg Activella® Tablets reference product dosed in either period.

Measured Values
   Estradiol/Norethindrone Acetate (Test)   Activella® (Reference) 
Participants Analyzed 
[Units: Participants]
 34   34 
Cmax for Corrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma) 
[Units: pg/mL]
Mean (Standard Deviation)
 43997.17  (10387.84)   47015.47  (9894.22) 


Statistical Analysis 1 for Cmax for Corrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma)
Groups [1] All groups
Non-Inferiority/Equivalence Test [2] Yes
Ratio of the T/R geometric mean x 100 [3] 92.51
90% Confidence Interval 88.64 to 96.55
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  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).
[3] Other relevant estimation information:
  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:   AUC0-t for Corrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)   [ Time Frame: Blood samples collected over a 72 hour period. ]

6.  Primary:   AUC0-inf for Corrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity)   [ Time Frame: Blood samples collected over a 72 hour period. ]

7.  Secondary:   Cmax for Uncorrected Total Estrone(Maximum Observed Concentration of Drug Substance in Plasma)   [ Time Frame: Blood samples collected over a 72 hour period. ]

8.  Secondary:   AUC0-t for Uncorrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)   [ Time Frame: Blood samples collected over a 72 hour period. ]

9.  Secondary:   AUC0-inf for Uncorrected Total Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity)   [ Time Frame: Blood samples collected over a 72 hour period. ]

10.  Secondary:   Cmax for Uncorrected Unconjugated Estradiol(Maximum Observed Concentration of Drug Substance in Plasma)   [ Time Frame: Blood samples collected over a 72 hour period. ]

11.  Secondary:   AUC0-t for Uncorrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)   [ Time Frame: Blood samples collected over a 72 hour period. ]

12.  Secondary:   AUC0-inf for Uncorrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity)   [ Time Frame: Blood samples collected over a 72 hour period. ]

13.  Secondary:   Cmax for Uncorrected Unconjugated Estrone(Maximum Observed Concentration of Drug Substance in Plasma)   [ Time Frame: Blood samples collected over a 72 hour period. ]

14.  Secondary:   AUC0-t for Uncorrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)   [ Time Frame: Blood samples collected over a 72 hour period. ]

15.  Secondary:   AUC0-inf for Uncorrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity)   [ Time Frame: Blood samples collected over a 72 hour period. ]

16.  Secondary:   Cmax for Corrected Unconjugated Estradiol(Maximum Observed Concentration of Drug Substance in Plasma)   [ Time Frame: Blood samples collected over a 72 hour period. ]

17.  Secondary:   AUC0-t for Corrected Unconjugated Estradiol.(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)   [ Time Frame: Blood samples collected over a 72 hour period. ]

18.  Secondary:   AUC0-inf for Corrected Unconjugated Estradiol(Area Under the Concentration-time Curve From Time Zero to Infinity)   [ Time Frame: Blood samples collected over a 72 hour period. ]

19.  Secondary:   Cmax for Corrected Unconjugated Estrone(Maximum Observed Concentration of Drug Substance in Plasma)   [ Time Frame: Blood samples collected over a 72 hour period. ]

20.  Secondary:   AUC0-t for Corrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Time of Last Measurable Concentration)   [ Time Frame: Blood samples collected over a 72 hour period. ]

21.  Secondary:   AUC0-inf for Corrected Unconjugated Estrone(Area Under the Concentration-time Curve From Time Zero to Infinity)   [ Time Frame: Blood samples collected over a 72 hour period. ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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