Identifying the Determinants of Bleeding and Hypermobility in Patients With Heavy Menstrual Bleeding

Study Overview
=================
Brief Summary
-----------------
In this study, researchers want to learn about the connection between heavy bleeding issues and joint hypermobility (loose joints). They want to know if these issues may indicate other connective tissue problems in girls and women with heavy menstrual bleeding who do not have a known cause. Primary Objective Compare the severity of heavy menstrual bleeding (HMB) in women with and without Generalized joint Hypermobility Syndrome Disorder/hypermobile Ehlers-Danlos Syndrome (G-HSD/hEDS). Secondary Objectives Compare the severity of heavy menstrual bleeding (HMB) in women with and without Generalized joint Hypermobility Syndrome Disorder/hypermobile Ehlers-Danlos Syndrome (G-HSD/hEDS).

Detailed Description
-----------------
The researchers will screen for patients referred to St. Jude due to heavy menstrual bleeding (HMB). Patients will be eligible for inclusion and offered to be screened for enrollment in this study if the duration of their menses was greater than or equal to 7 days, and they reported either flooding or bleeding through a tampon or napkin in 2 hours or less with most periods, and have no identifiable bleeding disorder. A Self-BAT score of ≥6 is required for eligibility for study enrollment. Once enrolled, joint hypermobility will be evaluated using a Beighton score which will be used to assign participants to two groups: with and without Generalized joint Hypermobility Syndrome Disorder/ hypermobile Ehlers-Danlos Syndrome (G-HSD/hEDS). Participants will then undergo a detailed clinical examination to further classify them using the 2017 diagnostic criteria and complete symptom questionnaires. Finally, participants will be consented to TBANK (NCT01354002) and INSIGHT HD (NCT02720679) so as to provide a sample of leftover blood for banking for future research. Participants will be seen annually for the next 3 years as part of their standard of care to document the course of their symptoms. Visit 1: Self-BAT Questionnaire, Beighton Score examination, 2017 hEDS examination, PROMIS (Peds/Parent) questionnaire, PHQ15 questionnaire, COMPASS31 questionnaire, Menstrual distress questionnaire (ENDOPAIN), and Heavy menstrual bleeding checklist (both pediatric and adult). Visit 2: Self-BAT Questionnaire, PROMIS (Peds/Parent) questionnaire, PHQ15 questionnaire, COMPASS31 questionnaire, Menstrual distress questionnaire (ENDOPAIN). Visit 3: Self-BAT Questionnaire, PROMIS (Peds/Parent) questionnaire, PHQ15 questionnaire, COMPASS31 questionnaire, Menstrual distress questionnaire (ENDOPAIN).

Official Title
-----------------
Identifying the Determinants of Bleeding and Hypermobility in Patients With Heavy Menstrual Bleeding

Conditions
-----------------
Hypermobile Ehlers-Danlos Syndrome, Heavy Menstrual Bleeding, Hypermobility Syndrome (Disorder)

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Female 12-40 years of age Not currently pregnant No documented uterine structural abnormality Self-BAT score of ≥6 Prothrombin Time/ activated Partial Thromboplastin Time/Fibrinogen and Von Willebrand Factor activity, antigen and Factor 8 are not reflective of a bleeding disorder Exclusion Criteria: Inability or unwillingness of research participant or legal guardian/representative to give written informed consent. Current use of anticoagulant and antiplatelet medications Medical conditions that could cause heavy menstrual bleeding but are not necessarily a bleeding disorder including, but not limited to: Uncontrolled hypertension, Insulin Dependent Diabetes Mellitus, Chronic Kidney Disease, Chronic Liver Disease, Thyroid disease, Documented Peripheral Arterial Disease, venous or arterial vascular events in the past A structural pathology that would explain the Heavy Menstrual Bleeding Persistent thrombocytopenia as defined by a platelet count of <150,000/uL If the participant answers yes to any of the pre-screening questions: Could the patient have a known connective tissue disorder? Family history of sudden death Family history/personal history of uterine rupture or bowel perforation Family history/personal history of arterial rupture Family history/personal history of aneurysm Family history/personal history of an established Ehlers Danlos Syndrome diagnosis based on genetic evaluation

