A Multinational Study to Evaluate the Effects of a 28-Day Oral Contraceptive on Hemostatic Parameters in Healthy Women

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01388491
• Collaborator: (none)
• Enrollment: 293
• Locations: 27
• Arms: 2
• Actual Duration (Months): 11
• Patients Per Site: 10.9
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

This study is being conducted to evaluate the impact of DR-102, a 28-day oral contraceptive compared to a standard 28-day oral contraceptive regimen on hemostatic parameters in healthy women.

Condition or Disease	Intervention/Treatment	Phase
Hemostasis; Oral Contraceptive	Drug: desogestrel/ethinyl estradiol and ethinyl estradiol; Drug: desogestrel/ethinyl estradiol	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 293 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: A Multinational, Multicenter, Randomized, Open-Label Study to Evaluate the Impact of DR-102 Compared to a 28-day Standard Oral Contraceptive Regimen, on Hemosatic Parameters in Healthy Women
• Actual Study Start Date: Oct 31, 2011
• Actual Primary Completion Date: Sep 30, 2012
• Actual Study Completion Date: Sep 30, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment I: (DR-102) 21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	Drug: desogestrel/ethinyl estradiol and ethinyl estradiol
Active Comparator: Treatment II 21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles	Drug: desogestrel/ethinyl estradiol

Outcome Measures

Primary Outcome Measures

1. Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Prothrombin Fragment 1 + 2 Levels [Baseline through Month 6]

   Normal range for this hemostatic parameter was 41 to 372 pmol/L. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.

Secondary Outcome Measures

1. Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in D-Dimer [Baseline through Month 6]

   Normal range for this hemostatic parameter was 0 to 729 mcg/L. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.

2. Least Squares Mean Change From Baseline Over the 6-Month Period in Protein S Total Antigen [Baseline through Month 6]

   The normal range for this hemostatic parameter was 50% to 147%. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.

3. Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Protein C Activity [Baseline through Month 6]

   The normal range for this hemostatic parameter was 70% to 180%. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.

4. Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Antithrombin [Baseline through Month 6]

   Normal range for this hemostatic parameter was 75% to 130%. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.

5. Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Factor II Activity [Baseline through Month 6]

   Normal range for this hemostatic parameter was 70% to 150%. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.

6. Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Factor VII [Baseline through Month 6]

   Normal range for this hemostatic parameter was 60% to 150%. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.

7. Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Factor VIII [Baseline through Month 6]

   Normal range for this hemostatic parameter was 50% to 180%. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.

8. Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Activated Partial Thromboplastin Time (APTT)-Based Activated Protein-C (APC) Resistance [Baseline through Month 6]

   This hemostatic parameter is calculated by dividing the clotting time with APC by the clotting time without APC. Normal range for this measure was defined as a ratio of 2.00 to 3.36. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.

9. Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Endogenous Thrombin Potential (EPT)-Based Activated Protein-C (APC) Resistance [Baseline through Month 6]

   This hemostatic parameter is calculated by dividing the clotting time with APC by the clotting time without APC. Normal range for this measure was defined as a ratio of 0.32 to 1.79. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.

10. Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Corticosteroid-Binding Globulin [Baseline through Month 6]

    Normal range for this adrenal parameter was 1906.448 to 4520.504 mg/L. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.

11. Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Serum Random Total Cortisol [Baseline through Month 6]

    Normal range for this adrenal parameter was 85.6 to 618.2 nmol/L. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.

12. Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Thyroid-Stimulating Hormone (TSH) [Baseline through Month 6]

    Normal range for this parameter was 0.35 to 5.5 mIU/L. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.

13. Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Sex Hormone Binding Globulin [Baseline through Month 6]

    Normal range for this parameter was 28 to 146 nmol/L. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Premenopausal, non-pregnant, non-lactating women age 18-40 years old

• Body Mass Index (BMI) ≥18 kg/m² and <30 kg/m²

• Regular spontaneous menstrual cycle

• Others as dictated by FDA-approved protocol

Exclusion Criteria:

• Any condition which contraindicates the use of combination oral contraceptives

• Any history of, or active, deep vein thrombosis, pulmonary embolism, or arterial thromboembolic disease within one year of screening

• Thrombophlebitis or thromboembolic disorders; known or suspected clotting disorders; thrombogenetic valvulopathies or rhythm disorders

