Clinical trial NCT04090957: Estetrol for the Treatment of Moderate to Severe Vasomotor Symptoms in Postmenopausal Women
Official 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 II)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Vasomotor Symptoms
Menopausal Symptoms
Keywords: Estetrol
Hot Flushes
Vasomotor symptoms
Lead sponsor: Estetra
Sponsor class: INDUSTRY
Collaborators: name: ICON Clinical Research
First posted: 2019-09-16
Enrollment: 1015
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: There are 3 blinded arms in the Efficacy part and 1 open-labeled arm in the Safety part.
Primary purpose: TREATMENT

Brief summary: This is a two-part study designed to evaluate the effect of Estetrol (E4) 15 or 20 mg, or placebo on the severity and frequency of vasomotor symptoms (VMS) (Efficacy Study Part) and the safety of E4 20 mg (Safety Study Part).

Detailed description: This is a two-part study:

* The first part is the Efficacy Study mainly designed to evaluate the frequency and severity of vasomotor symptoms \[VMS\] in both hysterectomized and non hysterectomized postmenopausal participants after treatment with two doses of E4 (15 mg or 20 mg) or placebo for 12 consecutive weeks. Thereafter, treatment will proceed for a total duration of up to 53 weeks, to continue the evaluation of secondary efficacy, safety and the effect on the endometrium. For endometrial protection, all non-hysterectomized subjects will receive treatment with 200 mg progesterone (P4) once daily for 14 consecutive days, after completion of the E4/placebo treatment.
* The second part is the Safety Study designed to evaluate the general safety, secondary efficacy (lipid and glucose metabolism, health-related quality of life \[HRQoL\] and treatment satisfaction \[TS\]) after treatment with E4 20 mg for up to 53 weeks in hysterectomized and non hysterectomized postmenopausal participants. For endometrial protection, all non-hysterectomized subjects will receive treatment with 200 mg progesterone (P4) once daily for 14 consecutive days, after completion of the E4 treatment.

Eligibility criteria: Inclusion Criteria:

1. Signed and dated written informed consent form and any required privacy authorization prior to the initiation of any trial procedure, after the nature of the trial has been explained according to local regulatory requirements;
2. Females ≥ 40 up to ≤ 65 years of age at randomization/treatment allocation;
3. For hysterectomized subjects: documented hysterectomy must have occurred at least 6 weeks prior to the start of screening. Hysterectomy can be total or subtotal (i.e., cervix was not removed).
4. For non-hysterectomized subjects: uterus with bi-layer endometrial thickness ≤ 4 mm on TVUS
5. For non-hysterectomized subjects: endometrial biopsy taken during screening that reveals no abnormal result, i.e., presence of hyperplasia (simple or complex, with or without atypia), presence of carcinoma, and presence of disordered proliferative endometrium findings. The screening biopsy should have sufficient endometrial tissue for diagnosis. Biopsies without tissue or with insufficient tissue may be repeated once;
6. Seeking treatment for relief of VMS associated with menopause;

   1. For the Efficacy Study part: at least 7 moderate to severe bothersome VMS per day or at least 50 moderate to severe bothersome VMS per week in the last 7 consecutive days during the Screening period;
   2. For the Safety Study part: at least 1 moderate to severe VMS per week;
7. Body mass index ≥ 18.0 kg/m² up to ≤ 38.0 kg/m²;
8. A mammogram that shows no sign of significant disease performed during screening or within 9 months prior to the start of screening;
9. Post-menopausal status defined as any of the following:

   1. For non-hysterectomized subjects:

      * At least 12 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) \>40 mIU/mL (value obtained after washout of estrogen/progestin containing drugs, see exclusion criteria 18 and 20);
      * or at least 6 months of spontaneous amenorrhea with serum FSH \>40 mIU /mL and E2 \<20 pg/mL (value obtained after washout of estrogen/progestin containing drugs, see exclusion criteria 18 and 20);
      * or at least 6 weeks postsurgical bilateral oophorectomy;
   2. For hysterectomized subjects:

      * serum FSH \>40 mIU/mL and E2 \<20 pg/mL (values obtained after washout of estrogen/progestin containing drug, see exclusion criteria 18 and 20);
      * or at least 6 weeks post-surgical bilateral oophorectomy;
10. Good physical and mental health, in the judgement of the Investigator as based on medical history, physical and gynecological examination, and clinical assessments performed prior to Visit 1;
11. Able to understand and comply with the protocol requirements, instructions, and protocol-stated restrictions;
12. Able and willing to complete trial daily diaries and questionnaires.

Exclusion Criteria:

1. History of malignancy, with the exception of basal cell or squamous cell carcinoma of the skin if diagnosed more than 1 year prior to the Screening visit;
2. Any clinically significant findings found by the Investigator at the breast examination and/or on mammography suspicious of breast malignancy that would require additional clinical testing to rule out breast cancer (however, simple cysts confirmed by ultrasound are allowed);
3. Papanicolaou (PAP) test with atypical squamous cells undetermined significance (ASC-US) or higher (low-grade squamous intraepithelial lesion \[LSIL\], atypical squamous cells- cannot exclude high-grade squamous intraepithelial lesion \[HSIL\] \[ASC-H\], HSIL dysplastic or malignant cells) in sub-totally hysterectomized and non-hysterectomized subjects. Note: ASC-US is allowed if a reflex human papilloma virus (HPV) testing is performed and is negative for high risk oncogene HPV subtypes 16 and 18;
4. For non-hysterectomized subjects:

   1. History or presence of uterine cancer, endometrial hyperplasia, or disordered proliferative endometrium;
   2. Presence of endometrial polyp;
   3. Undiagnosed vaginal bleeding or undiagnosed abnormal uterine bleeding;
   4. Endometrial ablation;
   5. Any uterine/endometrial abnormality that in the judgment of the investigator contraindicates the use of estrogen and/or progestin therapy. This includes presence or history of adenomyosis or significant myoma;
5. Systolic blood pressure (BP) higher than 130 mmHg, diastolic BP higher than 80 mmHg during screening;
6. History of venous or arterial thromboembolic disease (e.g., superficial or deep vein thrombosis, pulmonary embolism, stroke, myocardial infarction, angina pectoris, etc.), or first-degree family history of venous thromboembolism (VTE);
7. History of known acquired of congenital coagulopathy or abnormal coagulation factors, including known thrombophilia's;
8. Laboratory values of fasting glucose above 125 mg/dL and/or glycated hemoglobin above 7%;
9. Dyslipoproteinaemia (LDL \>190 mg/dL and/or triglycerides \>300 mg/dL);
10. Subjects smoking \>15 cigarettes per day;
11. Presence or history of gallbladder disease, unless cholecystectomy has been performed;
12. Systemic lupus erythematosus;
13. Any malabsorption disorders including gastric bypass surgery;
14. History of acute liver disease in the preceding 12 months before the start of screening or presence or history of chronic or severe liver disease \[alanine transaminase (ALT) or aspartate transaminase (AST) \>2 x upper limit of normal (ULN), bilirubin \>1.5 ULN\], or liver tumors;
15. Chronic or current acute renal impairment (estimated glomerular filtration rate \<60 ml/min);
16. Porphyria;
17. Diagnosis or treatment of major psychiatric disorder (e.g., schizophrenia, bipolar disorder, etc.) in the judgement of the Investigator;
18. Use of estrogen/progestin containing drug(s) up to:

    1. 1 week before screening start for vaginal non-systemic hormonal products (rings, creams, gels);
    2. 4 weeks before screening start for vaginal or transdermal estrogen or estrogen/progestin products;
    3. 8 weeks before screening start for oral estrogen and/or progestin products and/or selective estrogen receptor modulator therapy;
    4. 8 weeks before screening start for intrauterine progestin therapy;
    5. 3 months before screening start for progestin implants or estrogen alone injectable drug therapy;
    6. 6 months before screening start for estrogen pellet therapy or progestin injectable drug therapy;
19. Use of androgen/dehydroepiandrosterone (DHEA) containing drugs:

    1. 8 weeks before screening start for oral, topical, vaginal or transdermal androgen;
    2. 6 months before screening start for implantable or injectable androgen therapy;
20. Use of phytoestrogens or black cohosh for treatment of VMS up to 2 weeks before the start of screening;
21. For the women participating in the Efficacy Study part: use of prescription or over-the-counter products used for the treatment of VMS, e.g., anti-depressants: paroxetine, escitalopram, methyldopa, opioid and clonidine up to 4 weeks before the start of screening, and venlafaxine and desvenlafaxine up to 3 months before the start of screening , and not willing to stop these during their participation in the trial;
22. Not willing to stop any hormonal products as described in exclusion criteria 18, 19 and 20 during their participation in the trial;
23. Inadequately treated hyperthyroidism with abnormal TSH and free T4 at screening. Subjects with low or high TSH are allowed if free T4 at screening is within normal range;
24. History or presence of allergy/intolerance to the investigational product or drugs of this class or any component of it, or history of drug or other allergy that, in the opinion of the Investigator contraindicates subject participation;
25. For non-hysterectomized subjects: history or presence of allergy to peanuts;
26. History of alcohol or substance abuse (including marijuana, even if legally allowed) or dependence in the previous 12 months before the start of screening as determined by the Investigator, based on reported observations;
27. Sponsor or contract research organization (CRO) employees or employees under the direct supervision of the Investigator and/or involved directly in the trial;
28. Subjects with known or suspected history of a clinically significant systemic disease, unstable medical disorders, life-threatening disease or current malignancies that would pose a risk to the subject in the opinion of the Investigator;
29. Participation in another investigational drug clinical trial within 1 month (30 days) or having received an investigational drug within the last month (30 days) before the start of screening;
30. Is judged by the Investigator to be unsuitable for any reason.