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
Female

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Case Group<br>Participants with heavy menstrual bleeding (HMB) | |
| Control Group<br>Participants without heavy menstrual bleeding (HMB) | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of bleeding symptoms in women with and without Generalized joint Hypermobility Syndrome Disorder/ hypermobile Ehlers-Danlos Syndrome (G-HSD/hEDS): Self-Bleeding Assessment Tool (Self-Bat) | Summary statistics of bleed score including mean, median, standard deviation and range will be reported for women with and without G-HSD/hEDS. The Self-BAT which consist of 14 categories for assessing bleeding symptom will be used. Each of the 14 variables is scored from 0-4 (except CNS bleeding when the scores are 0, 3 and 4) and on the basis of this a final score is derived. Scores of ≥ 3 in children, ≥ 4 in adult males and ≥ 6 in adult females is considered abnormal. | Yearly for 3 years | 
| Number of patients with and without Generalized joint Hypermobility Syndrome Disorder/ hypermobile Ehlers-Danlos Syndrome (G-HSD/hEDS). | The number of patients with G-HSD/hEDS will be reported | Approximately 3 years | 
| Proportion of patients with and without Generalized joint Hypermobility Syndrome Disorder/ hypermobile Ehlers-Danlos Syndrome (G-HSD/hEDS). | The proportion of patients with G-HSD/hEDS will be reported | Approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Co-morbidities in women with and without Generalized joint Hypermobility Syndrome Disorder/ hypermobile Ehlers-Danlos Syndrome (G-HSD/hEDS) - PHQ15 | Investigators will compare co-morbidities in women with and without Generalized joint Hypermobility Syndrome Disorder/ hypermobile Ehlers-Danlos Syndrome (G-HSD/hEDS) using PHQ 15. The PHQ-15 is a subscale of the full Patient Health Questionnaire (PHQ) and screens for 15 somatic symptoms. It scores symptom presence and severity on a 3-point Likert scale (0-2). The total score ranges from 0-30 with higher values indicating increased severity as follows: Minimal (0-4); Low (5-9); Medium (10-14); High (15-30). | Yearly for 3 years | 
| Co-morbidities in women with and without Generalized joint Hypermobility Syndrome Disorder/ hypermobile Ehlers-Danlos Syndrome (G-HSD/hEDS): Peds Patient-reported Outcomes Measurement Information System (PROMIS) 49 and Parent Proxy 49 | Investigators will compare co-morbidities in women with and without Generalized joint Hypermobility Syndrome Disorder/ hypermobile Ehlers-Danlos Syndrome (G-HSD/hEDS) using Peds PROMIS 49 and Parent Proxy 49. The Peds PROMIS 49 is self-reported measures of global, physical, mental, and social health for children (ages 8-17) in the general population and those living with a chronic condition. The Parent Proxy 49 is intended for parents serving as proxy for their child (youth ages 5-17). PROMIS scores are reported as T scores ranging from 0-100. A higher PROMIS T-score represents more of the concept being measured. For negatively-worded concepts like Anxiety, a T-score of 60 is one SD worse than average. By comparison, an Anxiety T-score of 40 is one SD better than average. However, for positively-worded concepts like Physical Function-Mobility, a T-score of 60 is one SD better than average while a T-score of 40 is one SD worse than average. | Yearly for 3 years | 
| Co-morbidities in women with and without Generalized joint Hypermobility Syndrome Disorder/ hypermobile Ehlers-Danlos Syndrome (G-HSD/hEDS): PROMIS 57 | Investigators will compare co-morbidities in women with and without Generalized joint Hypermobility Syndrome Disorder/ hypermobile Ehlers-Danlos Syndrome (G-HSD/hEDS) using adult PROMIS 57. The PROMIS 57 is for self-reporting measures of global, physical, mental, and social health for adults in the general population and those living with a chronic condition. PROMIS scores are reported as T scores ranging from 0-100. A higher PROMIS T-score represents more of the concept being measured. For negatively-worded concepts like Anxiety, a T-score of 60 is one SD worse than average. By comparison, an Anxiety T-score of 40 is one SD better than average. However, for positively-worded concepts like Physical Function-Mobility, a T-score of 60 is one SD better than average while a T-score of 40 is one SD worse than average. | Yearly for 3 years | 
| Co-morbidities in women with and without Generalized joint Hypermobility Syndrome Disorder/ hypermobile Ehlers-Danlos Syndrome (G-HSD/hEDS): Compass 31 | Investigators will compare co-morbidities in women with and without Generalized joint Hypermobility Syndrome Disorder/ hypermobile Ehlers-Danlos Syndrome (G-HSD/hEDS) using COMPASS31. The COMPASS31 contains 31 questions with Likert scales ranging in length from 2 to 6 items with higher scores indicating increased severity. COMPASS31 provides raw scores and standardized scores providing a total weighted score (0-100) of severity. The scale yields 6 subscales and a total score as follows: Orthostatic intolerance (4-10), Vasomotor (3-6); Secretomotor (4-7); Gastrointestinal (12-28); Bladder (3-9); Pupillomotor (5-15); Total (31-75) | Yearly for 3 years | 
| Co-morbidities in women with and without Generalized joint Hypermobility Syndrome Disorder/ hypermobile Ehlers-Danlos Syndrome (G-HSD/hEDS): Menstrual Distress Questionnaire | Investigators will compare co-morbidities in women with and without Generalized joint Hypermobility Syndrome Disorder/ hypermobile Ehlers-Danlos Syndrome (G-HSD/hEDS)using the Menstrual Distress Questionnaire. This is a 21-element survey (ENDOPAIN 4D) which measures the gynecological and pelvic pain symptoms associated with periods. Each question is on a 11-point Likert scale with higher scores reflecting more severe symptoms or symptoms that most closely resemble the description. | Yearly for 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Heavy Menstrual Bleeding, Joint Hypermobility, Hypermobile Ehlers-Danlos Syndrome, Generalized joint Hypermobility Syndrome Disorder, Loose Joints