Trial Outcomes & Findings for Synthetic vs Natural Estrogen in Combined Oral Contraception (NCT NCT02352090)

NCT ID: NCT02352090

Last Updated: 2023-06-22

Results Overview

Matsuda index is calculated from the standard 2h Oral Glucose Tolerance Test and corresponding insulin values. Matsuda index = 10,000/square root of \[fasting glucose x fasting insulin\] x \[mean glucose x mean insulin during OGTT\]) The Matsuda index is correlated (r = 0.73) with the rate of whole-body glucose disposal during the euglycemic insulin clamp. Matsuda index \<2.5 is considered insulin resistant, higher values indicate less insulin resistance. A decrease in matsuda index over the study period would indicate decreased insulin sensitivity.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 59 participants
• Primary outcome timeframe: We calculated the change in Matsuda index from baseline to 9 weeks.
• Results posted on: 2023-06-22

Participant Flow

Participant milestones

Measure	Synthetic Estrogen + Progestin Ethinyl estradiol / dienogest Ethinyl estradiol / dienogest: One tablet orally for 9 weeks, continuous use	Natural Estrogen + Progestin Estradiol valerate / dienogest Estradiol valerate / dienogest: One tablet orally for 9 weeks, continuous use	Progestin-Only Dienogest Dienogest: One tablet orally for 9 weeks, continuous use
Overall Study STARTED	20	20	19
Overall Study COMPLETED	19	20	17
Overall Study NOT COMPLETED	1	0	2

Reasons for withdrawal

Measure	Synthetic Estrogen + Progestin Ethinyl estradiol / dienogest Ethinyl estradiol / dienogest: One tablet orally for 9 weeks, continuous use	Natural Estrogen + Progestin Estradiol valerate / dienogest Estradiol valerate / dienogest: One tablet orally for 9 weeks, continuous use	Progestin-Only Dienogest Dienogest: One tablet orally for 9 weeks, continuous use
Overall Study general malaise	1	0	0
Overall Study non-specified mild side-effects	0	0	2

Baseline Characteristics

Synthetic vs Natural Estrogen in Combined Oral Contraception

Baseline characteristics by cohort

Measure	Synthetic Estrogen + Progestin n=19 Participants Ethinyl estradiol / dienogest Ethinyl estradiol / dienogest: One tablet orally for 9 weeks, continuous use	Natural Estrogen + Progestin n=20 Participants Estradiol valerate / dienogest Estradiol valerate / dienogest: One tablet orally for 9 weeks, continuous use	Progestin-Only n=17 Participants Dienogest Dienogest: One tablet orally for 9 weeks, continuous use	Total n=56 Participants Total of all reporting groups
Age, Continuous	25.8 years STANDARD_DEVIATION 3.8 • n=5 Participants	24.1 years STANDARD_DEVIATION 3.6 • n=7 Participants	24.0 years STANDARD_DEVIATION 3.9 • n=5 Participants	24.6 years STANDARD_DEVIATION 3.8 • n=4 Participants
Sex: Female, Male Female	19 Participants n=5 Participants	20 Participants n=7 Participants	17 Participants n=5 Participants	56 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	19 Participants n=5 Participants	20 Participants n=7 Participants	17 Participants n=5 Participants	56 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Weight	63.3 kg STANDARD_DEVIATION 4.5 • n=5 Participants	61.4 kg STANDARD_DEVIATION 5.8 • n=7 Participants	58.0 kg STANDARD_DEVIATION 7.1 • n=5 Participants	61.0 kg STANDARD_DEVIATION 6.1 • n=4 Participants
BMI	23.1 kg/m^2 STANDARD_DEVIATION 1.9 • n=5 Participants	22.4 kg/m^2 STANDARD_DEVIATION 1.6 • n=7 Participants	21.9 kg/m^2 STANDARD_DEVIATION 1.9 • n=5 Participants	22.5 kg/m^2 STANDARD_DEVIATION 1.8 • n=4 Participants

PRIMARY outcome

Timeframe: We calculated the change in Matsuda index from baseline to 9 weeks.

Matsuda index is calculated from the standard 2h Oral Glucose Tolerance Test and corresponding insulin values.

Matsuda index = 10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during OGTT]) The Matsuda index is correlated (r = 0.73) with the rate of whole-body glucose disposal during the euglycemic insulin clamp.

Matsuda index <2.5 is considered insulin resistant, higher values indicate less insulin resistance. A decrease in matsuda index over the study period would indicate decreased insulin sensitivity.