• Others as dictated by FDA-approved protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 32064	Essen		Germany	45127
2	Teva Investigational Site 32066	Frankfurt am Main		Germany	60439
3	Teva Investigational Site 32065	Frankfurt		Germany	60311
4	Teva Investigational Site 32062	Hamburg		Germany	22159
5	Teva Investigational Site 32063	Hamburg		Germany	22359
6	Teva Investigational Site 32061	Magdeburg		Germany	39112
7	Teva Investigational Site 80013	Givataim		Israel	53425
8	Teva Investigational Site 80015	Haifa		Israel	34466
9	Teva Investigational Site 80017	Modi'in		Israel	71705
10	Teva Investigational Site 80014	RishonLe'zio		Israel
11	Teva Investigational Site 80018	Tel-Aviv		Israel	62304
12	Teva Investigational Site 80016	Tel-Aviv		Israel	69379
13	Teva Investigational Site 30014	Brescia		Italy	25123
14	Teva Investigational Site 30009	Cagliari		Italy	09124
15	Teva Investigational Site 30012	Catania		Italy	95123
16	Teva Investigational Site 30013	Napoli		Italy	80131
17	Teva Investigational Site 30010	Pavia		Italy	27100
18	Teva Investigational Site 30007	Pisa		Italy	56126
19	Teva Investigational Site 30016	Siena		Italy	53100
20	Teva Investigational Site 31017	Barcelona		Spain	08025
21	Teva Investigational Site 31015	Barcelona		Spain	08028
22	Teva Investigational Site 31014	Barcelona		Spain	08035
23	Teva Investigational Site 31016	Gava, Barcelona		Spain	08850
24	Teva Investigational Site 31012	Lugo		Spain	27002
25	Teva Investigational Site 31010	Madrid		Spain	28001
26	Teva Investigational Site 31011	Madrid		Spain	28009
27	Teva Investigational Site 31009	Vitoria-Gasteiz		Spain	01004

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Chair: Teva Women's Health Research Protocol Chair, Teva Women's Health Research

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT01388491
• Other Study ID Numbers: DSG-HSP-201
• First Posted: Jul 6, 2011
• Last Update Posted: Dec 6, 2021
• Last Verified: Dec 1, 2021

• Keywords provided by Teva Branded Pharmaceutical Products R&D, Inc.: Contraception; Hemostasis; Blood Coagulation
• Additional relevant MeSH terms: Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Ethinyl Estradiol; Desogestrel; Estradiol; Polyestradiol phosphate

Study Results

Participant Flow

Recruitment Details	Of the 351 healthy women screened for enrollment, 293 at 26 centers in the European Union (EU) (21 centers) and Israel (5 centers) met entry criteria and were considered to be eligible for this study.
Pre-assignment Detail	Of the 58 women who were screened but not randomly assigned to receive treatment, 10 were excluded on the basis of inclusion/exclusion criteria, 32 withdrew consent, and 6 were lost to follow-up before the baseline visit. An additional 10 participants were not randomly assigned to treatment for other reasons.

Arm/Group Title	Treatment I: (DR-102)	Treatment II
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles
Period Title: Overall Study
STARTED	150	143
Safety Population	145	142
Intent-to-Treat (ITT) Population	140	136
Per Protocol (PP) Population	125	121
COMPLETED	116	114
NOT COMPLETED	34	29

Baseline Characteristics

Arm/Group Title	Treatment I: (DR-102)	Treatment II	Total
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles	Total of all reporting groups
Overall Participants	145	142	287
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26.4 (4.98)	27.0 (5.26)	26.7 (5.12)
Sex: Female, Male (Count of Participants)
Female	145 100%	142 100%	287 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
White	140 96.6%	136 95.8%	276 96.2%
Black	1 0.7%	1 0.7%	2 0.7%
Asian	0 0%	1 0.7%	1 0.3%
American Indian or Alaskan Native	0 0%	1 0.7%	1 0.3%
Other	4 2.8%	3 2.1%	7 2.4%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	61.6 (10.35)	60.1 (9.36)	60.9 (9.89)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	22.9 (3.62)	22.4 (3.06)	22.6 (3.36)

Outcome Measures

1. Primary Outcome

Title	Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Prothrombin Fragment 1 + 2 Levels
Description	Normal range for this hemostatic parameter was 41 to 372 pmol/L. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.
Time Frame	Baseline through Month 6

Outcome Measure Data

Analysis Population Description

Per-protocol (PP) population. PP population included all data from intent-to-treat (ITT) participants obtained prior to any major protocol violations. PP participants were analyzed according to the treatment actually received.

