Treatment of mod-severe vasomotor symptoms associated with menopause.
Research type
Research Study
Full title
A Randomized Double-blind Placebo Controlled Phase 3 Trial to evaluate the Efficacy and Safety of Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women (E4Comfort Study I)
IRAS ID
270902
Contact name
Nicholas Panay
Contact email
Sponsor organisation
Estetra SPRL
Eudract number
2019-001289-14
Duration of Study in the UK
1 years, 9 months, 5 days
Research summary
Research summary
This clinical study is trying to see if the investigational product, Estetrol (E4), is safe and if it could be used as a menopausal hormone therapy (MHT) to treat symptoms of menopause in women such as hot flushes and night sweats also called vasomotor symptoms VMS.
Vasomotor symptoms occur most often in the late menopausal transition and the early post menopause and they are the most common menopausal complaints. Estimates suggest that about 75% of women who are more than 50 years of age will suffer from VMS. Most experience VMS for about 2 to 5 years, although at least 10% suffer for more than 10 years. VMS can negatively affect physical and mental wellness, with a consequent reduction in health related quality of life & is one of the main reasons women may seek medical care for the menopause.
E4 is a natural oestrogen which in humans is only ever produced during pregnancy, by the liver of the developing baby. The E4 used in this study is produced in the lab and has the properties of a natural oestrogen. Since early 2000, E4 has been extensively studied in several women’s health areas such as contraception, VMS & thinning, drying & inflammation of the vaginal walls (vulvovaginal atrophy (VVA)) related to menopause breast cancer. Data obtained to date indicates that E4 may be promising for use in women.
The study will involve approx 1200 participants across multiple centres globally.
Within the UK, the study will be conducted within Hospitals, GP Clinics, private health clinics and academic healthcare settings.
Eligible patients will be post-menopausal women, 40 - 65 years of age (inclusive), seeking treatment for relief of moderate to severe VMS associated with menopause. Participation duration may be up to 65 weeks or up to 25 weeks depending on which part of the study participants take part in.
Lay Summary of study results
Overall, the results of this Phase 3 study demonstrate that single oral doses of both Estetrol (E4) 15 mg and E4 20 mg daily are effective in reducing both the frequency and severity of vasomotor symptoms (VMS) after 4 weeks and 12 weeks. The effect of the E4 15 mg dose was slightly weaker than that observed with the E4 20 mg dose. The data collected in this study also suggest that E4 may have a positive influence on cholesterol lipid profile.
As expected after treatment of non-hysterectomised women with an unopposed estrogen, biopsies confirmed the proliferative effect of E4 15 mg and E4 20 mg on the endometrium, thereby confirming the need of adding a progestogen to curb E4 related effects on the endometrium in this population. In this study treatment with progesterone (P4) 200 mg after discontinuation of E4 treatment diminished these effects.Overall, the results of this Phase 3 study demonstrated that the continuous concomitant daily administration of P4 100 mg protected the endometrium from the proliferative effect of E4. In conclusion, the primary endpoint showed an incidence rate of hyperplasia of 0.3% up to 1 year of daily oral treatment with E4 20 mg + P4 100 mg. No cases of simple hyperplasia or hyperplasia with atypia or carcinoma were reported and only 1 case of hyperplasia without atypia was reported. A total of 99.7% of subjects were diagnosed with benign endometrium. Consistent with these results, endometrial thickness showed a modest increase over time.
Vaginal hemorrhage and endometrial disorder were the most common treatment-emergent adverse events (TEAEs) and the most common reasons for discontinuation. About half of the subjects experienced bleeding and/or spotting up to 1 year of treatment.
There were no safety concerns, with no deaths, no clinically relevant changes in vital signs, ECG, laboratory parameters, physical, gynecological and breast examinations.
Daily concomitant treatment with E4 20 mg + P4 100 mg reduced both the frequency and severity of VMS, markedly improved the subject’s quality of life, increased treatment satisfaction over time, and had an overall beneficial effect on cholesterol, lipid, and glucose profiles.REC name
East of England - Cambridge East Research Ethics Committee
REC reference
19/EE/0326
Date of REC Opinion
19 Dec 2019
REC opinion
Further Information Favourable Opinion