Hormone Interaction Study in Healthy Subjects

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: AstraZeneca

Must not be taking: Sex hormones, QT prolongation drugs

Disqualifiers: Gastrointestinal, Hepatic, Renal, Cardiovascular, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how the drug baxdrostat affects the body when taken with a common oral contraceptive combination of ethinyl estradiol and levonorgestrel (EE/LNG). The study aims to understand the interaction between these drugs and to ensure that baxdrostat is safe and well-tolerated alongside the contraceptive. Women who are postmenopausal or have undergone certain types of permanent surgical sterilization may be suitable for this trial. Participants must have a body mass index (BMI) between 18 and 30 and should not have any significant medical conditions that could affect drug processing or pose health risks. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you must stop all current medications, but you cannot be on sex hormone therapy within one month before the study or strong CYP3A4 inhibitors or inducers within 3 months prior. Check with the trial team for more details.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Earlier studies have linked the combination of ethinyl estradiol and levonorgestrel (EE/LNG), commonly used in birth control, to side effects like nausea, headaches, and sometimes irregular periods. More serious risks include blood clots, especially for individuals over 35 who smoke. These risks are well-known and monitored.

Research shows that baxdrostat specifically targets an enzyme involved in controlling blood pressure, making it less likely to affect other enzymes and cause side effects. Previous studies did not find major safety concerns, but as it remains under study, more long-term information is being collected.

Both treatments are being tested together to assess their safety and interaction. Participants' experiences in these studies contribute to a better understanding of their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they explore how ethinyl estradiol/levonorgestrel (EE/LNG), a commonly used hormonal combination, interacts with baxdrostat, a promising new compound. Baxdrostat is unique as it targets the enzyme aldosterone synthase, potentially offering benefits in hormonal regulation that differ from existing treatments. Understanding these interactions could pave the way for more tailored and effective hormonal therapies, making them safer and more effective for users. This trial aims to uncover how these drugs can work together, potentially leading to innovative approaches in hormonal health management.

What evidence suggests that this trial's treatments could be effective?

Research has shown that Ethinyl Estradiol (EE) and Levonorgestrel (LNG) are effective ingredients in birth control pills. When used correctly, these hormones prevent pregnancy with an effectiveness of 93% to 96%. This means that 4 to 7 out of 100 women may become pregnant each year, mostly due to user mistakes. In this trial, participants will receive EE/LNG alone in one treatment arm.

Research has found that Baxdrostat can significantly lower blood pressure in people with high blood pressure that doesn't respond to other treatments. One study showed that Baxdrostat lowered the top number in blood pressure readings by an average of 15.7 mmHg. This indicates it can effectively manage high blood pressure when other treatments fail. In this trial, participants will receive Baxdrostat alone in one treatment arm and in combination with EE/LNG in another arm.

These findings provide insight into how these treatments might work in the current study. ^{1 3 4 6 7}

Are You a Good Fit for This Trial?

This trial is for healthy postmenopausal women or those who have had certain surgeries to ensure they cannot bear children. They should not be pregnant, lactating, and must have a BMI between 18-30 kg/m2. Women with a history of significant diseases, drug-related liver toxicity, thrombosis risks, cardiovascular issues, or severe allergies are excluded.

Inclusion Criteria

Have a Body Mass Index (BMI) between 18 and 30 kg/m2

I am not pregnant, breastfeeding, and cannot become pregnant.

I am postmenopausal, confirmed by lack of periods for 12 months, hormone levels, or surgery.

Exclusion Criteria

History of any clinically important disease or disorder which, in the opinion of the Investigator

Participants who are vegans or have medical dietary restrictions and vulnerable participants

Any positive result on screening for serum HBsAg, HBcAb, HCV or HIV

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

Up to 4 weeks

Period 1

Participants receive oral dose of EE/LNG in the fasted state on Day 1, followed by PK sampling for 120 hours

5 days

Period 2

Participants self-administer baxdrostat once a day from Day 6 to Day 16

11 days

Period 3

Participants receive baxdrostat once daily and EE/LNG on Day 18, followed by PK sampling for 120 hours

7 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

What Are the Treatments Tested in This Trial?

Interventions

• Baxdrostat
• EE/LNG

Trial Overview The study tests how multiple doses of Baxdrostat affect the body's handling of a single dose of combined oral contraceptives (Ethinyl Estradiol and Levonorgestrel). It also evaluates the safety and tolerability of Baxdrostat in these conditions.

How Is the Trial Designed?