Outcome measures

Measure	Synthetic Estrogen + Progestin n=19 Participants Ethinyl estradiol / dienogest Ethinyl estradiol / dienogest: One tablet orally for 9 weeks, continuous use	Natural Estrogen + Progestin n=20 Participants Estradiol valerate / dienogest Estradiol valerate / dienogest: One tablet orally for 9 weeks, continuous use	Progestin-Only n=17 Participants Dienogest Dienogest: One tablet orally for 9 weeks, continuous use
Matsuda Index- Whole Body Insulin Sensitivity Index	-1.02 units on a scale Interval -2.51 to 0.46	-0.10 units on a scale Interval -1.34 to 1.14	-1.45 units on a scale Interval -3.22 to 0.32

SECONDARY outcome

Timeframe: baseline and 9 weeks

Mean change in fasting serum insulin from baseline to nine weeks

Outcome measures

Measure	Synthetic Estrogen + Progestin n=19 Participants Ethinyl estradiol / dienogest Ethinyl estradiol / dienogest: One tablet orally for 9 weeks, continuous use	Natural Estrogen + Progestin n=20 Participants Estradiol valerate / dienogest Estradiol valerate / dienogest: One tablet orally for 9 weeks, continuous use	Progestin-Only n=17 Participants Dienogest Dienogest: One tablet orally for 9 weeks, continuous use
Fasting Insulin	1.4 mU/l Interval -0.45 to 3.24	1.02 mU/l Interval -0.6 to 2.6	1.99 mU/l Interval 0.33 to 3.65

SECONDARY outcome

Timeframe: baseline and 9 weeks

Change in plasma concentrations of acute phase protein 'C reactive protein' (CRP), a marker of chronic inflammation.

Outcome measures

Measure	Synthetic Estrogen + Progestin n=19 Participants Ethinyl estradiol / dienogest Ethinyl estradiol / dienogest: One tablet orally for 9 weeks, continuous use	Natural Estrogen + Progestin n=20 Participants Estradiol valerate / dienogest Estradiol valerate / dienogest: One tablet orally for 9 weeks, continuous use	Progestin-Only n=17 Participants Dienogest Dienogest: One tablet orally for 9 weeks, continuous use
High-sensitivity C Reactive Protein	1.10 mg/L Interval 0.05 to 2.15	-0.06 mg/L Interval -0.54 to 0.42	0.13 mg/L Interval -0.22 to 0.48

SECONDARY outcome

Timeframe: baseline and 9 weeks

Change in concentrations of total cholesterol from baseline to nine weeks

Outcome measures

Measure	Synthetic Estrogen + Progestin n=19 Participants Ethinyl estradiol / dienogest Ethinyl estradiol / dienogest: One tablet orally for 9 weeks, continuous use	Natural Estrogen + Progestin n=20 Participants Estradiol valerate / dienogest Estradiol valerate / dienogest: One tablet orally for 9 weeks, continuous use	Progestin-Only n=17 Participants Dienogest Dienogest: One tablet orally for 9 weeks, continuous use
Total Cholesterol	0.10 mmol/L Interval -0.18 to 0.38	-0.16 mmol/L Interval -0.33 to 0.02	0.11 mmol/L Interval -0.11 to 0.32

SECONDARY outcome

Timeframe: baseline and 9 weeks

Change in concentration of Low-Density Lipoprotein LDL from baseline to nine weeks

Outcome measures

Measure	Synthetic Estrogen + Progestin n=19 Participants Ethinyl estradiol / dienogest Ethinyl estradiol / dienogest: One tablet orally for 9 weeks, continuous use	Natural Estrogen + Progestin n=20 Participants Estradiol valerate / dienogest Estradiol valerate / dienogest: One tablet orally for 9 weeks, continuous use	Progestin-Only n=17 Participants Dienogest Dienogest: One tablet orally for 9 weeks, continuous use
Low-Density Lipoprotein (LDL)	-0.16 mmol/L Interval -0.41 to 0.08	-0.14 mmol/L Interval -0.31 to 0.04	0.01 mmol/L Interval -0.19 to 0.21

SECONDARY outcome

Timeframe: baseline and 9 weeks

Change in concentration of High-Density Lipoprotein HDL from baseline to nine weeks

Outcome measures

Measure	Synthetic Estrogen + Progestin n=19 Participants Ethinyl estradiol / dienogest Ethinyl estradiol / dienogest: One tablet orally for 9 weeks, continuous use	Natural Estrogen + Progestin n=20 Participants Estradiol valerate / dienogest Estradiol valerate / dienogest: One tablet orally for 9 weeks, continuous use	Progestin-Only n=17 Participants Dienogest Dienogest: One tablet orally for 9 weeks, continuous use
High-Density Lipoprotein (HDL)	0.20 mmol/L Interval 0.09 to 0.31	-0.02 mmol/L Interval -0.11 to 0.07	-0.02 mmol/L Interval -0.11 to 0.07