Arm/Group Title	Treatment I: (DR-102)	Treatment II
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles
Measure Participants	125	121
Least Squares Mean (Standard Error) [pmol/L]	45.0 (15.24)	56.8 (15.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment I: (DR-102), Treatment II
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.5892
	Comments	The p-value, least squares mean difference, and 95% CI for the treatment group comparison are based on a repeated measures ANCOVA with baseline, treatment, visit, and treatment-by-visit interaction as fixed factors, and subject as a random effect.
	Method	ANCOVA
	Comments	Least Squares mean difference: Treatment I - Treatment II
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-11.8
	Confidence Interval	(2-Sided) 95%; -54.75 to 31.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in D-Dimer
Description	Normal range for this hemostatic parameter was 0 to 729 mcg/L. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.
Time Frame	Baseline through Month 6

Outcome Measure Data

Analysis Population Description

Per protocol (PP) population with BL and at least 1 post-BL value for this measurement. PP population included all data from intent-to-treat (ITT) participants obtained prior to any major protocol violations. PP participants were analyzed according to the treatment actually received.

Arm/Group Title	Treatment I: (DR-102)	Treatment II
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles
Measure Participants	118	114
Least Squares Mean (Standard Error) [mcg/L]	16.4 (10.29)	13.4 (10.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment I: (DR-102), Treatment II
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.839
	Comments	The p-value, least squares mean difference, and 95% CI for the treatment group comparison are based on a repeated measures ANCOVA with baseline, treatment, visit, and treatment-by-visit interaction as fixed factors, and subject as a random effect.
	Method	ANCOVA
	Comments	Least Squares mean difference: Treatment I - Treatment II
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	3.0
	Confidence Interval	(2-Sided) 95%; -25.96 to 31.94
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Least Squares Mean Change From Baseline Over the 6-Month Period in Protein S Total Antigen
Description	The normal range for this hemostatic parameter was 50% to 147%. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.
Time Frame	Baseline through Month 6

Outcome Measure Data

Analysis Population Description

Per protocol (PP) population with BL and at least 1 post-BL value for this measurement. PP population included all data from intent-to-treat (ITT) participants obtained prior to any major protocol violations. PP participants were analyzed according to the treatment actually received.

Arm/Group Title	Treatment I: (DR-102)	Treatment II
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles
Measure Participants	124	121
Least Squares Mean (Standard Error) [percentage of normal 50% to 147%]	-11.4 (1.09)	-6.6 (1.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment I: (DR-102), Treatment II
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments	The p-value, least squares mean difference, and 95% CI for the treatment group comparison are based on a repeated measures ANCOVA with baseline, treatment, visit, and treatment-by-visit interaction as fixed factors, and subject as a random effect.
	Method	ANCOVA
	Comments	Least Squares mean difference: Treatment I - Treatment II
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-4.8
	Confidence Interval	(2-Sided) 95%; -7.87 to -1.77
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Protein C Activity
Description	The normal range for this hemostatic parameter was 70% to 180%. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.
Time Frame	Baseline through Month 6

Outcome Measure Data

Analysis Population Description

Per protocol (PP) population with BL and at least 1 post-BL value for this measurement. PP population included all data from intent-to-treat (ITT) participants obtained prior to any major protocol violations. PP participants were analyzed according to the treatment actually received.

Arm/Group Title	Treatment I: (DR-102)	Treatment II
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles
Measure Participants	124	121
Least Squares Mean (Standard Error) [percentage of normal]	16.3 (1.90)	13.0 (1.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment I: (DR-102), Treatment II
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2312
	Comments	The p-value, least squares mean difference, and 95% CI for the treatment group comparison are based on a repeated measures ANCOVA with baseline, treatment, visit, and treatment-by-visit interaction as fixed factors, and subject as a random effect.
	Method	ANCOVA
	Comments	Least Squares mean difference: Treatment I - Treatment II
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	3.2
	Confidence Interval	(2-Sided) 95%; -2.08 to 8.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Antithrombin
Description	Normal range for this hemostatic parameter was 75% to 130%. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.
Time Frame	Baseline through Month 6

Outcome Measure Data

Analysis Population Description

Per protocol (PP) population with BL and at least 1 post-BL value for this measurement. PP population included all data from intent-to-treat (ITT) participants obtained prior to any major protocol violations. PP participants were analyzed according to the treatment actually received.

