Evaluation of Estriol-Releasing Vaginal Ring for Vaginal Atrophy in Postmenopausal Women: A Placebo-Controlled, Double-Blind, Dose-Finding Study
- Trial ID
- 2024-514302-31-00
- Protocol
- 1452est24ct
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to conduct a **descriptive evaluation** of the change in the cytologic pattern of the vaginal epithelium after 90 days of treatment with three different doses of a newly developed vaginal ring releasing **estriol**. This evaluation is crucial for understanding the efficacy of the treatment in addressing **vaginal atrophy** in postmenopausal women. Additionally, the study aims to assess the change in vaginal pH after 90 days of treatment, which is an important indicator of vaginal health and can provide insights into the treatment's effectiveness. Furthermore, the trial will evaluate systemic total E3 exposure in a subgroup of patients, which is essential for understanding the pharmacokinetics and safety profile of the estriol-releasing vaginal ring.
Participants
The clinical trial focuses on **vaginal atrophy** and involves a study population exclusively composed of postmenopausal women aged 45 years or older. The participants are required to be in a postmenopausal state, defined by the absence of menstruation for at least one year and a follicle-stimulating hormone (FSH) level of 40 IU/l or higher. The trial does not include male subjects or vulnerable populations. Participants were selected based on specific criteria, including a **vaginal maturation value** of 50% or less and a vaginal pH greater than 5.0 at screening. Additionally, they must exhibit at least one subjective symptom of vaginal atrophy, such as dryness or dyspareunia, with a severity score of 65 or higher on the Visual Analogue Scale. Lifestyle considerations include being a non-smoker or having quit smoking at least three months prior to the study. The total number of participants is not provided by the sponsor.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of three different doses of a newly developed **vaginal ring** releasing **estriol** for the treatment of **vaginal atrophy** in postmenopausal women. This study is a placebo-controlled, double-blind, combined dose-finding and proof-of-concept trial with a parallel-group design. The trial will involve the administration of three different doses of the vaginal ring (1 µg/day, 10 µg/day, and 20 µg/day) and a placebo, with the primary objective being the descriptive evaluation of changes in the cytologic pattern of the vaginal epithelium, vaginal pH, and systemic total E3 exposure over a 90-day treatment period.
The trial will commence with a screening visit to assess eligibility based on specific inclusion criteria, such as age (45 years or older), postmenopausal status, and specific vaginal health parameters. Participants will be randomly assigned to one of the treatment groups or the placebo group. The study will be conducted over an estimated duration from July 2025 to April 2026, with participant involvement lasting approximately 90 days. During this period, participants will attend scheduled follow-up visits to monitor treatment effects and safety. These visits will include assessments of vaginal Maturation Value (MV), vaginal pH, and other relevant health indicators.
The primary endpoints of the study include changes from baseline in vaginal MV, the percentage of vaginal superficial and parabasal cells, and vaginal pH after 90 days of treatment. The proportion of responders with a vaginal pH ≤ 5 and total E3 exposure will also be evaluated. Participants may be withdrawn from the study if they experience adverse effects or if they do not adhere to the study protocol. The trial is not classified as a low-intervention study and is categorized as a Phase II trial, focusing on dose-finding and proof-of-concept in the target population.
Treatment
The clinical trial involves the administration of three different doses of a newly developed **vaginal ring** containing **estriol** for the treatment of vaginal atrophy in postmenopausal women. The first experimental medication is VR 102, which delivers a dose of 1 µg of estriol per day. This product is formulated as a **vaginal delivery system** and is administered via vaginal use. The maximum daily dose is 1 µg, with a total maximum dose of 90 µg over a treatment period of 90 days. The estriol used in this formulation is of chemical origin, and the product is manufactured by SOCRATEC R&D GMBH.
The second experimental medication is VR 102, delivering a dose of 10 µg of estriol per day. Similar to the first formulation, it is a vaginal delivery system administered vaginally. The maximum daily dose is 10 µg, with a total maximum dose of 900 µg over the same 90-day treatment period. The active substance, estriol, is also of chemical origin, and the product is produced by SOCRATEC R&D GMBH.