Primary outcomes:
measure: Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 (Efficacy part)
timeFrame: Baseline and Week 4
measure: Mean change in weekly frequency of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 (Efficacy part)
timeFrame: Baseline and Week 12
measure: Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 4 (Efficacy part)
timeFrame: Baseline and Week 4
measure: Mean change in severity of moderate to severe vasomotor symptoms (VMS) from Baseline to Week 12 (Efficacy part)
timeFrame: Baseline and Week 12
measure: Number of participants with treatment-emergent adverse events (TEAEs) (Safety part)
timeFrame: From Baseline to Follow-up visit (up to Week 56)
measure: Number of participants with changes in physical and gynecological examination results (Safety part)
timeFrame: Screening and Week 53
measure: Number of participants with changes in vital sign results (Safety part)
timeFrame: Screening and Week 53
measure: Number of participants with changes in electrocardiogram (ECG) results (Safety part)
timeFrame: Screening and Week 53
measure: Number of participants with changes in mammography results (Safety part)
timeFrame: Screening and Week 53
measure: Number of participants with changes in breast examination results (Safety part)
timeFrame: Screening, Week 29 and Week 53
measure: Number of participants with changes in routine clinical laboratory test (hematology and chemistry) results (Safety part)
timeFrame: Screening, Baseline and Week 53
Secondary outcomes:
measure: Mean change from Baseline to Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 in the weekly frequency of moderate to severe vasomotor symptoms (VMS) (Efficacy part)
timeFrame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12
measure: Mean change from Baseline to Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 in the severity of moderate to severe vasomotor symptoms (VMS) (Efficacy part)
timeFrame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12
measure: Mean change from Baseline to Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 in the weekly frequency and severity of moderate and severe vasomotor symptoms (VMS) (Efficacy part)
timeFrame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12
measure: Percentage of subjects with 50% reduction from Baseline in the weekly frequency of moderate to severe vasomotor symptoms (VMS) at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (Efficacy part)
timeFrame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12
measure: Percentage of subjects with 75% reduction from Baseline in the weekly frequency of moderate to severe vasomotor symptoms (VMS) at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (Efficacy part)
timeFrame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12
measure: Percentage of subjects with 50% reduction from Baseline in the weekly frequency of mild, moderate, and severe VMS at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (Efficacy part)
timeFrame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12
measure: Percentage of subjects with 75% reduction from Baseline in the weekly frequency of mild, moderate, and severe VMS at Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12 (Efficacy part)
timeFrame: Baseline, Week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12
measure: Percentage of subjects with a clinically important difference (CID) compared to Baseline in the weekly frequency of moderate to severe VMS after Week 4 and Week 12 using the Clinical Global Impression (CGI) questionnaire (Efficacy part)
timeFrame: Baseline, Week 4, Week 12
measure: Plasma concentration of Prothrombin fragment 1+2 (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Endogenous thrombin potential (ETP)-based activated Protein C sensitivity ratio (APCsr ETP) (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Activated partial thromboplastin time (aPTT) based activated Protein C resistance (APCr) (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Plasma concentration of anti-thrombin III (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Plasma concentration of Protein-C (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Plasma concentration of free Protein-S (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Plasma concentration of factor VIII (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Serum concentration of angiotensinogen (Efficacy part)
timeFrame: Baseline, Week 13 and Week 53
measure: Serum concentration Sex Hormone Binding Globulin (SHBG) (Efficacy part)
timeFrame: Baseline, Week 13 and Week 53
