Arterial Vascular Effects of Estetrol-drospirenone Combined Oral Contraceptive Pill

Effect of Estetrol-drospirenone Combined Oral Contraceptive Pill on Arterial Vascular Risks

The goals of this clinical trial are to investigate the effect of the estetrol (E4)-drospirenone combined oral contraceptive (COC) pill on flow-mediated dilatation (FMD) of the brachial artery and pulse wave velocity (PWV), in comparison to the ethinylestradiol (EE)-levonorgestrel COC pill, and to compare their respective effects on blood pressure, chronic inflammatory markers, as well as glycaemic and lipid indices.

The main questions it aims to answer are:

Does E4-drospirenone COC have significantly smaller effects then EE-levonorgestrel COC on FMD, PWV, blood pressure, chronic inflammatory markers, as well as glycemic and lipid indices.

Researchers will compare E4-drospirenone to EE-levonorgestrel to see if the former has lower arterial vascular and metabolic risks.

Participants will:

• be randomised to take E4-drospirenone or EE-levonorgestrel COC pill according to product insert;
• visit the clinic at baseline and 6 and 12 months post-recruitment for checkups and tests

Study Overview

• Status: Not yet recruiting
• Conditions: Contraception
• Intervention / Treatment: Drug: Estetrol-drospirenone; Drug: Ethinylestradiol-levonorgestrel

Detailed Description

Objectives: (1) To investigate the effect of the estetrol (E4)-drospirenone combined oral contraceptive (COC) pill on flow-mediated dilatation (FMD) of the brachial artery and pulse wave velocity (PWV), in comparison to the ethinyl-estradiol (EE)- levonorgestrel COC pill. (2) To investigate the effect of the E4-drospirenone COC pill on blood pressure, chronic inflammatory markers, as well as glycaemic /lipid indices.

Hypothesis to be tested: E4-drospirenone has non-significant effect on FMD and PWV, as well as on blood pressure, chronic inflammatory markers, glycaemic and lipid profile compared to EE-levonorgestrel.

Design and subjects: Open-label randomised controlled trial. Women (n=98) who are commencing COC pills for contraception or treatment of gynaecological conditions will be recruited.

Study instruments: FMD, carotid-femoral and brachial-ankle PWV, blood pressure, serum high-sensitivity C-reactive protein and interleukin-6 measurements, glycaemic and lipid profile

Interventions: (1) E4 15mg + drospirenone 3mg versus (2) EE 30mcg + levonorgestrel 150mcg

Main outcome measures: FMD, carotid-femoral and brachial-ankle PWV

Data analysis: Data will be analysed with both intention to treat and per protocol approaches. The primary and secondary outcome measures (continuous variables) at baseline and at 6 and 12 months after treatment will be compared by paired t-test (with logarithmic transformation of significantly skewed data). Changes in these parameters will be compared between the two study groups by linear mixed models. P values of <0.05 will be considered statistically significant.

Expected results: E4-drospirenone induces insignificant changes in FMD, PWV as well as blood pressure, chronic inflammatory markers, and glycaemic and lipid profile.

• Study Type: Interventional
• Enrollment (Estimated): 98
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Raymond HW Li, MD, FRCOG; Phone Number: +852 22554517; Email: raymondli@hku.hk
• Study Contact Backup: Name: Jennifer KY Ko, MBBS, FRCOG; Phone Number: +852 22554517; Email: jenko@hku.hk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Aged between 18 and 49 years inclusive
• Considering to use the COC pill for contraception or treatment of menstrual disorders

Exclusion Criteria:

• Being diagnosed with menopause
• Having contraindications to COC, including (but not confined to) hypertension, diabetes mellitus with complications, history of ischaemic heart disease, thromboembolism, stroke, severe liver disease, oestrogen-sensitive cancers, undiagnosed abnormal uterine bleeding, smokers aged 35 years or above, or having body mass index >=35 kg/m2
• Planning to get pregnant in the coming 1 year
• Having been pregnant in the past 3 months
• Having been on COC or hormone replacement therapy in the past 3 months (those who had been on these agents can stop these for 3 months as wash-out period before being recruited; this concurs with other similar studies in the literature)
• Having been on anti-hypertensive, anti-diabetic or lipid-lowering agents in the past 3 months
• Refusal to randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: E4-drospirenone; Estetrol-drospirenone	Drug: Estetrol-drospirenone; Estetrol 15mg + drospirenone 3mg; Other Names: Alyssa
Active Comparator: EE-levonorgestrel; Ethinylestradiol-levonorgestrel	Drug: Ethinylestradiol-levonorgestrel; Ethinylestradiol 30mcg + levonorgestrel 150mcg; Other Names: Microgynon

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Flow-mediated dilatation (FMD)	Flow-mediated dilatation of the brachial artery	0, 6 and 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulse wave velocity (PWV)	Pulse wave velocity (carotid-femoral and brachial-ankle)	0, 6 and 12 months
Body mass index	Body mass index	0, 6 and 12 months
Waist-hip ratio	Waist-hip ratio	0, 6 and 12 months
Blood pressure	Blood pressure (systolic and diastolic)	0, 6 and 12 months
Sex hormone-binding globulin	Serum sex hormone-binding globulin level	0, 6 and 12 months
High sensitivity C-reactive protein	Serum high sensitivity C-reactive protein level	0, 6 and 12 months
Fasting glucose	Fasting plasma glucose	0, 6 and 12 months
2-hour glucose	Plasma glucose at 2 hours after 75g oral glucose tolerance test	0, 6 and 12 months
Haemoglobin A1c	Haemoglobin A1c	0, 6 and 12 months
Fasting insulin	Serum fasting insulin level	0, 6 and 12 months
Lipid profile	Lipid profile (low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides)	0, 6 and 12 months

Collaborators and Investigators

• Sponsor: Dr. Hang Wun Raymond Li
• Collaborators: The Family Planning Association of Hong Kong
• Investigators: Principal Investigator: Raymond HW Li, MD, FRCOG, The University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: April 12, 2026
• First Submitted That Met QC Criteria: April 12, 2026
• First Posted (Actual): April 17, 2026

Study Record Updates

• Last Update Posted (Actual): April 27, 2026
• Last Update Submitted That Met QC Criteria: April 24, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Combined oral contraceptives; Estetrol-drospirenone; Ethinylestradiol-levonorgestrel; Arterial risks; Metabolic risks
• Additional Relevant MeSH Terms: ethinyl estradiol, levonorgestrel drug combination; drospirenone and estetrol
• Other Study ID Numbers: UW 26-044

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: IPD may be shared upon negotiation with reasonable justifications after publication of the results.
• IPD Sharing Time Frame: After publication of the results.
• IPD Sharing Access Criteria: IPD may be shared upon negotiation with reasonable justifications after publication of the results.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No