Effect of Menopause Hormone Therapy In Postmenopausal Women With CSVD And MCI (MIRACLE)

Effect of Menopause Hormone Therapy In Postmenopausal Women With CeRebral Small Vessel DiseAse And Mild Cognitive DecLinE

The objective of this clinical trial is to explore the efficacy of menopausal hormone therapy in early menopausal women with CSVD and MCI.

The main questions it aims to answer are:

• The efficacy of menopausal hormone mainly estrogen therapy for early menopausal women with CSVD and MCI
• The role of MHT in delaying the progression of cognitive function, CSVD imaging features, and other clinical symptoms and the potential pathophysiological mechanisms.

Participants will be divided randomly into two groups taking MHT drugs and placebo respectively and followed up for 12 months to collect relevant clinical data.

Study Overview

• Status: Not yet recruiting
• Conditions: Mild Cognitive Impairment; Cerebral Small Vessel Diseases; Postmenopausal Symptoms; White Matter Hyperintensity
• Intervention / Treatment: Drug: Estradiol Gel; Drug: Progesterone Soft Capsule; Drug: Estradiol Placebo Gel; Drug: Progesterone Placebo Soft Capsule

Detailed Description

Cerebral small vessel disease (CSVD) is a common chronic whole brain syndrome in middle-aged and elderly people, mainly involving small-arteries, arterioles, capillaries, venules and small-veins in the brain. CSVD mainly relies on typical imaging features for diagnosis. Aging is the most common risk factor for CSVD. With the acceleration of China's aging process, the Disease burden of CSVD is increasing.

Menopause refers to the permanent cessation of menstruation caused by ovarian failure. During menopause, drastic changes in hormones can have a series of effects on women.Research shows that menopause is an independent risk factor for WMH. Meanwhile, menopause is significantly associated with cognitive impairment, especially with decreased learning, memory, and attention. Menopause can also cause changes in cerebral hemodynamics, damage to the integrity of the Blood-brain barrier and atrophy of cortical structures.

Estrogen not only plays a crucial role in maintaining vascular function, but also has significant neuro-protective effects. Estrogen-based menopausal hormone therapy (MHT) is essentially a treatment measure taken to compensate for ovarian failure caused by aging.

However, it is still unclear whether MHT can effectively alleviate CSVD symptoms and delay CSVD progression. The MHT treatment plan may also be an important reason for the inconsistent conclusions on the impact of MHT on cognitive function in various clinical studies. In previous clinical studies, the MHT regimen was oral estrogen (with or without Progestogen).

Based on the above research background, MHT, especially the MHT regimen using transdermal estrogen, may be an effective treatment method to improve and alleviate the rapid progression of CSVD in perimenopausal women(without contraindications). So far, there have been no RCT studies evaluating the effectiveness and safety of MHT in CSVD patients internationally. Therefore, more research is needed to provide stronger evidence and provide new directions and basis for the treatment of CSVD.

Participates who met the inclusion criteria were randomly divided into two groups. Participants were treated with MHT/placebo followed up for 12 months, and collected and analyzed relevant clinical data to evaluate the efficacy.

• Study Type: Interventional
• Enrollment (Estimated): 328
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: yilong wang, MD,PhD; Phone Number: 0086-010-67092222; Email: yilong528@gmail.com

Study Locations

• China
  • Beijing, China
    • Beijing Tiantan Hospital
    • Contact: yilong Wang, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 40 ≤ age < 60 years
2. Female;
3. 1 year ≤ Natural menopause≤ 6 years;
4. FSH ≥ 35 miu/ml and E2 ≤ 25 pg/ml;

5. Head MRI shows CSVD-related image changes, meet one of the following:

   1. Parventricular or deep brain white matter hyperintense, Fazekas ≥ 2；
   2. Parventricular or deep brain white matter hyperintense, Fazekas = 1, with more than 2 vascular risk factors (hypertension, hyperlipidemia, type 2 diabetes, obesity, current smoking);
   3. Parventricular or deep brain white matter hyperintense, Fazekas = 1, with more than 1 vascular-derived lacunae;
   4. Recent small subcortical infarction within the last 3 months
6. Mild cognitive dysfunction (18 ≤ MoCA <26);
7. Independent in daily life (mRS ≤ 1）
8. Sign informed consent.