measure: Serum concentration of triglycerides (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Serum concentration of high-density lipoprotein (HDL)-cholesterol (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Serum concentration of low-density lipoprotein (LDL)-cholesterol (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Serum concentration of lipoprotein(a) (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Total cholesterol/HDL-cholesterol ratio (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Serum concentration of total cholesterol (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Plasma concentration of fasting glucose (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Serum concentration of insulin (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Glycated hemoglobin (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Homeostasis model assessment-estimated insulin resistance (HOMA-IR) (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Serum concentration of procollagen I N-propeptide (PINP) (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Serum concentration of C-terminal telopeptide type 1 (CTX-1) (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Serum concentration of calcium (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Serum concentration of Vitamine D (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Health-related quality of life assessment using the Menopause-specific Quality of Life (MENQOL) questionnaire (Efficacy part)
timeFrame: Baseline, Weeks 13 and 53
measure: Total score in treatment satisfaction using the Clinical Global Impression (CGI) questionnaire (Efficacy part)
timeFrame: Weeks 4, 12 and 52
measure: Number of participants with treatment-emergent adverse events (TEAEs) (Efficacy part)
timeFrame: From baseline to Follow-up visit (up to Week 56)
measure: Number of participants with changes in physical and gynecological examination results (Efficacy part)
timeFrame: Screening and Week 53
measure: Number of participants with changes in vital sign results (Efficacy part)
timeFrame: From screening to Week 53
measure: Number of participants with changes in electrocardiogram (ECG) results (Efficacy part)
timeFrame: Screening and Week 53
measure: Number of participants with changes in mammography results (Efficacy part)
timeFrame: Screening and Week 53
measure: Number of participants with changes in breast examination results (Efficacy part)
timeFrame: Screening, Week 29 and Week 53
measure: Number of participants with changes in routine clinical laboratory test results (Efficacy part)
timeFrame: Screening, Baseline and Week 53
measure: Mean endometrial thickness (Efficacy part)
timeFrame: Screening, Weeks 13, 29, 41, 53, and Follow-up (Week 55/56)
measure: Endometrial biopsy histology at Screening and Week 53 (Efficacy part)
timeFrame: Screening and Week 53
measure: Number of participants with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4 (Efficacy part)
timeFrame: From Baseline up to Follow-up (Week 55/56)
measure: Number of women with amenorrhea (absence of any bleeding or spotting) during each 28-day cycle of treatment with E4 (Efficacy part)
timeFrame: From Baseline up to Follow-up (Week 55/56)
measure: Serum concentration of triglycerides (Safety part)
timeFrame: Baseline, Weeks 13 and 53
measure: Serum concentration of HDL-cholesterol (Safety part)
timeFrame: Baseline, Weeks 13 and 53
measure: Serum concentration of LDL-cholesterol (Safety part)
timeFrame: Baseline, Weeks 13 and 53
measure: Serum concentration of total cholesterol (Safety part)
timeFrame: Baseline, Weeks 13 and 53
measure: Serum concentration of lipoprotein(a) (Safety part)
timeFrame: Baseline, Weeks 13 and 53
measure: Total cholesterol/HDL-cholesterol ratio (Safety part)
timeFrame: Baseline, Weeks 13 and 53
measure: Plasma concentration of fasting glucose (Safety part)
timeFrame: Baseline, Weeks 13 and 53
measure: Serum concentration of insulin (Safety part)
timeFrame: Baseline, Weeks 13 and 53
measure: Glycated hemoglobin (Safety part)
timeFrame: Baseline, Weeks 13 and 53
measure: Homeostasis model assessment-estimated insulin resistance (HOMA-IR) (Safety part)
timeFrame: Baseline, Weeks 13 and 53
measure: Health-related quality of life assessment using the Menopause-specific Quality of Life (MENQOL) questionnaire (Safety part)
timeFrame: Baseline, Weeks 12 and 52
measure: Total score in treatment satisfaction using the Clinical Global Impression (CGI) questionnaire (Safety part)
timeFrame: Weeks 4, 12 and 52
measure: Mean endometrial thickness (Safety part)
timeFrame: Screening, Weeks 13, 29, 41, 53, and Follow-up (Week 55/56)
measure: Endometrial biopsy histology at Screening and Week 53 (Safety part)
timeFrame: Screening and Week 53
measure: Number of women with vaginal bleeding and/or spotting during each 28-day cycle of treatment with E4 (Safety part)
timeFrame: From Baseline up to Follow-up (Week 55/56)
measure: Number of women with amenorrhea (absence of any bleeding or spotting) during each 28-day cycle of treatment with E4 (Safety part)
timeFrame: From Baseline up to Follow-up (Week 55/56)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Estetra Study Site