Group I: Period 3: Baxdrostat + EE/LNG Experimental Treatment 2 Interventions

Participants will receive baxdrostat once daily on Day 17 to Day 22 and will receive EE+LNG in the fasted state on Day 18, followed by oral dose of EE/LNG PK sampling for 120 hours (EE=72 hours and LNG=120 hours).

Group II: Period 2: Baxdrostat Experimental Treatment 1 Intervention

Participants will self-administer the baxdrostat tablet once a day from Day 6 to Day 16.

Group III: Period 1: Ethinyl estradiol/Levonorgestrel (EE/LNG) Experimental Treatment 1 Intervention

Participants will receive oral dose of EE/LNG in the fasted state on Day ,1 followed by PK sampling of EE/LNG for 120 hours (EE 72 hours and LNG 120 hours).

EE/LNG is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Ethinyl Estradiol/Levonorgestrel for:

• Contraception
• Menstrual disorders

Approved in European Union as Ethinyl Estradiol/Levonorgestrel for:

• Contraception
• Menstrual disorders
• Dysmenorrhea

Approved in Canada as Ethinyl Estradiol/Levonorgestrel for:

• Contraception
• Menstrual disorders

Approved in Japan as Ethinyl Estradiol/Levonorgestrel for:

• Contraception
• Menstrual disorders

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Published Research Related to This Trial

Recent studies show that the pharmacokinetics of oral contraceptives like ethinyl estradiol (EE) and levonorgestrel (LNG) have moderate variability in drug exposure among women, indicating a more consistent understanding of their behavior in the body.

Over the past two decades, extensive research has been conducted on LNG and EE, leading to 17 publications that demonstrate similar pharmacokinetic profiles across various products and studies, suggesting reliability in their use as reference drugs for assessing drug interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perspectives on variability in pharmacokinetics of an oral contraceptive product. Jusko, WJ.[2018]

The study found that the effectiveness of levonorgestrel (LNG) in combined oral contraceptives can be significantly reduced by the presence of strong CYP3A4 inducers, leading to a decrease in LNG plasma levels by 50-75% depending on the woman's body mass index (BMI).

In women with a BMI of less than 25 kg/m2, the Pearl Index (a measure of contraceptive effectiveness) increased to 1.2-2.1 when using LNG in conjunction with CYP3A4 inducers, while in obese women, it rose to 1.6-2.85, indicating a higher risk of unintended pregnancies under these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determining the Exposure Threshold for Levonorgestrel Efficacy Using an Integrated Model Based Meta-Analysis Approach. Lingineni, K., Chaturvedula, A., Cicali, B., et al.[2022]

Levonorgestrel (LNG) exposure can be significantly affected by drug-drug interactions (DDIs), particularly with CYP3A4 inducers like rifampicin, which can reduce LNG levels by 50%, potentially increasing the risk of unintended pregnancies.

Conversely, the presence of CYP3A4 inhibitors such as itraconazole can increase LNG exposure by 50%, highlighting the importance of monitoring and adjusting contraceptive methods in women taking these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative Assessment of Levonorgestrel Binding Partner Interplay and Drug-Drug Interactions Using Physiologically Based Pharmacokinetic Modeling. Cicali, B., Lingineni, K., Cristofoletti, R., et al.[2021]

In a study involving 1515 women over 13 to 19 cycles, the new oral contraceptive regimen containing gestodene (60 microg) and ethinylestradiol (15 microg) demonstrated a very low pregnancy rate, with a Pearl index of 0.21, indicating high contraceptive efficacy.

The regimen was generally well-tolerated, although common side effects included headaches (35% of subjects) and absence of bleeding (16%), suggesting that while effective, some users may experience notable adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and contraceptive efficacy of a 24-day low-dose oral contraceptive regimen containing gestodene 60 microg and ethinylestradiol 15 microg. [2022]

In a study involving 20 volunteers, the pharmacokinetics of two oral contraceptives showed that higher doses of ethinylestradiol (EE2) led to increased peak serum concentrations, particularly at steady-state conditions on day 21 of treatment.

Levonorgestrel (LNG) levels significantly increased with EE2 administration, but the relationship between LNG and sex hormone-binding globulin (SHBG) concentrations suggests that other mechanisms may also influence LNG binding in women taking these combined contraceptives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of ethinylestradiol and levonorgestrel after administration of two oral contraceptive preparations. Carol, W., Klinger, G., Jäger, R., et al.[2013]

Oral contraceptives (OCs) are widely used, making it crucial to understand potential drug-drug interactions (DDIs) with them, especially for new medications that could affect their efficacy or safety.