Arm/Group Title	Treatment I: (DR-102)	Treatment II
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles
Measure Participants	124	121
Least Squares Mean (Standard Error) [percentage of normal]	-1.6 (1.17)	-3.2 (1.18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment I: (DR-102), Treatment II
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3440
	Comments	The p-value, least squares mean difference, and 95% CI for the treatment group comparison are based on a repeated measures ANCOVA with baseline, treatment, visit, and treatment-by-visit interaction as fixed factors, and subject as a random effect.
	Method	ANCOVA
	Comments	Least Squares mean difference: Treatment I - Treatment II
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	1.6
	Confidence Interval	(2-Sided) 95%; -1.70 to 4.85
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Factor II Activity
Description	Normal range for this hemostatic parameter was 70% to 150%. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.
Time Frame	Baseline through Month 6

Outcome Measure Data

Analysis Population Description

Per protocol (PP) population with BL and at least 1 post-BL value for this measurement. PP population included all data from intent-to-treat (ITT) participants obtained prior to any major protocol violations. PP participants were analyzed according to the treatment actually received.

Arm/Group Title	Treatment I: (DR-102)	Treatment II
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles
Measure Participants	118	114
Least Squares Mean (Standard Error) [percentage of normal]	3.3 (0.21)	3.0 (0.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment I: (DR-102), Treatment II
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.2522
	Comments	The p-value, least squares mean difference, and 95% CI for the treatment group comparison are based on a repeated measures ANCOVA with baseline, treatment, visit, and treatment-by-visit interaction as fixed factors, and subject as a random effect.
	Method	ANCOVA
	Comments	Least Squares mean difference: Treatment I - Treatment II
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -0.24 to 0.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Factor VII
Description	Normal range for this hemostatic parameter was 60% to 150%. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.
Time Frame	Baseline through Month 6

Outcome Measure Data

Analysis Population Description

Per protocol (PP) population with BL and at least 1 post-BL value for this measurement. PP population included all data from intent-to-treat (ITT) participants obtained prior to any major protocol violations. PP participants were analyzed according to the treatment actually received.

Arm/Group Title	Treatment I: (DR-102)	Treatment II
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles
Measure Participants	118	114
Least Squares Mean (Standard Error) [percentage of normal]	17.9 (0.81)	15.1 (0.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment I: (DR-102), Treatment II
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0143
	Comments	The p-value, least squares mean difference, and 95% CI for the treatment group comparison are based on a repeated measures ANCOVA with baseline, treatment, visit, and treatment-by-visit interaction as fixed factors, and subject as a random effect.
	Method	ANCOVA
	Comments	Least Squares mean difference: Treatment I - Treatment II
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	2.9
	Confidence Interval	(2-Sided) 95%; 0.58 to 5.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Factor VIII
Description	Normal range for this hemostatic parameter was 50% to 180%. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.
Time Frame	Baseline through Month 6

Outcome Measure Data

Analysis Population Description

Per protocol (PP) population with BL and at least 1 post-BL value for this measurement. PP population included all data from intent-to-treat (ITT) participants obtained prior to any major protocol violations. PP participants were analyzed according to the treatment actually received.

Arm/Group Title	Treatment I: (DR-102)	Treatment II
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles
Measure Participants	118	114
Least Squares Mean (Standard Error) [percentage of normal]	11.1 (1.92)	10.6 (1.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment I: (DR-102), Treatment II
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.8507
	Comments	The p-value, least squares mean difference, and 95% CI for the treatment group comparison are based on a repeated measures ANCOVA with baseline, treatment, visit, and treatment-by-visit interaction as fixed factors, and subject as a random effect.
	Method	ANCOVA
	Comments	Least Squares mean difference: Treatment I - Treatment II
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -4.87 to 5.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Activated Partial Thromboplastin Time (APTT)-Based Activated Protein-C (APC) Resistance
Description	This hemostatic parameter is calculated by dividing the clotting time with APC by the clotting time without APC. Normal range for this measure was defined as a ratio of 2.00 to 3.36. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.
Time Frame	Baseline through Month 6

Outcome Measure Data

Analysis Population Description

Per protocol (PP) population with BL and at least 1 post-BL value for this measurement. PP population included all data from intent-to-treat (ITT) participants obtained prior to any major protocol violations. PP participants were analyzed according to the treatment actually received.