state: Alabama
city: Birmingham
country: United States
facility: Estetra Study Site
state: Alabama
city: Birmingham
country: United States
facility: Estetra Study Site
state: Alabama
city: Dothan
country: United States
facility: Estetra Study Site
state: Alabama
city: Phoenix
country: United States
facility: Estetra Study Site
state: Arizona
city: Phoenix
country: United States
facility: Estetra Study Site
state: Arizona
city: Tempe
country: United States
facility: Estetra Study Site
state: Arizona
city: Tucson
country: United States
facility: Estetra Study Site
state: Arizona
city: Tucson
country: United States
facility: Estetra Study Site
state: Arizona
city: Tucson
country: United States
facility: Estetra Study Site
state: Arizona
city: Tucson
country: United States
facility: Estetra Study Site
state: Arizona
city: Little Rock
country: United States
facility: Estetra Study Site
state: Arkansas
city: Bellflower
country: United States
facility: Estetra Study Site
state: California
city: Canoga Park
country: United States
facility: Estetra Study Site
state: California
city: Chula Vista
country: United States
facility: Estetra Study Site
state: California
city: Huntington Beach
country: United States
facility: Estetra Study Site
state: California
city: La Mesa
country: United States
facility: Estetra Study Site
state: California
city: Lincoln
country: United States
facility: Estetra Study Site
state: California
city: Los Angeles
country: United States
facility: Estetra Study Site
state: California
city: Pomona
country: United States
facility: Estetra Study Site
state: California
city: Sacramento
country: United States
facility: Estetra Study Site
state: California
city: San Diego
country: United States
facility: Estetra Study Site
state: California
city: San Diego
country: United States
facility: Estetra Study Site
state: California
city: Santa Ana
country: United States
facility: Estetra Study Site
state: California
city: Thousand Oaks
country: United States
facility: Estetra Study Site
state: California
city: West Covina
country: United States
facility: Estetra Study Site
state: California
city: Colorado Springs
country: United States
facility: Estetra Study Site
state: Colorado
city: Denver
country: United States
facility: Estetra Study Site
state: Colorado
city: Crystal River
country: United States
facility: Estetra Study Site
state: Florida
city: Jacksonville
country: United States
facility: Estetra Study Site
state: Florida
city: Jacksonville
country: United States
facility: Estetra Study Site
state: Florida
city: Miami Lakes
country: United States
facility: Estetra Study Site
state: Florida
city: Miami
country: United States
facility: Estetra Study Site
state: Florida
city: Miami
country: United States
facility: Estetra Study Site
state: Florida
city: Miami
country: United States
facility: Estetra Study Site
state: Florida
city: New Port Richey
country: United States
facility: Estetra Study Site
state: Florida
city: Ocoee
country: United States
facility: Estetra Study Site
state: Florida
city: Orlando
country: United States
facility: Estetra Study Site
state: Florida
city: Sarasota
country: United States
facility: Estetra Study Site
state: Florida
city: West Palm Beach
country: United States
facility: Estetra Study Site
state: Florida
city: Atlanta
country: United States
facility: Estetra Study Site
state: Georgia
city: Morrow
country: United States
facility: Estetra Study Site
state: Georgia
city: Sandy Springs
country: United States
facility: Estetra Study Site
state: Georgia
city: Savannah
country: United States
facility: Estetra Study Site
state: Georgia
city: Idaho Falls
country: United States
facility: Estetra Study Site
state: Idaho
city: Meridian
country: United States
facility: Estetra Study Site
state: Idaho
city: Evansville
country: United States
facility: Estetra Study Site
state: Indiana
city: Marrero
country: United States
facility: Estetra Study Site
state: Louisiana
city: Saginaw
country: United States
facility: Estetra Study Site
state: Michigan
city: Saginaw
country: United States
facility: Estetra Study Site
state: Michigan
city: Rochester
country: United States
facility: Estetra Study Site
state: Minnesota
city: Saint Louis
country: United States
facility: Estetra Study Site
state: Missouri
city: Lincoln
country: United States
facility: Estetra Study Site
state: Nebraska
city: Norfolk
country: United States
facility: Estetra Study Site
state: Nebraska
city: Las Vegas
country: United States
facility: Estetra Study Site
state: Nevada
city: Las Vegas
country: United States
facility: Estetra Study Site
state: Nevada
city: Albuquerque
country: United States
facility: Estetra Study Site
state: New Mexico
city: Albuquerque
country: United States
facility: Estetra Study Site
state: New Mexico
city: New York
country: United States
facility: Estetra Study Site