This review highlights the complexities of studying DDIs with OCs, emphasizing the need for pharmacokinetic (PK) and pharmacodynamic (PD) considerations in study design, and suggests that PK-based studies are essential for accurately assessing clinical drug interactions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug-Drug Interaction Studies With Oral Contraceptives: Pharmacokinetic/Pharmacodynamic and Study Design Considerations. Sun, H., Sivasubramanian, R., Vaidya, S., et al.[2021]

Levonorgestrel (LNG) can exhibit estrogen-like effects despite not binding to estrogen receptors, which may be due to its transformation into metabolites that activate estrogen-dependent gene transcription, particularly through the ER alpha subtype.

The study found that certain reduced metabolites of LNG, specifically the 3 beta,5 alpha-tetrahydro derivative, significantly activate estrogen-responsive genes, while showing lower activity on progesterone receptors, indicating a selective mechanism of action for LNG's estrogenic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The intrinsic transcriptional estrogenic activity of a non-phenolic derivative of levonorgestrel is mediated via the estrogen receptor-alpha. García-Becerra, R., Borja-Cacho, E., Cooney, AJ., et al.[2019]

In a study of 47 women using a combination of ethinyl estradiol (EE) 20 microg and levonorgestrel (LNG) 100 microg, there was no significant change in body weight or body composition compared to 31 control women.

The EE20/LNG100 combination also did not affect metabolic parameters like glycemia and lipid profile, suggesting it may have a favorable safety profile that could improve patient compliance with treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects on body weight and body composition of a low-dose oral estroprogestin containing ethinyl estradiol 20 microg plus levonorgestrel 100 microg. Lello, S., Vittori, G., Paoletti, AM., et al.[2013]

In a study of 31 regularly menstruating users of levonorgestrel subdermal implants (Norplant), nearly half of their menstrual cycles were found to be anovulatory, indicating that the implants primarily prevent ovulation as a mechanism of action.

Even in cycles that were presumed to be ovulatory, users exhibited hormonal dysfunctions such as diminished gonadotropin surges and luteal phase insufficiency, which likely enhance the contraceptive effectiveness of Norplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ovulatory dysfunction during continuous administration of low-dose levonorgestrel by subdermal implants. Faundes, A., Brache, V., Tejada, AS., et al.[2017]

Citations

1. astrazeneca.com astrazeneca.com/content/astraz/media-centre/press-releases/2025/bax24-phase-iii-trial-full-results.html

Baxdrostat demonstrated a statistically significant and ... Baxdrostat demonstrated a statistically significant placebo-adjusted reduction of 13.9 mmHg in night-time ambulatory systolic blood pressure ...

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa2213169

Phase 2 Trial of Baxdrostat for Treatment-Resistant ... Patients with treatment-resistant hypertension who received baxdrostat had dose-related reductions in blood pressure.

3. astrazeneca-us.com astrazeneca-us.com/media/press-releases/2025/Baxdrostat-demonstrated-statistically-significant-and-clinically-meaningful-reduction-in-systolic-blood-pressure-in-patients-with-hard-to-control-hypertension-in-the-BaxHTN-Phase-III-trial.html

Baxdrostat demonstrated statistically significant and ... Baxdrostat 2mg lowered systolic blood pressure by 15.7 mmHg (9.8 mmHg placebo-adjusted) from baseline, and was generally well tolerated with ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12563783/

Baxdrostat: A Next-Generation Aldosterone Synthase Inhibitor ... Studies indicate that weight loss of approximately 5 kg results in an average reduction in SBP by 4.4 mmHg and DBP by 3.6 mmHg [45]. 5.2. Pharmacological. The ...

5. nature.com nature.com/articles/s41440-022-01070-4

Results from a phase 1, randomized, double-blind, multiple ... This study evaluated the safety, pharmacokinetics, and pharmacodynamics of multiple ascending doses of baxdrostat in healthy volunteers.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05966324?term=AREA%5BInterventionSearch%5D(ALDOS)%20AND%20AREA%5BStudyType%5D(INTERVENTIONAL)&rank=2

Study Details | NCT05966324 | Baxdrostat Safety, ... The baxdrostat blood levels over time and the levels of certain hormones that regulate blood pressure will be compared between the dose groups and between the ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11166670/

Aldosterone synthase inhibitor “Baxdrostat” for resistant ... Baxdrostat, a drug in phase 2 clinical trials, exemplifies exceptional selective suppression of aldosterone synthase without blocking 11‐beta hydroxylase.