Note:

1. Natural menopause: The self-reported last menstrual date of the subject
2. CSVD related image changes: evaluated according to the STRIVE2 standard issued in 2023;
3. Fazekas score: The total score is 6 , which is the sum of Fazekas scores for subcortical and periventricular white matter lesions;
4. Recent subcortical small infarcts: lesions with a diameter of<20mm in the subcortical, basal ganglia, or brainstem regions that exhibit high signal intensity (ADC diffusion limitation) on DWI imaging, with or without corresponding clinical symptoms; With new clinical symptoms, FLAIR hyperintense lesions (<20mm in diameter) in subcortical, basal ganglia or corresponding parts of pons can be seen in FLAIR sequence of head MRI.
5. MoCA: Montreal Cognitive Assessment; If the subject's education period ≤ 12 years, then increase by 1 point, with a maximum score of 30 points;
6. mRS: Modified Rankin Scale

Exclusion Criteria:

1. Inheritable CSVD, such as CADASIL, CARASIL, etc.
2. Confirmed neurodegenerative diseases, such as AD and PD;
3. Clear non-vascular white matter lesions, such as multiple sclerosis, adult brain white matter dysplasia, metabolic encephalopathy, etc.
4. History of intracranial hemorrhagic disease within the recent 6 months, including cerebral parenchymal hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage, subdural / extradural hematoma, etc., as well as untreated aneurysms (diameter> 3mm) and cerebrovascular malformations.
5. Cardiovascular and cerebrovascular events within the past 6 months, such as myocardial infarction, unstable angina pectoris, cerebral infarction, etc.
6. Previously received or initiated menopausal hormone therapy.
7. Previous Hysterectomy
8. Vaginal bleeding of unknown origin
9. Intra- and extra- cranial Atherosclerosis large artery stenosis (50-99%) or occlusion.
10. Active venous or arterial thromboembolic diseases, such as Deep vein thrombosis, Pulmonary embolism, myocardial infarction, angina pectoris or congestive heart failure, in the last 6 months.
11. Used drugs and Phytoestrogen supplements that affect estrogen levels in the past 3 months, such as soybean concentrate or extract, Kuntai capsule, Dingkundan, Lifumin, etc.
12. Endometrial hyperplasia, vaginal ultrasound indicates endometrial ≥ 5mm (note: those confirmed as benign lesions by pathology can be included).
13. Severe liver and kidney dysfunction: severe liver dysfunction refers to Alanine transaminase>3 times the upper limit of normal value or cereal grass Transaminase>3 times the upper limit of normal value; Severe renal insufficiency refers to blood creatinine>3.0 mg/dl (265.2 μmol/L) or glomerular filtration rate<30 ml/min/1.73m^2;
14. Hypertension is still difficult to control after standardized treatment (blood pressure>160/100mmHg); Type 2 diabetes is still difficult to control after standard treatment (Glycated hemoglobin ≥ 8%).
15. Known or suspected to have sex hormone dependent malignant tumors, such as breast cancer, endometrial cancer, cervical adenocarcinoma, ovarian cancer, and meningioma.
16. Suffering from severe organic diseases with an expected survival time of<5 years.
17. Other situations that are not suitable for menopausal hormone treatment, such as porphyria, otosclerosis, etc.
18. Mental disorders diagnosed according to DSM-5 diagnostic criteria, or previous mental system diseases that cannot be fully communicated.
19. Allergies to the active ingredients or any of the excipients of the research drug.
20. Contraindications to MRI examination, such as Claustrophobia, metal implants in the body, etc.
21. Unable to cooperate in completing follow-up due to geographical or other reasons.
22. Situations deemed unsuitable by other researchers to participate in the study.
23. Participating in other interventional clinical trials. -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: treatment group; Estradiol gel 2.5 g (containing 17β estradiol 1.5mg) once daily (percutaneous application)* in combination with progesterone soft capsules 100mg once daily (oral) for 12 months Note : * Usage and dosage of estradiol gel: A dose of ruler is applied to the skin of the arm, shoulder, head and neck, abdomen, thigh or face every morning or evening. It is dry about two minutes after application. It is non-irritating, colorless, or milky white and tasteless, and is best used after bathing.	Drug: Estradiol Gel; Estradiol gel 2.5 g (containing 17β estradiol 1.5mg) once daily (percutaneous application) for 12 months; Drug: Progesterone Soft Capsule; Progesterone soft capsules 100mg once daily (oral) for 12 months
Placebo Comparator: control group; Estradiol placebo gel 2.5g (containing 17β estradiol 0mg) once daily (percutaneous application) *in combination with progesterone placebo soft capsules(containing progesterone 0mg) 100mg once daily (oral) for 12 months Note : * Usage and dosage of estradiol placebo gel : A dose of ruler is applied to the skin of the arm, shoulder, head and neck, abdomen, thigh or face every morning or evening. It is dry about two minutes after application. It is non-irritating, colorless, or milky white and tasteless, and is best used after bathing.	Drug: Estradiol Placebo Gel; Estradiol placebo gel 2.5 g (containing 17β estradiol 1.5mg) once daily (percutaneous application) for 12 months; Drug: Progesterone Placebo Soft Capsule; Progesterone placebo soft capsules 100mg once daily (oral) for 12 months