state: New York
city: Charlotte
country: United States
facility: Estetra Study Site
state: North Carolina
city: Charlotte
country: United States
facility: Estetra Study Site
state: North Carolina
city: Columbus
country: United States
facility: Estetra Study Site
state: North Carolina
city: Fayetteville
country: United States
facility: Estetra Study Site
state: North Carolina
city: Hickory
country: United States
facility: Estetra Study Site
state: North Carolina
city: New Bern
country: United States
facility: Estetra Study Site
state: North Carolina
city: Raleigh
country: United States
facility: Estetra Study Site
state: North Carolina
city: Raleigh
country: United States
facility: Estetra Study Site
state: North Carolina
city: Rocky Mount
country: United States
facility: Estetra Study Site
state: North Carolina
city: Cincinnati
country: United States
facility: Estetra Study Site
state: Ohio
city: Cincinnati
country: United States
facility: Estetra Study Site
state: Ohio
city: Cleveland
country: United States
facility: Estetra Study Site
state: Ohio
city: Columbus
country: United States
facility: Estetra Study Site
state: Ohio
city: Columbus
country: United States
facility: Estetra Study Site
state: Ohio
city: Fairfield
country: United States
facility: Estetra Study Site
state: Ohio
city: Erie
country: United States
facility: Estetra Study Site
state: Pennsylvania
city: Philadelphia
country: United States
facility: Estetra Study Site
state: Pennsylvania
city: Bluffton
country: United States
facility: Estetra Study Site
state: South Carolina
city: Columbia
country: United States
facility: Estetra Study Site
state: South Carolina
city: Mount Pleasant
country: United States
facility: Estetra Study Site
state: South Carolina
city: Myrtle Beach
country: United States
facility: Estetra Study Site
state: South Carolina
city: North Charleston
country: United States
facility: Estetra Study Site
state: South Carolina
city: Chattanooga
country: United States
facility: Estetra Study Site
state: Tennessee
city: Jefferson City
country: United States
facility: Estetra Study Site
state: Tennessee
city: Knoxville
country: United States
facility: Estetra Study Site
state: Tennessee
city: Knoxville
country: United States
facility: Estetra Study Site
state: Tennessee
city: Memphis
country: United States
facility: Estetra Study Site
state: Tennessee
city: Memphis
country: United States
facility: Estetra Study Site
state: Tennessee
city: Dallas
country: United States
facility: Estetra Study Site
state: Texas
city: Fort Worth
country: United States
facility: Estetra Study Site
state: Texas
city: Fort Worth
country: United States
facility: Estetra Study Site
state: Texas
city: Georgetown
country: United States
facility: Estetra Study Site
state: Texas
city: Houston
country: United States
facility: Estetra Study Site
state: Texas
city: Houston
country: United States
facility: Estetra Study Site
state: Texas
city: Houston
country: United States
facility: Estetra Study Site
state: Texas
city: Houston
country: United States
facility: Estetra Study Site
state: Texas
city: Houston
country: United States
facility: Estetra Study Site
state: Texas
city: Houston
country: United States
facility: Estetra Study Site
state: Texas
city: McAllen
country: United States
facility: Estetra Study Site
state: Texas
city: McAllen
country: United States
facility: Estetra Study Site
state: Texas
city: Pearland
country: United States
facility: Estetra Study Site
state: Texas
city: Plano
country: United States
facility: Estetra Study Site
state: Texas
city: San Antonio
country: United States
facility: Estetra Study Site
state: Texas
city: Draper
country: United States
facility: Estetra Study Site
state: Utah
city: Pleasant Grove
country: United States
facility: Estetra Study Site
state: Utah
city: West Jordan
country: United States
facility: Estetra Study Site
state: Utah
city: Charlottesville
country: United States
facility: Estetra Study Site
state: Virginia
city: Norfolk
country: United States
facility: Estetra Study Site
state: Virginia
city: Virginia Beach
country: United States
facility: Estetra Study Site
state: Virginia
city: Bellevue
country: United States
facility: Estetra Study Site
state: Washington
city: Seattle
country: United States
facility: Estetra Study Site
state: Washington
city: Morgantown
country: United States
facility: Estetra Study Site
state: West Virginia
city: Red Deer
country: Canada
facility: Estetra Study Site
state: Alberta
city: Montréal
country: Canada
facility: Estetra Study Site
state: Quebec
city: Brampton
country: Canada
facility: Estetra Study Site
city: Quebec City
country: Canada
facility: Estetra Study Site
city: Quebec
country: Canada
facility: Estetra Study Site
city: Waterloo
country: Canada
facility: Estetra Study Site
Study officials:
affiliation: Estetra
name: Estetra
role: STUDY_DIRECTOR
References: