xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05982470</url>
    </required_header>
    <id_info>
      <org_study_id>KY2023-117</org_study_id>
      <nct_id>NCT05982470</nct_id>
    </id_info>
    <brief_title>Effect of Menopause Hormone Therapy In Postmenopausal Women With CSVD And MCI</brief_title>
    <acronym>MIRACLE</acronym>
    <official_title>Effect of Menopause Hormone Therapy In Postmenopausal Women With CeRebral Small Vessel DiseAse And Mild Cognitive DecLinE</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Beijing Tiantan Hospital</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Beijing Tiantan Hospital</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        The objective of this clinical trial is to explore the efficacy of menopausal hormone therapy&#xD;
        in early menopausal women with CSVD and MCI.&#xD;
  &#xD;
        The main questions it aims to answer are:&#xD;
  &#xD;
          -  The efficacy of menopausal hormone mainly estrogen therapy for early menopausal women&#xD;
             with CSVD and MCI&#xD;
  &#xD;
          -  The role of MHT in delaying the progression of cognitive function, CSVD imaging&#xD;
             features, and other clinical symptoms and the potential pathophysiological mechanisms.&#xD;
  &#xD;
        Participants will be divided randomly into two groups taking MHT drugs and placebo&#xD;
        respectively and followed up for 12 months to collect relevant clinical data.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Cerebral small vessel disease (CSVD) is a common chronic whole brain syndrome in middle-aged&#xD;
        and elderly people, mainly involving small-arteries, arterioles, capillaries, venules and&#xD;
        small-veins in the brain. CSVD mainly relies on typical imaging features for diagnosis. Aging&#xD;
        is the most common risk factor for CSVD. With the acceleration of China's aging process, the&#xD;
        Disease burden of CSVD is increasing.&#xD;
  &#xD;
        Menopause refers to the permanent cessation of menstruation caused by ovarian failure. During&#xD;
        menopause, drastic changes in hormones can have a series of effects on women.Research shows&#xD;
        that menopause is an independent risk factor for WMH. Meanwhile, menopause is significantly&#xD;
        associated with cognitive impairment, especially with decreased learning, memory, and&#xD;
        attention. Menopause can also cause changes in cerebral hemodynamics, damage to the integrity&#xD;
        of the Blood-brain barrier and atrophy of cortical structures.&#xD;
  &#xD;
        Estrogen not only plays a crucial role in maintaining vascular function, but also has&#xD;
        significant neuro-protective effects. Estrogen-based menopausal hormone therapy (MHT) is&#xD;
        essentially a treatment measure taken to compensate for ovarian failure caused by aging.&#xD;
  &#xD;
        However, it is still unclear whether MHT can effectively alleviate CSVD symptoms and delay&#xD;
        CSVD progression. The MHT treatment plan may also be an important reason for the inconsistent&#xD;
        conclusions on the impact of MHT on cognitive function in various clinical studies. In&#xD;
        previous clinical studies, the MHT regimen was oral estrogen (with or without Progestogen).&#xD;
  &#xD;
        Based on the above research background, MHT, especially the MHT regimen using transdermal&#xD;
        estrogen, may be an effective treatment method to improve and alleviate the rapid progression&#xD;
        of CSVD in perimenopausal women(without contraindications). So far, there have been no RCT&#xD;
        studies evaluating the effectiveness and safety of MHT in CSVD patients internationally.&#xD;
        Therefore, more research is needed to provide stronger evidence and provide new directions&#xD;
        and basis for the treatment of CSVD.&#xD;
  &#xD;
        Participates who met the inclusion criteria were randomly divided into two groups.&#xD;
        Participants were treated with MHT/placebo followed up for 12 months, and collected and&#xD;
        analyzed relevant clinical data to evaluate the efficacy.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">August 18, 2023</start_date>
    <completion_date type="Anticipated">October 1, 2025</completion_date>
    <primary_completion_date type="Anticipated">June 1, 2025</primary_completion_date>
    <phase>Phase 2</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <primary_purpose>Treatment</primary_purpose>
      <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>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</measure>
