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Norethindrone/Ethinyl Estradiol 0.4 mg/35 Mcg Chewable Tablets Under Fasting Conditions

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ClinicalTrials.gov Identifier: NCT01340625
Recruitment Status : Completed
First Posted : April 22, 2011
Results First Posted : May 25, 2011
Last Update Posted : May 25, 2011
Sponsor:
Information provided by:
Teva Pharmaceuticals USA

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label)
Condition Bioequivalence
Interventions Drug: Norethindrone/Ethinyl Estradiol
Drug: Ovcon® 35 Fe
Enrollment 36
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Norethindrone/Ethinyl Estradiol (Test) First Ovcon® 35 Fe (Reference) First
Hide Arm/Group Description 0.4 mg/35 mcg Norethindrone/Ethinyl Estradiol Chewable Tablets test product dosed in first period followed by 0.4 mg/35 mcg Ovcon® 35 Fe Chewable Tablets reference product dosed in the second period. 0.4 mg/35 mcg Ovcon® 35 Fe Chewable Tablets reference product dosed in first period followed by 0.4 mg/35 mcg Norethindrone/Ethinyl Estradiol Chewable Tablets test product dosed in the second period.
Period Title: First Intervention
Started 18 18
Completed 17 18
Not Completed 1 0
Reason Not Completed
Adverse Event             1             0
Period Title: Washout Period of 28 Days
Started 17 18
Completed 16 18
Not Completed 1 0
Reason Not Completed
Withdrawal by Subject             1             0
Period Title: Second Intervention
Started 16 18
Completed 16 18
Not Completed 0 0
Arm/Group Title Norethindrone/Ethinyl Estradiol (Test) First Ovcon® 35 Fe (Reference) First Total
Hide Arm/Group Description 0.4 mg/35 mcg Norethindrone/Ethinyl Estradiol Chewable Tablets test product dosed in first period followed by 0.4 mg/35 mcg Ovcon® 35 Fe Chewable Tablets reference product dosed in the second period. 0.4 mg/35 mcg Ovcon® 35 Fe Chewable Tablets reference product dosed in first period followed by 0.4 mg/35 mcg 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
American Indian 0 1 1
Caucasian 18 17 35
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.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Norethindrone/Ethinyl Estradiol (Test) Ovcon® 35 Fe (Reference)
Hide Arm/Group Description:
0.4 mg/35 mcg Norethindrone/Ethinyl Estradiol Chewable Tablets test product dosed in either period.
0.4 mg/35 mcg Ovcon® 35 Fe Chewable Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: ng/mL
10.94  (5.22) 10.00  (4.13)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Norethindrone/Ethinyl Estradiol (Test), Ovcon® 35 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 107.84
Confidence Interval (2-Sided) 90%
100.91 to 115.24
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.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Norethindrone/Ethinyl Estradiol (Test) Ovcon® 35 Fe (Reference)
Hide Arm/Group Description:
0.4 mg/35 mcg Norethindrone/Ethinyl Estradiol Chewable Tablets test product dosed in either period.
0.4 mg/35 mcg Ovcon® 35 Fe Chewable Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: ng*h/mL
43.83  (30.50) 40.73  (22.41)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Norethindrone/Ethinyl Estradiol (Test), Ovcon® 35 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 104.03
Confidence Interval (2-Sided) 90%
96.74 to 111.88
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.
Hide Outcome Measure Data
Hide Analysis Population Description
All participants that completed the study had their samples analyzed.
Arm/Group Title Norethindrone/Ethinyl Estradiol (Test) Ovcon® 35 Fe (Reference)
Hide Arm/Group Description:
0.4 mg/35 mcg Norethindrone/Ethinyl Estradiol Chewable Tablets test product dosed in either period.
0.4 mg/35 mcg Ovcon® 35 Fe Chewable Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 34 34
Mean (Standard Deviation)
Unit of Measure: ng*h/mL
48.67  (34.36) 45.43  (27.03)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Norethindrone/Ethinyl Estradiol (Test), Ovcon® 35 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 101.97
Confidence Interval (2-Sided) 90%
95.73 to 108.62
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.
Hide Outcome Measure Data
Hide Analysis Population Description
34 out of 36 subjects completed the study. Subjects 13 & 35 were excluded from the statistical analysis for Ethinyl Estradiol due to pre-dose concentrations greater than 5% of Cmax; therefore analysis included 32 data sets.