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the changes in the Montreal Cognitive Assessment (MoCA; range, 0-30; with lower scores indicating more severe cognitive impairment) scores 1 year after randomization compared to baseline	the changes of the Montreal Cognitive Assessment (MoCA; range, 0-30; with lower scores indicating more severe cognitive impairment) scores	1 year after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the changes in each cognitive domain estimated bythe Montreal Cognitive Assessment (MoCA; range, 0-30; with lower scores indicating more severe cognitive impairment) sub-items 1 year after randomization compared to baseline	the changes in each cognitive domain estimated by the Montreal Cognitive Assessment (MoCA; range, 0-30; with lower scores indicating more severe cognitive impairment) sub-items	1 year after randomization
the changes of modified Kupperman scores (0-63; with higher scores indicating more severe symptoms) 1 year after randomization compared to baseline	the changes of modified Kupperman scores (0-63; with higher scores indicating more severe symptoms)	1 year after randomization
the changes of Pittsburgh sleep quality index(PSQI; with higher scores indicating more severe sleep quality) 1 year after randomization compared to baseline	the changes of Pittsburgh sleep quality index(PSQI; with higher scores indicating more severe sleep quality)	1 year after randomization
the changes of Hamilton Depression Scale(HAMD; ranges, 0-54; with higher scores indicating more severe depression) 1 year after randomization compared to baseline	the changes of Hamilton Depression Scale(HAMD; ranges, 0-54; with higher scores indicating more severe depression)	1 year after randomization
the changes of Hamilton Anxiety Scale(HAMA; ranges, 0-56; with higher scores indicating more severe anxiety) 1 year after randomization compared to baseline	the changes of Hamilton Anxiety Scale(HAMA; ranges, 0-56; with higher scores indicating more severe anxiety)	1 year after randomization
the changes of the volume of white matter hyperintensity 1 year after randomization compared to baseline	the changes of the volume of white matter hyperintensity	1 year after randomization
Serum levels of estradiol 1 year after randomization compared to baseline	Serum levels of estradiol	1 year after randomization
Serum levels of follicle stimulating hormone 1 year after randomization compared to baseline	Serum levels of follicle stimulating hormone	1 year after randomization

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
the incidence of combined outcome (including recent small subcortical infarct and combined vascular events) 1 year after randomization	the incidence of combined outcome (including recent small subcortical infarct and combined vascular events)	1 year after randomization

Collaborators and Investigators

• Sponsor: Beijing Tiantan Hospital
• Investigators: Principal Investigator: yilong wang, MD,PhD, Beiiing Tiantan Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): August 18, 2023
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): October 1, 2025

Study Registration Dates

• First Submitted: July 18, 2023
• First Submitted That Met QC Criteria: August 6, 2023
• First Posted (Actual): August 8, 2023

Study Record Updates

• Last Update Posted (Actual): August 8, 2023
• Last Update Submitted That Met QC Criteria: August 6, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Mild Cognitive Impairment; White Matter Hyperintensity; cerebral small vessel diseases; Postmenopausal Symptoms; Menopausal Hormone Therapy
• Additional Relevant MeSH Terms: Mental Disorders; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Cognition Disorders; Cognitive Dysfunction; Cerebral Small Vessel Diseases; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptive Agents, Female; Progestins; Estradiol; Progesterone; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Polyestradiol phosphate
• Other Study ID Numbers: KY2023-117

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No