      <time_frame>1 year after randomization</time_frame>
      <description>the changes of the Montreal Cognitive Assessment (MoCA; range, 0-30; with lower scores indicating more severe cognitive impairment) scores</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>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</measure>
      <time_frame>1 year after randomization</time_frame>
      <description>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</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>the changes of modified Kupperman scores (0-63; with higher scores indicating more severe symptoms) 1 year after randomization compared to baseline</measure>
      <time_frame>1 year after randomization</time_frame>
      <description>the changes of modified Kupperman scores (0-63; with higher scores indicating more severe symptoms)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>the changes of Pittsburgh sleep quality index(PSQI; with higher scores indicating more severe sleep quality) 1 year after randomization compared to baseline</measure>
      <time_frame>1 year after randomization</time_frame>
      <description>the changes of Pittsburgh sleep quality index(PSQI; with higher scores indicating more severe sleep quality)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>the changes of Hamilton Depression Scale(HAMD; ranges, 0-54; with higher scores indicating more severe depression) 1 year after randomization compared to baseline</measure>
      <time_frame>1 year after randomization</time_frame>
      <description>the changes of Hamilton Depression Scale(HAMD; ranges, 0-54; with higher scores indicating more severe depression)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>the changes of Hamilton Anxiety Scale(HAMA; ranges, 0-56; with higher scores indicating more severe anxiety) 1 year after randomization compared to baseline</measure>
      <time_frame>1 year after randomization</time_frame>
      <description>the changes of Hamilton Anxiety Scale(HAMA; ranges, 0-56; with higher scores indicating more severe anxiety)</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>the changes of the volume of white matter hyperintensity 1 year after randomization compared to baseline</measure>
      <time_frame>1 year after randomization</time_frame>
      <description>the changes of the volume of white matter hyperintensity</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Serum levels of estradiol 1 year after randomization compared to baseline</measure>
      <time_frame>1 year after randomization</time_frame>
      <description>Serum levels of estradiol</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Serum levels of follicle stimulating hormone 1 year after randomization compared to baseline</measure>
      <time_frame>1 year after randomization</time_frame>
      <description>Serum levels of follicle stimulating hormone</description>
    </secondary_outcome>
    <other_outcome>
      <measure>the incidence of combined outcome (including recent small subcortical infarct and combined vascular events) 1 year after randomization</measure>
      <time_frame>1 year after randomization</time_frame>
      <description>the incidence of combined outcome (including recent small subcortical infarct and combined vascular events)</description>
    </other_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">328</enrollment>
    <condition>Cerebral Small Vessel Diseases</condition>
    <condition>Postmenopausal Symptoms</condition>
    <condition>Mild Cognitive Impairment</condition>
    <condition>White Matter Hyperintensity</condition>
    <arm_group>
      <arm_group_label>treatment group</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>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&#xD;
  Note :&#xD;
  * 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.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>control group</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>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&#xD;
  Note :&#xD;
  * 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.</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Estradiol Gel</intervention_name>
      <description>Estradiol gel 2.5 g (containing 17β estradiol 1.5mg) once daily (percutaneous application) for 12 months</description>
      <arm_group_label>treatment group</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Estradiol Placebo Gel</intervention_name>
      <description>Estradiol placebo gel 2.5 g (containing 17β estradiol 1.5mg) once daily (percutaneous application) for 12 months</description>
      <arm_group_label>control group</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Progesterone Soft Capsule</intervention_name>
      <description>Progesterone soft capsules 100mg once daily (oral) for 12 months</description>
      <arm_group_label>treatment group</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Progesterone Placebo Soft Capsule</intervention_name>
      <description>Progesterone placebo soft capsules 100mg once daily (oral) for 12 months</description>
      <arm_group_label>control group</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. 40 ≤ age &lt; 60 years&#xD;
  &#xD;
            2. Female;&#xD;
  &#xD;
            3. 1 year ≤ Natural menopause≤ 6 years;&#xD;
  &#xD;
            4. FSH ≥ 35 miu/ml and E2 ≤ 25 pg/ml;&#xD;
  &#xD;
            5. Head MRI shows CSVD-related image changes, meet one of the following:&#xD;
  &#xD;
                 1. Parventricular or deep brain white matter hyperintense, Fazekas ≥ 2；&#xD;
  &#xD;
                 2. Parventricular or deep brain white matter hyperintense, Fazekas = 1, with more&#xD;
                    than 2 vascular risk factors (hypertension, hyperlipidemia, type 2 diabetes,&#xD;
                    obesity, current smoking);&#xD;
  &#xD;
                 3. Parventricular or deep brain white matter hyperintense, Fazekas = 1, with more&#xD;
                    than 1 vascular-derived lacunae;&#xD;
  &#xD;
                 4. Recent small subcortical infarction within the last 3 months&#xD;
  &#xD;
            6. Mild cognitive dysfunction (18 ≤ MoCA &lt;26);&#xD;
  &#xD;
            7. Independent in daily life (mRS ≤ 1）&#xD;
  &#xD;
            8. Sign informed consent.&#xD;
  &#xD;
          Note:&#xD;
  &#xD;
            1. Natural menopause: The self-reported last menstrual date of the subject&#xD;
  &#xD;
            2. CSVD related image changes: evaluated according to the STRIVE2 standard issued in&#xD;
               2023;&#xD;
  &#xD;
            3. Fazekas score: The total score is 6 , which is the sum of Fazekas scores for&#xD;
               subcortical and periventricular white matter lesions;&#xD;
  &#xD;
            4. Recent subcortical small infarcts: lesions with a diameter of&lt;20mm in the subcortical,&#xD;
               basal ganglia, or brainstem regions that exhibit high signal intensity (ADC diffusion&#xD;
               limitation) on DWI imaging, with or without corresponding clinical symptoms; With new&#xD;
               clinical symptoms, FLAIR hyperintense lesions (&lt;20mm in diameter) in subcortical,&#xD;
               basal ganglia or corresponding parts of pons can be seen in FLAIR sequence of head&#xD;
               MRI.&#xD;
  &#xD;
            5. MoCA: Montreal Cognitive Assessment; If the subject's education period ≤ 12 years,&#xD;
               then increase by 1 point, with a maximum score of 30 points;&#xD;
  &#xD;
            6. mRS: Modified Rankin Scale&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Inheritable CSVD, such as CADASIL, CARASIL, etc.&#xD;
  &#xD;
            2. Confirmed neurodegenerative diseases, such as AD and PD;&#xD;
  &#xD;
            3. Clear non-vascular white matter lesions, such as multiple sclerosis, adult brain white&#xD;
               matter dysplasia, metabolic encephalopathy, etc.&#xD;
  &#xD;
            4. History of intracranial hemorrhagic disease within the recent 6 months, including&#xD;
               cerebral parenchymal hemorrhage, intraventricular hemorrhage, subarachnoid hemorrhage,&#xD;
               subdural / extradural hematoma, etc., as well as untreated aneurysms (diameter&gt; 3mm)&#xD;
               and cerebrovascular malformations.&#xD;
  &#xD;
            5. Cardiovascular and cerebrovascular events within the past 6 months, such as myocardial&#xD;
               infarction, unstable angina pectoris, cerebral infarction, etc.&#xD;
  &#xD;
            6. Previously received or initiated menopausal hormone therapy.&#xD;
  &#xD;
            7. Previous Hysterectomy&#xD;
  &#xD;
            8. Vaginal bleeding of unknown origin&#xD;
  &#xD;
            9. Intra- and extra- cranial Atherosclerosis large artery stenosis (50-99%) or occlusion.&#xD;
  &#xD;
           10. Active venous or arterial thromboembolic diseases, such as Deep vein thrombosis,&#xD;
               Pulmonary embolism, myocardial infarction, angina pectoris or congestive heart&#xD;
               failure, in the last 6 months.&#xD;
  &#xD;
           11. Used drugs and Phytoestrogen supplements that affect estrogen levels in the past 3&#xD;
               months, such as soybean concentrate or extract, Kuntai capsule, Dingkundan, Lifumin,&#xD;
               etc.&#xD;
  &#xD;
           12. Endometrial hyperplasia, vaginal ultrasound indicates endometrial ≥ 5mm (note: those&#xD;
               confirmed as benign lesions by pathology can be included).&#xD;
  &#xD;
           13. Severe liver and kidney dysfunction: severe liver dysfunction refers to Alanine&#xD;
               transaminase&gt;3 times the upper limit of normal value or cereal grass Transaminase&gt;3&#xD;
               times the upper limit of normal value; Severe renal insufficiency refers to blood&#xD;
               creatinine&gt;3.0 mg/dl (265.2 μmol/L) or glomerular filtration rate&lt;30 ml/min/1.73m^2;&#xD;
  &#xD;
           14. Hypertension is still difficult to control after standardized treatment (blood&#xD;
               pressure&gt;160/100mmHg); Type 2 diabetes is still difficult to control after standard&#xD;
               treatment (Glycated hemoglobin ≥ 8%).&#xD;
  &#xD;
           15. Known or suspected to have sex hormone dependent malignant tumors, such as breast&#xD;
               cancer, endometrial cancer, cervical adenocarcinoma, ovarian cancer, and meningioma.&#xD;
  &#xD;
           16. Suffering from severe organic diseases with an expected survival time of&lt;5 years.&#xD;
  &#xD;
           17. Other situations that are not suitable for menopausal hormone treatment, such as&#xD;
               porphyria, otosclerosis, etc.&#xD;
  &#xD;
           18. Mental disorders diagnosed according to DSM-5 diagnostic criteria, or previous mental&#xD;
               system diseases that cannot be fully communicated.&#xD;
  &#xD;
           19. Allergies to the active ingredients or any of the excipients of the research drug.&#xD;
  &#xD;
           20. Contraindications to MRI examination, such as Claustrophobia, metal implants in the&#xD;
               body, etc.&#xD;
  &#xD;
           21. Unable to cooperate in completing follow-up due to geographical or other reasons.&#xD;
  &#xD;
           22. Situations deemed unsuitable by other researchers to participate in the study.&#xD;
  &#xD;
           23. Participating in other interventional clinical trials. -&#xD;
        </textblock>
      </criteria>
      <gender>Female</gender>
      <gender_based>Yes</gender_based>
      <gender_description>Early menopause of female</gender_description>
      <minimum_age>40 Years</minimum_age>
      <maximum_age>60 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>yilong wang, MD,PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Beiiing Tiantan Hospital</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>yilong wang, MD,PhD</last_name>
      <phone>0086-010-67092222</phone>
      <email>yilong528@gmail.com</email>
    </overall_contact>
    <location>
      <facility>
        <name>Beijing Tiantan Hospital</name>
        <address>
          <city>Beijing</city>
          <country>China</country>
        </address>
      </facility>
      <contact>
        <last_name>yilong Wang, MD, PhD</last_name>
      </contact>
    </location>
    <location_countries>
      <country>China</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 18, 2023</study_first_submitted>
    <study_first_submitted_qc>August 6, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 8, 2023</study_first_posted>
    <last_update_submitted>August 6, 2023</last_update_submitted>
    <last_update_submitted_qc>August 6, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 8, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Beijing Tiantan Hospital</investigator_affiliation>
      <investigator_full_name>yilong Wang</investigator_full_name>
      <investigator_title>Vice President of Beijing Tiantan Hospital</investigator_title>
    </responsible_party>
    <keyword>cerebral small vessel diseases</keyword>
    <keyword>Menopausal Hormone Therapy</keyword>
    <keyword>Postmenopausal Symptoms</keyword>
    <keyword>Mild Cognitive Impairment</keyword>
    <keyword>White Matter Hyperintensity</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Cerebral Small Vessel Diseases</mesh_term>
      <mesh_term>Cognitive Dysfunction</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Estradiol 17 beta-cypionate</mesh_term>
      <mesh_term>Estradiol 3-benzoate</mesh_term>
      <mesh_term>Estradiol</mesh_term>
      <mesh_term>Polyestradiol phosphate</mesh_term>
      <mesh_term>Progesterone</mesh_term>
    </intervention_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05982470
  org study id: KY2023-117
  nct id: NCT05982470
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: No
  is fda regulated device: No
  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.
  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.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  measure: 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
  time frame: 1 year after randomization
  description: the changes of the Montreal Cognitive Assessment (MoCA; range, 0-30; with lower scores indicating more severe cognitive impairment) scores
  measure: 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
  time frame: 1 year after randomization
  description: 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
  measure: the changes of modified Kupperman scores (0-63; with higher scores indicating more severe symptoms) 1 year after randomization compared to baseline
  time frame: 1 year after randomization
  description: the changes of modified Kupperman scores (0-63; with higher scores indicating more severe symptoms)
  measure: the changes of Pittsburgh sleep quality index(PSQI; with higher scores indicating more severe sleep quality) 1 year after randomization compared to baseline
  time frame: 1 year after randomization
  description: the changes of Pittsburgh sleep quality index(PSQI; with higher scores indicating more severe sleep quality)
  measure: the changes of Hamilton Depression Scale(HAMD; ranges, 0-54; with higher scores indicating more severe depression) 1 year after randomization compared to baseline
  time frame: 1 year after randomization
  description: the changes of Hamilton Depression Scale(HAMD; ranges, 0-54; with higher scores indicating more severe depression)
  measure: the changes of Hamilton Anxiety Scale(HAMA; ranges, 0-56; with higher scores indicating more severe anxiety) 1 year after randomization compared to baseline
  time frame: 1 year after randomization
  description: the changes of Hamilton Anxiety Scale(HAMA; ranges, 0-56; with higher scores indicating more severe anxiety)
  measure: the changes of the volume of white matter hyperintensity 1 year after randomization compared to baseline
  time frame: 1 year after randomization
  description: the changes of the volume of white matter hyperintensity
  measure: Serum levels of estradiol 1 year after randomization compared to baseline
  time frame: 1 year after randomization
  description: Serum levels of estradiol
  measure: Serum levels of follicle stimulating hormone 1 year after randomization compared to baseline
  time frame: 1 year after randomization
  description: Serum levels of follicle stimulating hormone
  measure: the incidence of combined outcome (including recent small subcortical infarct and combined vascular events) 1 year after randomization
  time frame: 1 year after randomization
  description: the incidence of combined outcome (including recent small subcortical infarct and combined vascular events)
  arm group label: treatment group
  arm group type: Experimental
  description: 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.
  arm group label: control group
  arm group type: Placebo Comparator
  description: 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.
  intervention type: Drug
  intervention name: Estradiol Gel
  description: Estradiol gel 2.5 g (containing 17β estradiol 1.5mg) once daily (percutaneous application) for 12 months
  arm group label: treatment group
  intervention type: Drug
  intervention name: Estradiol Placebo Gel
  description: Estradiol placebo gel 2.5 g (containing 17β estradiol 1.5mg) once daily (percutaneous application) for 12 months
  arm group label: control group
  intervention type: Drug
  intervention name: Progesterone Soft Capsule
  description: Progesterone soft capsules 100mg once daily (oral) for 12 months
  arm group label: treatment group
  intervention type: Drug
  intervention name: Progesterone Placebo Soft Capsule
  description: Progesterone placebo soft capsules 100mg once daily (oral) for 12 months
  arm group label: control group
  criteria: 
  gender: Female
  gender based: Yes
  gender description: Early menopause of female
  minimum age: 40 Years
  maximum age: 60 Years
  healthy volunteers: No
  last name: yilong wang, MD,PhD
  role: Principal Investigator
  affiliation: Beiiing Tiantan Hospital
  last name: yilong wang, MD,PhD
  phone: 0086-010-67092222
  email: yilong528@gmail.com
  facility: 
  contact: 
  country: China
  responsible party type: Principal Investigator
  investigator affiliation: Beijing Tiantan Hospital
  investigator full name: yilong Wang
  investigator title: Vice President of Beijing Tiantan Hospital
  mesh term: Cerebral Small Vessel Diseases
  mesh term: Cognitive Dysfunction
  mesh term: Estradiol 17 beta-cypionate
  mesh term: Estradiol 3-benzoate
  mesh term: Estradiol
  mesh term: Polyestradiol phosphate
  mesh term: Progesterone