The third experimental medication is VR 102, which delivers a dose of 20 µg of estriol per day. This formulation is also a vaginal delivery system for vaginal use. The maximum daily dose is 20 µg, with a total maximum dose of 1800 µg over the 90-day treatment period. The estriol in this formulation is chemically derived, and the product is developed by SOCRATEC R&D GMBH.
The study also includes a placebo group, which receives a placebo vaginal ring without any active drug. This placebo is used to compare the effects of the active treatments and ensure the validity of the trial results. The placebo ring is designed to mimic the appearance and administration route of the active vaginal rings but does not contain estriol or any other active substance.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen. The trial is designed to evaluate the change in the cytologic pattern of the vaginal epithelium, vaginal pH, and systemic total E3 exposure over the 90-day treatment period.
Efficacy
The efficacy of the clinical trial investigating the use of a newly developed vaginal ring releasing **estriol** for the treatment of vaginal atrophy will be assessed through several primary endpoints. These endpoints include the change from baseline in vaginal Maturation Value (MV) after 90 days of treatment, the change in the percentage of vaginal superficial and parabasal cells, and the change in vaginal pH. Additionally, the proportion of responders with a vaginal pH ≤ 5 after 90 days of treatment and the total area under the curve (AUC) for E3 exposure over the course of treatment will be evaluated.
The trial will employ a placebo-controlled, double-blind, parallel-group design to ensure the reliability of the results. Efficacy parameters will be measured at baseline and after 90 days of treatment. The change in the cytologic pattern of vaginal epithelium and vaginal pH will be descriptively evaluated, along with systemic total E3 exposure in a pharmacokinetic (PK) subgroup of patients. The trial aims to provide a comprehensive assessment of the treatment's impact on vaginal atrophy in postmenopausal women.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age: 45 years or older
- Postmenopausal state defined as last spontaneous menstruation at least 1 year prior to the study and FSH (serum) ≥ 40 IU/l (≥ 40 E/l)
- Vaginal Maturation Value (MV) ≤ 50% at screening
- Vaginal pH > 5.0 at screening
- At least one subjective symptom of VA (dryness, pain/burning sensation, pruritus, discharge, dysuria, urinary incontinence, dyspareunia) rated at a score of ≥ 65 on the Visual Analogue Scale (VAS)
- Non-smoker or ex-smoker for at least 3 months
- Written informed consent, after having been informed about benefits and potential risks of the clinical trial, as well as details of the insurance taken out to cover the participants in this clinical trial
Exclusion Criteria
- History or presence of cardiac and/or haematological diseases or pathological findings, which, in the opinion of the investigator, might interfere with the safety or tolerability of the active ingredient
- History or presence of hepatic and/or renal diseases or pathological findings, which, in the opinion of the investigator, might interfere with the safety or tolerability, and/or pharmacokinetics of the active ingredient
- History or presence of relevant Central Nervous System (CNS) and/or psychiatric disorders and/or currently treated CNS and/or psychiatric disorders, which in the opinion of the investigator, might affect the safety of the participant
- Known allergic reactions/hypersensitivity to the active ingredient used or to constituents of the pharmaceutical preparations
- Participants with severe allergies or multiple drug allergies unless it is judged as not relevant for the clinical trial by the investigator
- Systolic blood pressure > 139 mmHg
- Diastolic blood pressure >89 mmHg
- Pulse rate < 50 bpm or > 100 bpm
- Any clinically relevant abnormality as observed during breast examination at screening
- Any laboratory value outside of normal and judged by investigator as relevant for participation under safety considerations
- Any further contraindication to estrogen therapy; Known, past or suspected breast cancer; Known, past or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer); Current or undiagnosed genital bleeding; Untreated endometrial hyperplasia; Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism); Known thrombophilic disorders; Active or recent (within the last 24 months) arterial thromboembolic disease (e.g. angina pectoris, myocardial infarction) if not cured without cardiovascular consequences; Porphyria
