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Norethindrone/Ethinyl Estradiol 0.4 mg/35 Mcg Chewable Tablets Under Non-Fasted Conditions

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ClinicalTrials.gov Identifier: NCT01344369
Recruitment Status : Completed
First Posted : April 29, 2011
Results First Posted : May 30, 2011
Last Update Posted : May 30, 2011
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: Norethindrone/Ethinyl Estradiol
Drug: FEMCON® Fe
Enrollment 36

Recruitment Details  
Pre-assignment Details  
Arm/Group Title Norethindrone/Ethinyl Estradiol (Test) First FEMCON® Fe (Reference) First
Hide Arm/Group Description 0.4 mg/0.035 mg Norethindrone/Ethinyl Estradiol 0.4 mg/0.035 mg Chewable Tablets test product dosed in first period followed by 0.4 mg/0.035 mg FEMCON® Fe Chewable Tablets reference product dosed in the second period. 0.4 mg/0.035 mg FEMCON® Fe Chewable tablets reference product dosed in first period followed by 0.4 mg/0.035 mg Norethindrone/Ethinyl Estradiol Chewable 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 17 17
Not Completed 1 1
Reason Not Completed
Withdrawal by Subject             1             0
Physician Decision             0             1
Period Title: Second Intervention
Started 17 17
Completed 17 16
Not Completed 0 1
Reason Not Completed
Emesis within 2 x Tmax             0             1
Arm/Group Title Norethindrone/Ethinyl Estradiol (Test) First FEMCON® Fe (Reference) First Total
Hide Arm/Group Description 0.4 mg/0.035 mg Norethindrone/Ethinyl Estradiol 0.4 mg/0.035 mg Chewable Tablets test product dosed in first period followed by 0.4 mg/0.035 mg FEMCON® Fe Chewable Tablets reference product dosed in the second period. 0.4 mg/0.035 mg FEMCON® Fe Chewable tablets reference product dosed in first period followed by 0.4 mg/0.035 mg Norethindrone/Ethinyl Estradiol Chewable 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
18
 100.0%
18
 100.0%
36
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
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
Black 12 14 26
Caucasian 2 1 3
Hispanic 4 3 7
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 18 participants 18 participants 36 participants
18 18 36
1.Primary Outcome
Title Cmax of Norethindrone
Hide Description Bioequivalence based on Norethindrone Cmax (maximum observed concentration of drug substance in plasma).
Time Frame Blood samples collected over a 60 hour period.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Norethindrone/Ethinyl Estradiol (Test) FEMCON® Fe (Reference)
Hide Arm/Group Description:
0.4 mg/0.035 mg Norethindrone/Ethinyl Estradiol 0.4 mg/0.035 mg Chewable Tablets test product dosed in either period.
0.4 mg/0.035 mg FEMCON® Fe Chewable tablets reference product dosed in either period.
Overall Number of Participants Analyzed 33 33
Mean (Standard Deviation)
Unit of Measure: ng/mL
4.3306  (1.7393) 4.2282  (1.6696)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Norethindrone/Ethinyl Estradiol (Test), FEMCON® Fe (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 102.44
Confidence Interval (2-Sided) 90%
93.08 to 112.75
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 of Norethindrone
Hide Description Bioequivalence based on Norethindrone AUC0-t (area under the concentration-time curve from time zero to time of last measurable concentration).
Time Frame Blood samples collected over a 60 hour period.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Norethindrone/Ethinyl Estradiol (Test) FEMCON® Fe (Reference)
Hide Arm/Group Description:
0.4 mg/0.035 mg Norethindrone/Ethinyl Estradiol 0.4 mg/0.035 mg Chewable Tablets test product dosed in either period.
0.4 mg/0.035 mg FEMCON® Fe Chewable tablets reference product dosed in either period.
Overall Number of Participants Analyzed 33 33
Mean (Standard Deviation)
Unit of Measure: ng*h/mL
37.8065  (16.1921) 37.3991  (15.3939)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Norethindrone/Ethinyl Estradiol (Test), FEMCON® Fe (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 100.58
Confidence Interval (2-Sided) 90%
96.66 to 104.66
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 of Norethindrone
Hide Description Bioequivalence based on Norethindrone AUC0-inf (area under the concentration-time curve from time zero to infinity).
Time Frame Blood samples collected over a 60 hour period.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Norethindrone/Ethinyl Estradiol (Test) FEMCON® Fe (Reference)
Hide Arm/Group Description:
0.4 mg/0.035 mg Norethindrone/Ethinyl Estradiol 0.4 mg/0.035 mg Chewable Tablets test product dosed in either period.
0.4 mg/0.035 mg FEMCON® Fe Chewable tablets reference product dosed in either period.
Overall Number of Participants Analyzed 33 33
Mean (Standard Deviation)
Unit of Measure: ng*h/mL
43.9982  (19.4559) 43.8819  (18.8478)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Norethindrone/Ethinyl Estradiol (Test), FEMCON® Fe (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 100.85
Confidence Interval (2-Sided) 90%
96.43 to 105.48
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 of Ethinyl Estradiol
Hide Description Bioequivalence based on Ethinyl Estradiol Cmax (maximum observed concentration of drug substance in plasma).