Arm/Group Title	Treatment I: (DR-102)	Treatment II
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles
Measure Participants	124	120
Least Squares Mean (Standard Error) [ratio]	-0.3 (0.02)	-0.4 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment I: (DR-102), Treatment II
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0459
	Comments	The p-value, least squares mean difference, and 95% CI for the treatment group comparison are based on a repeated measures ANCOVA with baseline, treatment, visit, and treatment-by-visit interaction as fixed factors, and subject as a random effect.
	Method	ANCOVA
	Comments	Least Squares mean difference: Treatment I - Treatment II
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; 0.00 to 0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Endogenous Thrombin Potential (EPT)-Based Activated Protein-C (APC) Resistance
Description	This hemostatic parameter is calculated by dividing the clotting time with APC by the clotting time without APC. Normal range for this measure was defined as a ratio of 0.32 to 1.79. Participants were in a fasting state and had refrained from moderate to vigorous exercise prior to phlebotomy on the day of this lab draw. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.
Time Frame	Baseline through Month 6

Outcome Measure Data

Analysis Population Description

Per protocol (PP) population with BL and at least 1 post-BL value for this measurement. PP population included all data from intent-to-treat (ITT) participants obtained prior to any major protocol violations. PP participants were analyzed according to the treatment actually received.

Arm/Group Title	Treatment I: (DR-102)	Treatment II
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles
Measure Participants	124	121
Least Squares Mean (Standard Error) [ratio]	0.8 (0.04)	0.7 (0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment I: (DR-102), Treatment II
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0318
	Comments	The p-value, least squares mean difference, and 95% CI for the treatment group comparison are based on a repeated measures ANCOVA with baseline, treatment, visit, and treatment-by-visit interaction as fixed factors, and subject as a random effect.
	Method	ANCOVA
	Comments	Least Squares mean difference: Treatment I - Treatment II
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Corticosteroid-Binding Globulin
Description	Normal range for this adrenal parameter was 1906.448 to 4520.504 mg/L. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.
Time Frame	Baseline through Month 6

Outcome Measure Data

Analysis Population Description

Per protocol (PP) population with BL and at least 1 post-BL value for this measurement. PP population included all data from intent-to-treat (ITT) participants obtained prior to any major protocol violations. PP participants were analyzed according to the treatment actually received.

Arm/Group Title	Treatment I: (DR-102)	Treatment II
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles
Measure Participants	122	117
Least Squares Mean (Standard Error) [mg/L]	4083.3 (159.45)	3721.8 (162.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment I: (DR-102), Treatment II
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1148
	Comments	The p-value, least squares mean difference, and 95% CI for the treatment group comparison are based on a repeated measures ANCOVA with baseline, treatment, visit, and treatment-by-visit interaction as fixed factors, and subject as a random effect.
	Method	ANCOVA
	Comments	Least Squares mean difference: Treatment I - Treatment II
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	361.6
	Confidence Interval	(2-Sided) 95%; -88.45 to 811.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Serum Random Total Cortisol
Description	Normal range for this adrenal parameter was 85.6 to 618.2 nmol/L. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.
Time Frame	Baseline through Month 6

Outcome Measure Data

Analysis Population Description

Per protocol (PP) population with BL and at least 1 post-BL value for this measurement. PP population included all data from intent-to-treat (ITT) participants obtained prior to any major protocol violations. PP participants were analyzed according to the treatment actually received.

Arm/Group Title	Treatment I: (DR-102)	Treatment II
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles
Measure Participants	125	120
Least Squares Mean (Standard Error) [nmol/L]	239.0 (15.67)	230.8 (16.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment I: (DR-102), Treatment II
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.7136
	Comments	The p-value, least squares mean difference, and 95% CI for the treatment group comparison are based on a repeated measures ANCOVA with baseline, treatment, visit, and treatment-by-visit interaction as fixed factors, and subject as a random effect.
	Method	ANCOVA
	Comments	Least Squares mean difference: Treatment I - Treatment II
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	8.2
	Confidence Interval	(2-Sided) 95%; -35.92 to 52.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Thyroid-Stimulating Hormone (TSH)
Description	Normal range for this parameter was 0.35 to 5.5 mIU/L. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.
Time Frame	Baseline through Month 6

Outcome Measure Data

Analysis Population Description

Per protocol (PP) population with BL and at least 1 post-BL value for this measurement. PP population included all data from intent-to-treat (ITT) participants obtained prior to any major protocol violations. PP participants were analyzed according to the treatment actually received.

Arm/Group Title	Treatment I: (DR-102)	Treatment II
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles
Measure Participants	125	120
Least Squares Mean (Standard Error) [mIU/L]	0.2 (0.07)	0.3 (0.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment I: (DR-102), Treatment II
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.3903
	Comments	The p-value, least squares mean difference, and 95% CI for the treatment group comparison are based on a repeated measures ANCOVA with baseline, treatment, visit, and treatment-by-visit interaction as fixed factors, and subject as a random effect.
	Method	ANCOVA
	Comments	Least Squares mean difference: Treatment I - Treatment II
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Least Squares Mean Change From Baseline Over the 6-Month Treatment Period in Sex Hormone Binding Globulin
Description	Normal range for this parameter was 28 to 146 nmol/L. Change from baseline was analyzed using a repeated measures analysis of covariance with covariate adjustment for baseline, treatment, month, and the treatment by month interaction.
Time Frame	Baseline through Month 6

Outcome Measure Data

Analysis Population Description

Per protocol (PP) population with BL and at least 1 post-BL value for this measurement. PP population included all data from intent-to-treat (ITT) participants obtained prior to any major protocol violations. PP participants were analyzed according to the treatment actually received.

Arm/Group Title	Treatment I: (DR-102)	Treatment II
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles	21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles
Measure Participants	125	120
Least Squares Mean (Standard Error) [nmol/L]	163.4 (7.29)	149.1 (7.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment I: (DR-102), Treatment II
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.1731
	Comments	The p-value, least squares mean difference, and 95% CI for the treatment group comparison are based on a repeated measures ANCOVA with baseline, treatment, visit, and treatment-by-visit interaction as fixed factors, and subject as a random effect.
	Method	ANCOVA
	Comments	Least Squares mean difference: Treatment I - Treatment II
Method of Estimation	Estimation Parameter	Least Squares Mean Difference
	Estimated Value	14.3
	Confidence Interval	(2-Sided) 95%; -6.29 to 34.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events/serious adverse events were collected from the time of signed informed consent until the the Final Telephone Contact (14 days after completing investigational product) or the Early Termination Visit. Treatment period was 6 28-day cycles.
Arm/Group Title	Treatment I: (DR-102)		Treatment II
Arm/Group Description	21 days of combination active pills (containing 150 mcg desogestrel [DSG]/20 mcg ethinyl estradiol [EE]), followed by 7 days of 10 mcg EE, taken orally for 6 consecutive 28-day cycles		21 days combination active pills (containing 150 mcg DSG/20 mcg EE), taken orally and followed by 7 days of no treatment for a total of 6 consecutive 28-day cycles
All Cause Mortality
	Treatment I: (DR-102)		Treatment II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Treatment I: (DR-102)		Treatment II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/145 (0%)		1/142 (0.7%)
Infections and infestations
Appendicitis	0/145 (0%)		1/142 (0.7%)
Other (Not Including Serious) Adverse Events
	Treatment I: (DR-102)		Treatment II
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	84/145 (57.9%)		66/142 (46.5%)
Gastrointestinal disorders
Nausea	4/145 (2.8%)		2/142 (1.4%)
Infections and infestations
Nasopharyngitis	3/145 (2.1%)		3/142 (2.1%)
Gastroenteritis	1/145 (0.7%)		4/142 (2.8%)
Influenza	1/145 (0.7%)		4/142 (2.8%)
Urinary tract infection	1/145 (0.7%)		3/142 (2.1%)
Investigations
Alpha globulin increased	11/145 (7.6%)		8/142 (5.6%)
Prothrombin level increased	8/145 (5.5%)		7/142 (4.9%)
Antithrombin III decreased	1/145 (0.7%)		3/142 (2.1%)
Nervous system disorders
Headache	9/145 (6.2%)		16/142 (11.3%)
Dizziness	4/145 (2.8%)		0/142 (0%)
Psychiatric disorders
Libido decreased	3/145 (2.1%)		1/142 (0.7%)
Reproductive system and breast disorders
Metrorrhagia	50/145 (34.5%)		28/142 (19.7%)
Breast pain	5/145 (3.4%)		2/142 (1.4%)
Dysmenorrhoea	4/145 (2.8%)		7/142 (4.9%)
Menorrhagia	4/145 (2.8%)		1/142 (0.7%)
Amenorrhoea	1/145 (0.7%)		3/142 (2.1%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/145 (0.7%)		3/142 (2.1%)
Skin and subcutaneous tissue disorders
Acne	4/145 (2.8%)		2/142 (1.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Investigator/Institution must submit proposed publication to Sponsor for review within a prespecified number of days before submission for publication. If Sponsor's review shows that potentially patentable subject matter would be disclosed, publication/public disclosure shall be delayed to enable Sponsor, or Sponsor's designees, to file necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.