- If any of the conditions listed below are present or have occurred previously. Patients might participate if either these conditions have not aggravated during pregnancy or previous sex hormone treatment, or if they are judged by the investigator not to pose a current safety risk for the participant; Leiomyoma (uterine fibroids) or endometriosis; Risk factors for thromboembolic disorders; Risk factors for oestrogen-dependent tumours, e.g. 1st degree relative for breast cancer; Untreated or uncontrolled hypertension; Liver adenoma or estrogen-dependent liver disorders (e.g. liver cysts, liver angioma); uncontrolled Diabetes mellitus; Cholelithiasis; Migraine or category II or higher non-migraine headaches (grading of non-migraine headaches acc. to Sjaastad et al. 2002); Systemic lupus erythematosus; A history of endometrial hyperplasia (endometrial thickness of ≥5 mm); Epilepsy; Asthma; Otosclerosis; Endometrial polyps
- Diagnosis of a cervical smear: findings classified in a group higher than IIa according to the Munich III nomenclature or history of documented abnormal cervical smear (higher than IIa) within one year of screening
- Confirmation of endometrial thickness of ≥5 mm
- Untreated vaginal infection that would hinder the insertion of the ring according to the decision of the investigator
- The following washout periods must be observed before screening: 1 week or longer for prior non-hormonal vaginal or vulvar treatment (including cosmetics expected to affect vaginal pH such as special feminine wash gels); 4 weeks or longer for prior vaginal hormonal products (rings, creams, gels); 4 weeks or longer for prior transdermal estrogen alone or estrogen/progestin products; 8 weeks or longer for prior oral estrogen and/or progestin therapy; 8 weeks or longer for prior intrauterine progestin therapy; 8 weeks or longer for prior testosterone or testosterone derivatives, DHEA, tibolone, or SERMs by any route; 3 months or longer for prior progestin implants and estrogen alone injectable drug therapy; 6 months or longer for prior estrogen pellet therapy or progestin injectable drug therapy
- Use of systemic or intravaginal corticosteroids within 8 weeks prior to the IMP administration
- Treatment with strong inductors or inhibitors of CYP3A4, e.g. anticonvulsants (barbiturates, hydantoins, carbamazepine), certain antibiotics (e.g. erythromycin, clarithromycin, telithromycin), antimycotics (e.g. ketoconazole, itraconazole) and other antiinfective medicinal products (e.g. rifampicin, rifabutin, nevirapine, efavirenz); phenylbutazone; ritonavir and nelfinavir; preparations based on medicinal plants that contain St. John’s Wort within 2 weeks prior to the IMP administration
- Women with hysterectomy and/or bilateral oophorectomy
- Acute or chronic diseases which may interfere with the aims of the clinical trial
- Vaginal descensus or other condition which might interfere with the vaginal application of IMP
- History of or current drug or alcohol dependence or abuse
- Participation in a clinical trial with administration of any investigational medicinal product during the last 2 months prior to screening
- Simultaneous participation in another clinical trial with active ingredients
- Participant is judged by the Investigator to be unsuitable for any reason
- Non-availability of prompt access to eDiary at any time
- Participants suspected or known not to follow instructions
- Participants who are unable to understand the written and verbal instructions, in particular regarding the risks and inconveniences they will be exposed to during their participation in the clinical trial
- Participant is vulnerable such as detained or committed to an institution by a court of law or by legal authorities or has close affiliation with the sponsor or the investigational site (e.g. a close relative, dependent person (e.g. employee or student))
- Positive anti-HIV-test (if positive to be verified by western blot), HBs-AG-test (if positive to be verified by test for HBc-IgM) or anti-HCV-test
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 09 Jul 2025 | 112 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
VR 10220 µg/day | Test | VAGINAL DELIVERY SYSTEM | VAGINAL USE | 20 | 90 | PRD12099358 |
Placebo vaginal ring without active drug | Placebo | N/A | — | — | — | N/A |
VR 1021 µg/day | Test | VAGINAL DELIVERY SYSTEM | VAGINAL USE | 1 | 90 | PRD12099331 |
VR 10210 µg/day | Test | VAGINAL DELIVERY SYSTEM | VAGINAL USE | 10 | 90 | PRD12101201 |