Time Frame Blood samples collected over a 60 hour period.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Norethindrone/Ethinyl Estradiol (Test) FEMCON® Fe (Reference)
Hide Arm/Group Description:
0.4 mg/0.035 mg Norethindrone/Ethinyl Estradiol 0.4 mg/0.035 mg Chewable Tablets test product dosed in either period.
0.4 mg/0.035 mg FEMCON® Fe Chewable tablets reference product dosed in either period.
Overall Number of Participants Analyzed 33 33
Mean (Standard Deviation)
Unit of Measure: pg/mL
137.6758  (33.6231) 137.8485  (37.6177)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Norethindrone/Ethinyl Estradiol (Test), FEMCON® Fe (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 100.59
Confidence Interval (2-Sided) 90%
93.69 to 108.00
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 of Ethinyl Estradiol
Hide Description Bioequivalence based on Ethinyl Estradiol AUC0-t (area under the concentration-time curve from time zero to time of last measurable concentration).
Time Frame Blood samples collected over a 60 hour period.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Norethindrone/Ethinyl Estradiol (Test) FEMCON® Fe (Reference)
Hide Arm/Group Description:
0.4 mg/0.035 mg Norethindrone/Ethinyl Estradiol 0.4 mg/0.035 mg Chewable Tablets test product dosed in either period.
0.4 mg/0.035 mg FEMCON® Fe Chewable tablets reference product dosed in either period.
Overall Number of Participants Analyzed 33 33
Mean (Standard Deviation)
Unit of Measure: pg*h/mL
1916.2311  (433.4875) 1987.6311  (478.7842)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Norethindrone/Ethinyl Estradiol (Test), FEMCON® Fe (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 96.68
Confidence Interval (2-Sided) 90%
92.76 to 100.77
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 of Ethinyl Estradiol
Hide Description Bioequivalence based on Ethinyl Estradiol AUC0-inf (area under the concentration-time curve from time zero to infinity).
Time Frame Blood samples collected over a 60 hour period.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Norethindrone/Ethinyl Estradiol (Test) FEMCON® Fe (Reference)
Hide Arm/Group Description:
0.4 mg/0.035 mg Norethindrone/Ethinyl Estradiol 0.4 mg/0.035 mg Chewable Tablets test product dosed in either period.
0.4 mg/0.035 mg FEMCON® Fe Chewable tablets reference product dosed in either period.
Overall Number of Participants Analyzed 33 33
Mean (Standard Deviation)
Unit of Measure: pg*h/mL
2072.5423  (483.0176) 2152.3775  (517.5977)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Norethindrone/Ethinyl Estradiol (Test), FEMCON® Fe (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 96.44
Confidence Interval (2-Sided) 90%
92.22 to 100.84
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%.
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 Norethindrone/Ethinyl Estradiol (Test) FEMCON® Fe (Reference)
Hide Arm/Group Description 0.4 mg/0.035 mg Norethindrone/Ethinyl Estradiol 0.4 mg/0.035 mg Chewable Tablets test product dosed in either period. 0.4 mg/0.035 mg FEMCON® Fe Chewable tablets reference product dosed in either period.
All-Cause Mortality
Norethindrone/Ethinyl Estradiol (Test) FEMCON® Fe (Reference)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Norethindrone/Ethinyl Estradiol (Test) FEMCON® Fe (Reference)
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%
Norethindrone/Ethinyl Estradiol (Test) FEMCON® Fe (Reference)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   13/36 (36.11%)      10/36 (27.78%)    
General disorders     
Abdominal Cramping * 1  4/36 (11.11%)  4 0/36 (0.00%)  0
Sinus Congestion * 1  0/36 (0.00%)  0 2/36 (5.56%)  2
Decreased Blood Pressure * 1  2/36 (5.56%)  2 2/36 (5.56%)  2
Vomiting * 1  5/36 (13.89%)  5 3/36 (8.33%)  3
Nausea * 1  6/36 (16.67%)  6 3/36 (8.33%)  3
Headache * 1  5/36 (13.89%)  5 1/36 (2.78%)  1
Increased Temperature * 1  0/36 (0.00%)  0 2/36 (5.56%)  2
Increased Blood Pressure * 1  1/36 (2.78%)  1 2/36 (5.56%)  3
*
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
Name/Title: Associate Director, Biopharmaceutics
Organization: Teva Pharmaceuticals, USA
Phone: 1-866-384-5525
Responsible Party: Associate Director, Biopharmaceutics, Teva Pharmaceuticals, USA
ClinicalTrials.gov Identifier: NCT01344369     History of Changes
Other Study ID Numbers: 10816221
First Submitted: April 27, 2011
First Posted: April 29, 2011
Results First Submitted: May 4, 2011
Results First Posted: May 30, 2011
Last Update Posted: May 30, 2011