SECONDARY outcome

Timeframe: baseline and 9 weeks

Change in triglyceride concentrations from baseline to nine weeks

Outcome measures

Measure	Synthetic Estrogen + Progestin n=19 Participants Ethinyl estradiol / dienogest Ethinyl estradiol / dienogest: One tablet orally for 9 weeks, continuous use	Natural Estrogen + Progestin n=20 Participants Estradiol valerate / dienogest Estradiol valerate / dienogest: One tablet orally for 9 weeks, continuous use	Progestin-Only n=17 Participants Dienogest Dienogest: One tablet orally for 9 weeks, continuous use
Triglyceride	0.45 mmol/L Interval 0.35 to 0.56	0.18 mmol/L Interval 0.01 to 0.35	0.06 mmol/L Interval -0.04 to 0.15

SECONDARY outcome

Timeframe: baseline and 9 weeks

Markers of coagulation activation

Outcome measures

Measure	Synthetic Estrogen + Progestin n=18 Participants Ethinyl estradiol / dienogest Ethinyl estradiol / dienogest: One tablet orally for 9 weeks, continuous use	Natural Estrogen + Progestin n=18 Participants Estradiol valerate / dienogest Estradiol valerate / dienogest: One tablet orally for 9 weeks, continuous use	Progestin-Only n=16 Participants Dienogest Dienogest: One tablet orally for 9 weeks, continuous use
D-dimer	12.6 percentage change from baseline Interval -3.3 to 28.4	2.4 percentage change from baseline Interval -14.0 to 18.7	-1.6 percentage change from baseline Interval -3.6 to 0.4

SECONDARY outcome

Timeframe: baseline and 9 weeks

Change in plasma concentrations of F1+2 a marker of coagulation activation

Outcome measures

Measure	Synthetic Estrogen + Progestin n=18 Participants Ethinyl estradiol / dienogest Ethinyl estradiol / dienogest: One tablet orally for 9 weeks, continuous use	Natural Estrogen + Progestin n=18 Participants Estradiol valerate / dienogest Estradiol valerate / dienogest: One tablet orally for 9 weeks, continuous use	Progestin-Only n=16 Participants Dienogest Dienogest: One tablet orally for 9 weeks, continuous use
F1+2	24.1 percentage change from baseline Interval 4.2 to 43.9	-5.5 percentage change from baseline Interval -19.4 to 8.4	-8.5 percentage change from baseline Interval -20.4 to 3.5

SECONDARY outcome

Timeframe: baseline and 9 weeks

Change from baseline in thrombin generation, measured by thrombin generation assay-Calibrated automated thrombogram

Outcome measures

Measure	Synthetic Estrogen + Progestin n=18 Participants Ethinyl estradiol / dienogest Ethinyl estradiol / dienogest: One tablet orally for 9 weeks, continuous use	Natural Estrogen + Progestin n=18 Participants Estradiol valerate / dienogest Estradiol valerate / dienogest: One tablet orally for 9 weeks, continuous use	Progestin-Only n=16 Participants Dienogest Dienogest: One tablet orally for 9 weeks, continuous use
Thrombin Generation, ETP Endogenous Thrombin Potential	63.9 percentage change from baseline Interval 51.4 to 76.3	26.4 percentage change from baseline Interval 14.5 to 38.2	7.1 percentage change from baseline Interval -3.2 to 17.4

OTHER_PRE_SPECIFIED outcome

Timeframe: baseline and 9 weeks

Change in Serum concentrations of anti-mullerian hormone reflecting ovarian reserve from baseline to nine weeks

Outcome measures

Measure	Synthetic Estrogen + Progestin n=19 Participants Ethinyl estradiol / dienogest Ethinyl estradiol / dienogest: One tablet orally for 9 weeks, continuous use	Natural Estrogen + Progestin n=20 Participants Estradiol valerate / dienogest Estradiol valerate / dienogest: One tablet orally for 9 weeks, continuous use	Progestin-Only n=17 Participants Dienogest Dienogest: One tablet orally for 9 weeks, continuous use
Anti Mullerian Hormone (AMH)	-0.8 ng/mL Interval -1.4 to -0.2	-0.4 ng/mL Interval -0.7 to 0.004	0.07 ng/mL Interval -0.3 to 0.4

Adverse Events

Synthetic Estrogen + Progestin

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Natural Estrogen + Progestin

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Progestin-Only

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Oskari Heikinheimo

Helsinki University Central Hospital

Phone: +358 50 4271533

Email: oskari.heikinheimo@helsinki.fi

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place