Arm/Group Title Norethindrone/Ethinyl Estradiol (Test) Ovcon® 35 Fe (Reference)
Hide Arm/Group Description:
0.4 mg/35 mcg Norethindrone/Ethinyl Estradiol Chewable Tablets test product dosed in either period.
0.4 mg/35 mcg Ovcon® 35 Fe Chewable Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 32 32
Mean (Standard Deviation)
Unit of Measure: pg/mL
230.56  (74.02) 237.00  (62.90)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Norethindrone/Ethinyl Estradiol (Test), Ovcon® 35 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 96.24
Confidence Interval (2-Sided) 90%
90.04 to 102.86
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.
Hide Outcome Measure Data
Hide Analysis Population Description
34 out of 36 subjects completed the study. Subjects 13 & 35 were excluded from the statistical analysis for Ethinyl Estradiol due to pre-dose concentrations greater than 5% of Cmax; therefore analysis included 32 data sets.
Arm/Group Title Norethindrone/Ethinyl Estradiol (Test) Ovcon® 35 Fe (Reference)
Hide Arm/Group Description:
0.4 mg/35 mcg Norethindrone/Ethinyl Estradiol Chewable Tablets test product dosed in either period.
0.4 mg/35 mcg Ovcon® 35 Fe Chewable Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 32 32
Mean (Standard Deviation)
Unit of Measure: pg*h/mL
1976.72  (518.96) 1989.82  (475.30)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Norethindrone/Ethinyl Estradiol (Test)
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 98.80
Confidence Interval (2-Sided) 90%
93.89 to 103.97
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.
Hide Outcome Measure Data
Hide Analysis Population Description
34 out of 36 subjects completed the study. Subjects 13 & 35 were excluded from the statistical analysis for Ethinyl Estradiol due to pre-dose concentrations greater than 5% of Cmax; therefore analysis included 32 data sets.
Arm/Group Title Norethindrone/Ethinyl Estradiol (Test) Ovcon® 35 Fe (Reference)
Hide Arm/Group Description:
0.4 mg/35 mcg Norethindrone/Ethinyl Estradiol Chewable Tablets test product dosed in either period.
0.4 mg/35 mcg Ovcon® 35 Fe Chewable Tablets reference product dosed in either period.
Overall Number of Participants Analyzed 32 32
Mean (Standard Deviation)
Unit of Measure: pg*h/mL
2129.43  (560.04) 2131.84  (545.91)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Norethindrone/Ethinyl Estradiol (Test), Ovcon® 35 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 99.59
Confidence Interval (2-Sided) 90%
94.91 to 104.50
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) First Ovcon® 35 Fe (Reference) First
Hide Arm/Group Description 0.4 mg/35 mcg Norethindrone/Ethinyl Estradiol Chewable Tablets test product dosed in first period followed by 0.4 mg/35 mcg Ovcon® 35 Fe Chewable Tablets reference product dosed in the second period. 0.4 mg/35 mcg Ovcon® 35 Fe Chewable Tablets reference product dosed in first period followed by 0.4 mg/35 mcg Norethindrone/Ethinyl Estradiol Chewable Tablets test product dosed in the second period.
All-Cause Mortality
Norethindrone/Ethinyl Estradiol (Test) First Ovcon® 35 Fe (Reference) First
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Norethindrone/Ethinyl Estradiol (Test) First Ovcon® 35 Fe (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%
Norethindrone/Ethinyl Estradiol (Test) First Ovcon® 35 Fe (Reference) First
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   14/36 (38.89%)      12/36 (33.33%)    
General disorders     
Diarrhoea * 1  0/36 (0.00%)  0 2/36 (5.56%)  2
Headache * 1  9/36 (25.00%)  11 9/36 (25.00%)  11
Nausea * 1  8/36 (22.22%)  9 1/36 (2.78%)  2
Pallor * 1  2/36 (5.56%)  2 0/36 (0.00%)  0
Syncope * 1  2/36 (5.56%)  2 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
ClinicalTrials.gov Identifier: NCT01340625     History of Changes
Other Study ID Numbers: R06-1188
First Submitted: April 20, 2011
First Posted: April 22, 2011
Results First Submitted: April 27, 2011
Results First Posted: May 25, 2011
Last Update Posted: May 25, 2011